WO2023116702A1 - pH敏感的破膜聚肽及其应用 - Google Patents
pH敏感的破膜聚肽及其应用 Download PDFInfo
- Publication number
- WO2023116702A1 WO2023116702A1 PCT/CN2022/140396 CN2022140396W WO2023116702A1 WO 2023116702 A1 WO2023116702 A1 WO 2023116702A1 CN 2022140396 W CN2022140396 W CN 2022140396W WO 2023116702 A1 WO2023116702 A1 WO 2023116702A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- polypeptide
- membrane
- breaking
- pharmaceutically acceptable
- stereoisomer
- Prior art date
Links
- 108090000765 processed proteins & peptides Proteins 0.000 title claims abstract description 239
- 102000004196 processed proteins & peptides Human genes 0.000 title claims abstract description 209
- 229920001184 polypeptide Polymers 0.000 title claims abstract description 198
- 150000003839 salts Chemical class 0.000 claims abstract description 45
- 239000002105 nanoparticle Substances 0.000 claims abstract description 38
- 241000894006 Bacteria Species 0.000 claims abstract description 21
- 239000003814 drug Substances 0.000 claims description 61
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 54
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical group CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 52
- 229940079593 drug Drugs 0.000 claims description 51
- -1 phenyl substituted Chemical class 0.000 claims description 43
- 206010028980 Neoplasm Diseases 0.000 claims description 41
- 238000002360 preparation method Methods 0.000 claims description 35
- 229920000642 polymer Polymers 0.000 claims description 32
- 239000004480 active ingredient Substances 0.000 claims description 24
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 23
- 238000003756 stirring Methods 0.000 claims description 23
- 125000000217 alkyl group Chemical group 0.000 claims description 20
- 229910052757 nitrogen Inorganic materials 0.000 claims description 20
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 19
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 18
- 238000000502 dialysis Methods 0.000 claims description 17
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 claims description 16
- 125000003118 aryl group Chemical group 0.000 claims description 15
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 15
- 125000002947 alkylene group Chemical group 0.000 claims description 14
- 229940076838 Immune checkpoint inhibitor Drugs 0.000 claims description 13
- 102000037984 Inhibitory immune checkpoint proteins Human genes 0.000 claims description 13
- 108091008026 Inhibitory immune checkpoint proteins Proteins 0.000 claims description 13
- 239000012274 immune-checkpoint protein inhibitor Substances 0.000 claims description 13
- 239000002904 solvent Substances 0.000 claims description 13
- 125000001624 naphthyl group Chemical group 0.000 claims description 12
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 claims description 12
- 208000035143 Bacterial infection Diseases 0.000 claims description 10
- 208000022362 bacterial infectious disease Diseases 0.000 claims description 10
- 239000012528 membrane Substances 0.000 claims description 10
- 239000002671 adjuvant Substances 0.000 claims description 9
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical group C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 claims description 8
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 8
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 8
- 239000003960 organic solvent Substances 0.000 claims description 7
- 125000003161 (C1-C6) alkylene group Chemical group 0.000 claims description 6
- 241000589517 Pseudomonas aeruginosa Species 0.000 claims description 6
- 229940041181 antineoplastic drug Drugs 0.000 claims description 6
- 125000001313 C5-C10 heteroaryl group Chemical group 0.000 claims description 5
- 241000588724 Escherichia coli Species 0.000 claims description 5
- 239000002246 antineoplastic agent Substances 0.000 claims description 5
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 5
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 5
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 5
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 5
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 5
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 claims description 5
- 206010009944 Colon cancer Diseases 0.000 claims description 4
- SNRUBQQJIBEYMU-UHFFFAOYSA-N Dodecane Chemical group CCCCCCCCCCCC SNRUBQQJIBEYMU-UHFFFAOYSA-N 0.000 claims description 4
- 239000012270 PD-1 inhibitor Substances 0.000 claims description 4
- 239000012668 PD-1-inhibitor Substances 0.000 claims description 4
- 125000002704 decyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 4
- 125000003438 dodecyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 4
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 4
- 125000001400 nonyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 4
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 4
- 229940121655 pd-1 inhibitor Drugs 0.000 claims description 4
- 206010006187 Breast cancer Diseases 0.000 claims description 3
- 208000026310 Breast neoplasm Diseases 0.000 claims description 3
- 241000193998 Streptococcus pneumoniae Species 0.000 claims description 3
- 239000012736 aqueous medium Substances 0.000 claims description 3
- 239000000969 carrier Substances 0.000 claims description 3
- 241000588626 Acinetobacter baumannii Species 0.000 claims description 2
- 241000193830 Bacillus <bacterium> Species 0.000 claims description 2
- 206010005003 Bladder cancer Diseases 0.000 claims description 2
- 206010008342 Cervix carcinoma Diseases 0.000 claims description 2
- 208000001333 Colorectal Neoplasms Diseases 0.000 claims description 2
- 241000194032 Enterococcus faecalis Species 0.000 claims description 2
- 241000588747 Klebsiella pneumoniae Species 0.000 claims description 2
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 2
- 208000030070 Malignant epithelial tumor of ovary Diseases 0.000 claims description 2
- RSJKGSCJYJTIGS-UHFFFAOYSA-N N-undecane Natural products CCCCCCCCCCC RSJKGSCJYJTIGS-UHFFFAOYSA-N 0.000 claims description 2
- 208000007571 Ovarian Epithelial Carcinoma Diseases 0.000 claims description 2
- 206010033128 Ovarian cancer Diseases 0.000 claims description 2
- 206010061328 Ovarian epithelial cancer Diseases 0.000 claims description 2
- 206010061535 Ovarian neoplasm Diseases 0.000 claims description 2
- 206010061902 Pancreatic neoplasm Diseases 0.000 claims description 2
- 241000589516 Pseudomonas Species 0.000 claims description 2
- 241000607142 Salmonella Species 0.000 claims description 2
- 206010041865 Squamous cell carcinoma of the tongue Diseases 0.000 claims description 2
- 241000191967 Staphylococcus aureus Species 0.000 claims description 2
- 241000193996 Streptococcus pyogenes Species 0.000 claims description 2
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 claims description 2
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 claims description 2
- 201000010881 cervical cancer Diseases 0.000 claims description 2
- 208000029742 colonic neoplasm Diseases 0.000 claims description 2
- 229940032049 enterococcus faecalis Drugs 0.000 claims description 2
- 201000007270 liver cancer Diseases 0.000 claims description 2
- 208000014018 liver neoplasm Diseases 0.000 claims description 2
- 201000005202 lung cancer Diseases 0.000 claims description 2
- 208000020816 lung neoplasm Diseases 0.000 claims description 2
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 claims description 2
- 201000001441 melanoma Diseases 0.000 claims description 2
- 201000008968 osteosarcoma Diseases 0.000 claims description 2
- 201000002528 pancreatic cancer Diseases 0.000 claims description 2
- 208000008443 pancreatic carcinoma Diseases 0.000 claims description 2
- 238000001338 self-assembly Methods 0.000 claims description 2
- 229940031000 streptococcus pneumoniae Drugs 0.000 claims description 2
- 201000002743 tongue squamous cell carcinoma Diseases 0.000 claims description 2
- 125000002948 undecyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 201000005112 urinary bladder cancer Diseases 0.000 claims description 2
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims 3
- 241000304886 Bacilli Species 0.000 claims 1
- 241000295644 Staphylococcaceae Species 0.000 claims 1
- 230000000694 effects Effects 0.000 abstract description 26
- 230000002209 hydrophobic effect Effects 0.000 abstract description 23
- 210000000170 cell membrane Anatomy 0.000 abstract description 21
- 239000000463 material Substances 0.000 abstract description 17
- 210000004881 tumor cell Anatomy 0.000 abstract description 14
- 125000002091 cationic group Chemical group 0.000 abstract description 7
- 230000002378 acidificating effect Effects 0.000 abstract description 5
- 230000007935 neutral effect Effects 0.000 abstract description 3
- 229920001427 mPEG Polymers 0.000 description 115
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 84
- 239000000243 solution Substances 0.000 description 63
- 150000003512 tertiary amines Chemical group 0.000 description 50
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 47
- 238000006116 polymerization reaction Methods 0.000 description 40
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 39
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 28
- 238000000034 method Methods 0.000 description 28
- 239000004472 Lysine Substances 0.000 description 26
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 25
- 238000007334 copolymerization reaction Methods 0.000 description 25
- 229920000656 polylysine Polymers 0.000 description 25
- 108010039918 Polylysine Proteins 0.000 description 24
- 239000008367 deionised water Substances 0.000 description 24
- 229910021641 deionized water Inorganic materials 0.000 description 24
- 238000006243 chemical reaction Methods 0.000 description 23
- 230000005588 protonation Effects 0.000 description 23
- 230000000844 anti-bacterial effect Effects 0.000 description 21
- 210000004027 cell Anatomy 0.000 description 21
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 20
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 19
- 239000002609 medium Substances 0.000 description 17
- 230000004048 modification Effects 0.000 description 17
- 238000012986 modification Methods 0.000 description 17
- 238000002835 absorbance Methods 0.000 description 16
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 15
- 230000002949 hemolytic effect Effects 0.000 description 15
- 230000008859 change Effects 0.000 description 14
- 150000001875 compounds Chemical class 0.000 description 14
- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 description 13
- 229920001223 polyethylene glycol Polymers 0.000 description 13
- 239000006228 supernatant Substances 0.000 description 13
- 238000004448 titration Methods 0.000 description 13
- 238000005481 NMR spectroscopy Methods 0.000 description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- 230000001580 bacterial effect Effects 0.000 description 12
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 12
- 239000003921 oil Substances 0.000 description 12
- 235000019198 oils Nutrition 0.000 description 12
- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 description 12
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 11
- 239000000203 mixture Substances 0.000 description 11
- 238000011282 treatment Methods 0.000 description 11
- KZTWONRVIPPDKH-UHFFFAOYSA-N 2-(piperidin-1-yl)ethanol Chemical compound OCCN1CCCCC1 KZTWONRVIPPDKH-UHFFFAOYSA-N 0.000 description 10
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- ROHFNLRQFUQHCH-YFKPBYRVSA-N L-leucine Chemical compound CC(C)C[C@H](N)C(O)=O ROHFNLRQFUQHCH-YFKPBYRVSA-N 0.000 description 9
- 125000003277 amino group Chemical group 0.000 description 9
- 238000010511 deprotection reaction Methods 0.000 description 9
- 239000000499 gel Substances 0.000 description 9
- 230000003993 interaction Effects 0.000 description 9
- 230000002147 killing effect Effects 0.000 description 9
- ROHFNLRQFUQHCH-UHFFFAOYSA-N Leucine Natural products CC(C)CC(N)C(O)=O ROHFNLRQFUQHCH-UHFFFAOYSA-N 0.000 description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- 150000001413 amino acids Chemical class 0.000 description 8
- 230000007423 decrease Effects 0.000 description 8
- 238000002474 experimental method Methods 0.000 description 8
- 239000002861 polymer material Substances 0.000 description 8
- 239000000047 product Substances 0.000 description 8
- 239000000523 sample Substances 0.000 description 8
- 238000012546 transfer Methods 0.000 description 8
- LRQKBLKVPFOOQJ-YFKPBYRVSA-N L-norleucine Chemical compound CCCC[C@H]([NH3+])C([O-])=O LRQKBLKVPFOOQJ-YFKPBYRVSA-N 0.000 description 7
- 230000022534 cell killing Effects 0.000 description 7
- 238000005227 gel permeation chromatography Methods 0.000 description 7
- 239000013642 negative control Substances 0.000 description 7
- 239000002244 precipitate Substances 0.000 description 7
- 239000007787 solid Substances 0.000 description 7
- 230000007704 transition Effects 0.000 description 7
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- 239000004698 Polyethylene Substances 0.000 description 6
- 108010020346 Polyglutamic Acid Proteins 0.000 description 6
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- NKANXQFJJICGDU-QPLCGJKRSA-N Tamoxifen Chemical compound C=1C=CC=CC=1C(/CC)=C(C=1C=CC(OCCN(C)C)=CC=1)/C1=CC=CC=C1 NKANXQFJJICGDU-QPLCGJKRSA-N 0.000 description 6
- 230000000259 anti-tumor effect Effects 0.000 description 6
- 238000012512 characterization method Methods 0.000 description 6
- 125000001165 hydrophobic group Chemical group 0.000 description 6
- 238000001727 in vivo Methods 0.000 description 6
- 239000003112 inhibitor Substances 0.000 description 6
- 239000003999 initiator Substances 0.000 description 6
- 239000007788 liquid Substances 0.000 description 6
- 239000000178 monomer Substances 0.000 description 6
- 229920000573 polyethylene Polymers 0.000 description 6
- 229920002643 polyglutamic acid Polymers 0.000 description 6
- 239000013641 positive control Substances 0.000 description 6
- 229940121649 protein inhibitor Drugs 0.000 description 6
- 239000012268 protein inhibitor Substances 0.000 description 6
- 239000011780 sodium chloride Substances 0.000 description 6
- 210000001519 tissue Anatomy 0.000 description 6
- 125000004042 4-aminobutyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])N([H])[H] 0.000 description 5
- 229920001817 Agar Polymers 0.000 description 5
- 102000004190 Enzymes Human genes 0.000 description 5
- 108090000790 Enzymes Proteins 0.000 description 5
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 5
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 5
- 239000008272 agar Substances 0.000 description 5
- 125000004432 carbon atom Chemical group C* 0.000 description 5
- 230000003013 cytotoxicity Effects 0.000 description 5
- 231100000135 cytotoxicity Toxicity 0.000 description 5
- 230000006378 damage Effects 0.000 description 5
- 238000009826 distribution Methods 0.000 description 5
- 229940088598 enzyme Drugs 0.000 description 5
- 238000001228 spectrum Methods 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- 239000003826 tablet Substances 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- 230000001225 therapeutic effect Effects 0.000 description 5
- 231100000419 toxicity Toxicity 0.000 description 5
- 230000001988 toxicity Effects 0.000 description 5
- 230000005909 tumor killing Effects 0.000 description 5
- 229910021642 ultra pure water Inorganic materials 0.000 description 5
- 239000012498 ultrapure water Substances 0.000 description 5
- CKGCFBNYQJDIGS-LBPRGKRZSA-N (2s)-2-azaniumyl-6-(phenylmethoxycarbonylamino)hexanoate Chemical compound [O-]C(=O)[C@@H]([NH3+])CCCCNC(=O)OCC1=CC=CC=C1 CKGCFBNYQJDIGS-LBPRGKRZSA-N 0.000 description 4
- GQBIVYSGPXCELZ-QMMMGPOBSA-N (4s)-4-benzyl-1,3-oxazolidine-2,5-dione Chemical compound O=C1OC(=O)N[C@H]1CC1=CC=CC=C1 GQBIVYSGPXCELZ-QMMMGPOBSA-N 0.000 description 4
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 4
- 101100063523 Arabidopsis thaliana DMP2 gene Proteins 0.000 description 4
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 4
- 206010018910 Haemolysis Diseases 0.000 description 4
- 108010050904 Interferons Proteins 0.000 description 4
- 102000014150 Interferons Human genes 0.000 description 4
- 239000006142 Luria-Bertani Agar Substances 0.000 description 4
- 239000002202 Polyethylene glycol Substances 0.000 description 4
- 101100520664 Saccharomyces cerevisiae (strain ATCC 204508 / S288c) IRC25 gene Proteins 0.000 description 4
- 230000008901 benefit Effects 0.000 description 4
- 210000004369 blood Anatomy 0.000 description 4
- 239000008280 blood Substances 0.000 description 4
- 238000004364 calculation method Methods 0.000 description 4
- 239000003153 chemical reaction reagent Substances 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 4
- 229920001971 elastomer Polymers 0.000 description 4
- 239000003995 emulsifying agent Substances 0.000 description 4
- 210000003743 erythrocyte Anatomy 0.000 description 4
- 230000008588 hemolysis Effects 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- 229920000835 poly(gamma-benzyl-L-glutamate) polymer Polymers 0.000 description 4
- 239000000843 powder Substances 0.000 description 4
- 239000011734 sodium Substances 0.000 description 4
- 239000011550 stock solution Substances 0.000 description 4
- 125000001424 substituent group Chemical group 0.000 description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- JHWZWIVZROVFEM-YFKPBYRVSA-N (4s)-4-(2-methylpropyl)-1,3-oxazolidine-2,5-dione Chemical compound CC(C)C[C@@H]1NC(=O)OC1=O JHWZWIVZROVFEM-YFKPBYRVSA-N 0.000 description 3
- VOXZDWNPVJITMN-ZBRFXRBCSA-N 17β-estradiol Chemical compound OC1=CC=C2[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 VOXZDWNPVJITMN-ZBRFXRBCSA-N 0.000 description 3
- AKVBCGQVQXPRLD-UHFFFAOYSA-N 2-aminooctanoic acid Chemical class CCCCCCC(N)C(O)=O AKVBCGQVQXPRLD-UHFFFAOYSA-N 0.000 description 3
- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 description 3
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 3
- 102000003855 L-lactate dehydrogenase Human genes 0.000 description 3
- 108700023483 L-lactate dehydrogenases Proteins 0.000 description 3
- QIVBCDIJIAJPQS-VIFPVBQESA-N L-tryptophane Chemical compound C1=CC=C2C(C[C@H](N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-VIFPVBQESA-N 0.000 description 3
- 229930012538 Paclitaxel Natural products 0.000 description 3
- 241001494479 Pecora Species 0.000 description 3
- QIVBCDIJIAJPQS-UHFFFAOYSA-N Tryptophan Natural products C1=CC=C2C(CC(N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-UHFFFAOYSA-N 0.000 description 3
- 239000002775 capsule Substances 0.000 description 3
- 238000005119 centrifugation Methods 0.000 description 3
- 230000003247 decreasing effect Effects 0.000 description 3
- 238000010790 dilution Methods 0.000 description 3
- 239000012895 dilution Substances 0.000 description 3
- 239000000945 filler Substances 0.000 description 3
- 239000000796 flavoring agent Substances 0.000 description 3
- 239000001963 growth medium Substances 0.000 description 3
- 239000003906 humectant Substances 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- 208000015181 infectious disease Diseases 0.000 description 3
- 229940079322 interferon Drugs 0.000 description 3
- GFIJNRVAKGFPGQ-LIJARHBVSA-N leuprolide Chemical compound CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](CC(C)C)NC(=O)[C@@H](NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H]1NC(=O)CC1)CC1=CC=C(O)C=C1 GFIJNRVAKGFPGQ-LIJARHBVSA-N 0.000 description 3
- 229960004338 leuprorelin Drugs 0.000 description 3
- 229960003918 levothyroxine sodium Drugs 0.000 description 3
- YDTFRJLNMPSCFM-YDALLXLXSA-M levothyroxine sodium anhydrous Chemical compound [Na+].IC1=CC(C[C@H](N)C([O-])=O)=CC(I)=C1OC1=CC(I)=C(O)C(I)=C1 YDTFRJLNMPSCFM-YDALLXLXSA-M 0.000 description 3
- 239000000314 lubricant Substances 0.000 description 3
- 238000005259 measurement Methods 0.000 description 3
- 108091005601 modified peptides Proteins 0.000 description 3
- 210000003463 organelle Anatomy 0.000 description 3
- 229960001592 paclitaxel Drugs 0.000 description 3
- 125000004817 pentamethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[*:1] 0.000 description 3
- 239000000546 pharmaceutical excipient Substances 0.000 description 3
- 230000004043 responsiveness Effects 0.000 description 3
- 125000006413 ring segment Chemical group 0.000 description 3
- 229910052708 sodium Inorganic materials 0.000 description 3
- 239000007909 solid dosage form Substances 0.000 description 3
- 230000004083 survival effect Effects 0.000 description 3
- 239000000375 suspending agent Substances 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- 229960001603 tamoxifen Drugs 0.000 description 3
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 3
- 239000000080 wetting agent Substances 0.000 description 3
- PUPZLCDOIYMWBV-UHFFFAOYSA-N (+/-)-1,3-Butanediol Chemical compound CC(O)CCO PUPZLCDOIYMWBV-UHFFFAOYSA-N 0.000 description 2
- DEQANNDTNATYII-OULOTJBUSA-N (4r,7s,10s,13r,16s,19r)-10-(4-aminobutyl)-19-[[(2r)-2-amino-3-phenylpropanoyl]amino]-16-benzyl-n-[(2r,3r)-1,3-dihydroxybutan-2-yl]-7-[(1r)-1-hydroxyethyl]-13-(1h-indol-3-ylmethyl)-6,9,12,15,18-pentaoxo-1,2-dithia-5,8,11,14,17-pentazacycloicosane-4-carboxa Chemical compound C([C@@H](N)C(=O)N[C@H]1CSSC[C@H](NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CCCCN)NC(=O)[C@@H](CC=2C3=CC=CC=C3NC=2)NC(=O)[C@H](CC=2C=CC=CC=2)NC1=O)C(=O)N[C@H](CO)[C@H](O)C)C1=CC=CC=C1 DEQANNDTNATYII-OULOTJBUSA-N 0.000 description 2
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 2
- VRDBIJCCXDEZJN-UHFFFAOYSA-N 2-piperidin-1-ylacetic acid Chemical compound OC(=O)CN1CCCCC1 VRDBIJCCXDEZJN-UHFFFAOYSA-N 0.000 description 2
- KLDLRDSRCMJKGM-UHFFFAOYSA-N 3-[chloro-(2-oxo-1,3-oxazolidin-3-yl)phosphoryl]-1,3-oxazolidin-2-one Chemical compound C1COC(=O)N1P(=O)(Cl)N1CCOC1=O KLDLRDSRCMJKGM-UHFFFAOYSA-N 0.000 description 2
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 2
- OGWKCGZFUXNPDA-CFWMRBGOSA-N 5j49q6b70f Chemical compound C([C@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C=O)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 OGWKCGZFUXNPDA-CFWMRBGOSA-N 0.000 description 2
- STQGQHZAVUOBTE-UHFFFAOYSA-N 7-Cyan-hept-2t-en-4,6-diinsaeure Natural products C1=2C(O)=C3C(=O)C=4C(OC)=CC=CC=4C(=O)C3=C(O)C=2CC(O)(C(C)=O)CC1OC1CC(N)C(O)C(C)O1 STQGQHZAVUOBTE-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- PTOAARAWEBMLNO-KVQBGUIXSA-N Cladribine Chemical compound C1=NC=2C(N)=NC(Cl)=NC=2N1[C@H]1C[C@H](O)[C@@H](CO)O1 PTOAARAWEBMLNO-KVQBGUIXSA-N 0.000 description 2
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 2
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 2
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 2
- 108010029961 Filgrastim Proteins 0.000 description 2
- 108010010803 Gelatin Proteins 0.000 description 2
- 229940121710 HMGCoA reductase inhibitor Drugs 0.000 description 2
- 102100040018 Interferon alpha-2 Human genes 0.000 description 2
- 108010047761 Interferon-alpha Proteins 0.000 description 2
- 102000006992 Interferon-alpha Human genes 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- 108010000817 Leuprolide Proteins 0.000 description 2
- 229930195725 Mannitol Natural products 0.000 description 2
- 241000699670 Mus sp. Species 0.000 description 2
- NWIBSHFKIJFRCO-WUDYKRTCSA-N Mytomycin Chemical compound C1N2C(C(C(C)=C(N)C3=O)=O)=C3[C@@H](COC(N)=O)[C@@]2(OC)[C@@H]2[C@H]1N2 NWIBSHFKIJFRCO-WUDYKRTCSA-N 0.000 description 2
- ZDZOTLJHXYCWBA-VCVYQWHSSA-N N-debenzoyl-N-(tert-butoxycarbonyl)-10-deacetyltaxol Chemical compound O([C@H]1[C@H]2[C@@](C([C@H](O)C3=C(C)[C@@H](OC(=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)C=4C=CC=CC=4)C[C@]1(O)C3(C)C)=O)(C)[C@@H](O)C[C@H]1OC[C@]12OC(=O)C)C(=O)C1=CC=CC=C1 ZDZOTLJHXYCWBA-VCVYQWHSSA-N 0.000 description 2
- 108010016076 Octreotide Proteins 0.000 description 2
- 235000019483 Peanut oil Nutrition 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 2
- 229920002472 Starch Polymers 0.000 description 2
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 2
- 229930006000 Sucrose Natural products 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 2
- MUMGGOZAMZWBJJ-DYKIIFRCSA-N Testostosterone Chemical compound O=C1CC[C@]2(C)[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 MUMGGOZAMZWBJJ-DYKIIFRCSA-N 0.000 description 2
- 229920004890 Triton X-100 Polymers 0.000 description 2
- DRTQHJPVMGBUCF-XVFCMESISA-N Uridine Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C=C1 DRTQHJPVMGBUCF-XVFCMESISA-N 0.000 description 2
- 239000003655 absorption accelerator Substances 0.000 description 2
- RJURFGZVJUQBHK-UHFFFAOYSA-N actinomycin D Natural products CC1OC(=O)C(C(C)C)N(C)C(=O)CN(C)C(=O)C2CCCN2C(=O)C(C(C)C)NC(=O)C1NC(=O)C1=C(N)C(=O)C(C)=C2OC(C(C)=CC=C3C(=O)NC4C(=O)NC(C(N5CCCC5C(=O)N(C)CC(=O)N(C)C(C(C)C)C(=O)OC4C)=O)C(C)C)=C3N=C21 RJURFGZVJUQBHK-UHFFFAOYSA-N 0.000 description 2
- 230000004913 activation Effects 0.000 description 2
- 235000010419 agar Nutrition 0.000 description 2
- 235000010443 alginic acid Nutrition 0.000 description 2
- 229920000615 alginic acid Polymers 0.000 description 2
- 229960001097 amifostine Drugs 0.000 description 2
- JKOQGQFVAUAYPM-UHFFFAOYSA-N amifostine Chemical compound NCCCNCCSP(O)(O)=O JKOQGQFVAUAYPM-UHFFFAOYSA-N 0.000 description 2
- 230000006907 apoptotic process Effects 0.000 description 2
- 239000011230 binding agent Substances 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- OSGAYBCDTDRGGQ-UHFFFAOYSA-L calcium sulfate Chemical compound [Ca+2].[O-]S([O-])(=O)=O OSGAYBCDTDRGGQ-UHFFFAOYSA-L 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 238000004113 cell culture Methods 0.000 description 2
- 210000002390 cell membrane structure Anatomy 0.000 description 2
- 239000012295 chemical reaction liquid Substances 0.000 description 2
- NEHMKBQYUWJMIP-UHFFFAOYSA-N chloromethane Chemical compound ClC NEHMKBQYUWJMIP-UHFFFAOYSA-N 0.000 description 2
- 238000002983 circular dichroism Methods 0.000 description 2
- 238000001142 circular dichroism spectrum Methods 0.000 description 2
- 229960002436 cladribine Drugs 0.000 description 2
- 229920001577 copolymer Polymers 0.000 description 2
- 238000012258 culturing Methods 0.000 description 2
- 125000004122 cyclic group Chemical group 0.000 description 2
- 231100000433 cytotoxic Toxicity 0.000 description 2
- 230000001472 cytotoxic effect Effects 0.000 description 2
- STQGQHZAVUOBTE-VGBVRHCVSA-N daunorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(C)=O)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 STQGQHZAVUOBTE-VGBVRHCVSA-N 0.000 description 2
- 229960000975 daunorubicin Drugs 0.000 description 2
- 229960003957 dexamethasone Drugs 0.000 description 2
- UREBDLICKHMUKA-CXSFZGCWSA-N dexamethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O UREBDLICKHMUKA-CXSFZGCWSA-N 0.000 description 2
- 238000010586 diagram Methods 0.000 description 2
- 239000003085 diluting agent Substances 0.000 description 2
- 239000007884 disintegrant Substances 0.000 description 2
- 239000006185 dispersion Substances 0.000 description 2
- 229960004679 doxorubicin Drugs 0.000 description 2
- 239000000839 emulsion Substances 0.000 description 2
- 229960005309 estradiol Drugs 0.000 description 2
- RFHAOTPXVQNOHP-UHFFFAOYSA-N fluconazole Chemical compound C1=NC=NN1CC(C=1C(=CC(F)=CC=1)F)(O)CN1C=NC=N1 RFHAOTPXVQNOHP-UHFFFAOYSA-N 0.000 description 2
- 235000013355 food flavoring agent Nutrition 0.000 description 2
- 239000012634 fragment Substances 0.000 description 2
- 239000008273 gelatin Substances 0.000 description 2
- 229920000159 gelatin Polymers 0.000 description 2
- 235000019322 gelatine Nutrition 0.000 description 2
- 235000011852 gelatine desserts Nutrition 0.000 description 2
- 235000011187 glycerol Nutrition 0.000 description 2
- HHXHVIJIIXKSOE-QILQGKCVSA-N histrelin Chemical compound CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H]1NC(=O)CC1)CC(N=C1)=CN1CC1=CC=CC=C1 HHXHVIJIIXKSOE-QILQGKCVSA-N 0.000 description 2
- 108700020746 histrelin Proteins 0.000 description 2
- 229960002193 histrelin Drugs 0.000 description 2
- JYGXADMDTFJGBT-VWUMJDOOSA-N hydrocortisone Chemical compound O=C1CC[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 JYGXADMDTFJGBT-VWUMJDOOSA-N 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- 239000002471 hydroxymethylglutaryl coenzyme A reductase inhibitor Substances 0.000 description 2
- 239000003701 inert diluent Substances 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 150000002614 leucines Chemical class 0.000 description 2
- 239000008297 liquid dosage form Substances 0.000 description 2
- 231100000053 low toxicity Toxicity 0.000 description 2
- 235000019359 magnesium stearate Nutrition 0.000 description 2
- 239000000594 mannitol Substances 0.000 description 2
- 235000010355 mannitol Nutrition 0.000 description 2
- GLVAUDGFNGKCSF-UHFFFAOYSA-N mercaptopurine Chemical compound S=C1NC=NC2=C1NC=N2 GLVAUDGFNGKCSF-UHFFFAOYSA-N 0.000 description 2
- BBDGYADAMYMJNO-UHFFFAOYSA-N n-butyl-n-ethylbutan-1-amine Chemical compound CCCCN(CC)CCCC BBDGYADAMYMJNO-UHFFFAOYSA-N 0.000 description 2
- 229960002700 octreotide Drugs 0.000 description 2
- 239000004006 olive oil Substances 0.000 description 2
- 235000008390 olive oil Nutrition 0.000 description 2
- 239000000312 peanut oil Substances 0.000 description 2
- 239000006187 pill Substances 0.000 description 2
- 229960002139 pilocarpine hydrochloride Drugs 0.000 description 2
- RNAICSBVACLLGM-GNAZCLTHSA-N pilocarpine hydrochloride Chemical compound Cl.C1OC(=O)[C@@H](CC)[C@H]1CC1=CN=CN1C RNAICSBVACLLGM-GNAZCLTHSA-N 0.000 description 2
- 229920000193 polymethacrylate Polymers 0.000 description 2
- 229920005862 polyol Polymers 0.000 description 2
- 150000003077 polyols Chemical class 0.000 description 2
- 238000001556 precipitation Methods 0.000 description 2
- 229960004618 prednisone Drugs 0.000 description 2
- XOFYZVNMUHMLCC-ZPOLXVRWSA-N prednisone Chemical compound O=C1C=C[C@]2(C)[C@H]3C(=O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 XOFYZVNMUHMLCC-ZPOLXVRWSA-N 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- 239000000700 radioactive tracer Substances 0.000 description 2
- 210000002966 serum Anatomy 0.000 description 2
- 239000012679 serum free medium Substances 0.000 description 2
- 239000008159 sesame oil Substances 0.000 description 2
- 235000011803 sesame oil Nutrition 0.000 description 2
- 235000012239 silicon dioxide Nutrition 0.000 description 2
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 2
- 239000000600 sorbitol Substances 0.000 description 2
- 235000010356 sorbitol Nutrition 0.000 description 2
- 239000008107 starch Substances 0.000 description 2
- 235000019698 starch Nutrition 0.000 description 2
- 239000005720 sucrose Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 239000000454 talc Substances 0.000 description 2
- 229910052623 talc Inorganic materials 0.000 description 2
- 235000012222 talc Nutrition 0.000 description 2
- XFCLJVABOIYOMF-QPLCGJKRSA-N toremifene Chemical compound C1=CC(OCCN(C)C)=CC=C1C(\C=1C=CC=CC=1)=C(\CCCl)C1=CC=CC=C1 XFCLJVABOIYOMF-QPLCGJKRSA-N 0.000 description 2
- 229960005026 toremifene Drugs 0.000 description 2
- 230000001960 triggered effect Effects 0.000 description 2
- 230000004614 tumor growth Effects 0.000 description 2
- 239000012224 working solution Substances 0.000 description 2
- DNXHEGUUPJUMQT-UHFFFAOYSA-N (+)-estrone Natural products OC1=CC=C2C3CCC(C)(C(CC4)=O)C4C3CCC2=C1 DNXHEGUUPJUMQT-UHFFFAOYSA-N 0.000 description 1
- JNYAEWCLZODPBN-JGWLITMVSA-N (2r,3r,4s)-2-[(1r)-1,2-dihydroxyethyl]oxolane-3,4-diol Chemical class OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O JNYAEWCLZODPBN-JGWLITMVSA-N 0.000 description 1
- ZBVJFYPGLGEMIN-OYLNGHKZSA-N (2s)-n-[(2s)-1-[[(2s)-1-[[(2s)-1-[[(2s)-1-[[(2r)-1-[[(2s)-1-[[(2s)-1-[(2s)-2-[(2-amino-2-oxoethyl)carbamoyl]pyrrolidin-1-yl]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-3-(1h-indol-3-yl)-1-oxopropan-2-yl]amino]-3-( Chemical compound C1=CC=C2C(CC=3C4=CC=CC=C4C=C(C=3O)C(=O)O)=C(O)C(C(O)=O)=CC2=C1.C([C@@H](C(=O)N[C@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N1[C@@H](CCC1)C(=O)NCC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H]1NC(=O)CC1)C1=CC=C(O)C=C1 ZBVJFYPGLGEMIN-OYLNGHKZSA-N 0.000 description 1
- SWXOGPJRIDTIRL-DOUNNPEJSA-N (4r,7s,10s,13r,16s,19r)-10-(4-aminobutyl)-n-[(2s)-1-amino-3-(1h-indol-3-yl)-1-oxopropan-2-yl]-19-[[(2r)-2-amino-3-phenylpropanoyl]amino]-16-[(4-hydroxyphenyl)methyl]-13-(1h-indol-3-ylmethyl)-6,9,12,15,18-pentaoxo-7-propan-2-yl-1,2-dithia-5,8,11,14,17-pent Chemical compound C([C@H]1C(=O)N[C@H](CC=2C3=CC=CC=C3NC=2)C(=O)N[C@@H](CCCCN)C(=O)N[C@H](C(N[C@@H](CSSC[C@@H](C(=O)N1)NC(=O)[C@H](N)CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(N)=O)=O)C(C)C)C1=CC=C(O)C=C1 SWXOGPJRIDTIRL-DOUNNPEJSA-N 0.000 description 1
- PUDHBTGHUJUUFI-SCTWWAJVSA-N (4r,7s,10s,13r,16s,19r)-10-(4-aminobutyl)-n-[(2s,3r)-1-amino-3-hydroxy-1-oxobutan-2-yl]-19-[[(2r)-2-amino-3-naphthalen-2-ylpropanoyl]amino]-16-[(4-hydroxyphenyl)methyl]-13-(1h-indol-3-ylmethyl)-6,9,12,15,18-pentaoxo-7-propan-2-yl-1,2-dithia-5,8,11,14,17-p Chemical compound C([C@H]1C(=O)N[C@H](CC=2C3=CC=CC=C3NC=2)C(=O)N[C@@H](CCCCN)C(=O)N[C@H](C(N[C@@H](CSSC[C@@H](C(=O)N1)NC(=O)[C@H](N)CC=1C=C2C=CC=CC2=CC=1)C(=O)N[C@@H]([C@@H](C)O)C(N)=O)=O)C(C)C)C1=CC=C(O)C=C1 PUDHBTGHUJUUFI-SCTWWAJVSA-N 0.000 description 1
- MWWSFMDVAYGXBV-FGBSZODSSA-N (7s,9s)-7-[(2r,4s,5r,6s)-4-amino-5-hydroxy-6-methyloxan-2-yl]oxy-6,9,11-trihydroxy-9-(2-hydroxyacetyl)-4-methoxy-8,10-dihydro-7h-tetracene-5,12-dione;hydron;chloride Chemical compound Cl.O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@@H](O)[C@H](C)O1 MWWSFMDVAYGXBV-FGBSZODSSA-N 0.000 description 1
- FPVKHBSQESCIEP-UHFFFAOYSA-N (8S)-3-(2-deoxy-beta-D-erythro-pentofuranosyl)-3,6,7,8-tetrahydroimidazo[4,5-d][1,3]diazepin-8-ol Natural products C1C(O)C(CO)OC1N1C(NC=NCC2O)=C2N=C1 FPVKHBSQESCIEP-UHFFFAOYSA-N 0.000 description 1
- FDKXTQMXEQVLRF-ZHACJKMWSA-N (E)-dacarbazine Chemical compound CN(C)\N=N\c1[nH]cnc1C(N)=O FDKXTQMXEQVLRF-ZHACJKMWSA-N 0.000 description 1
- ZGMJYTYLTJFNCS-VQYXCCSOSA-N (e)-but-2-enedioic acid;1-[4-(2-hydroxy-3-quinolin-5-yloxypropyl)piperazin-1-yl]-2,2-diphenylethanone Chemical compound OC(=O)\C=C\C(O)=O.OC(=O)\C=C\C(O)=O.OC(=O)\C=C\C(O)=O.C=1C=CC2=NC=CC=C2C=1OCC(O)CN(CC1)CCN1C(=O)C(C=1C=CC=CC=1)C1=CC=CC=C1.C=1C=CC2=NC=CC=C2C=1OCC(O)CN(CC1)CCN1C(=O)C(C=1C=CC=CC=1)C1=CC=CC=C1 ZGMJYTYLTJFNCS-VQYXCCSOSA-N 0.000 description 1
- HJTAZXHBEBIQQX-UHFFFAOYSA-N 1,5-bis(chloromethyl)naphthalene Chemical compound C1=CC=C2C(CCl)=CC=CC2=C1CCl HJTAZXHBEBIQQX-UHFFFAOYSA-N 0.000 description 1
- CPKVUHPKYQGHMW-UHFFFAOYSA-N 1-ethenylpyrrolidin-2-one;molecular iodine Chemical compound II.C=CN1CCCC1=O CPKVUHPKYQGHMW-UHFFFAOYSA-N 0.000 description 1
- VSNHCAURESNICA-NJFSPNSNSA-N 1-oxidanylurea Chemical compound N[14C](=O)NO VSNHCAURESNICA-NJFSPNSNSA-N 0.000 description 1
- BFPYWIDHMRZLRN-UHFFFAOYSA-N 17alpha-ethynyl estradiol Natural products OC1=CC=C2C3CCC(C)(C(CC4)(O)C#C)C4C3CCC2=C1 BFPYWIDHMRZLRN-UHFFFAOYSA-N 0.000 description 1
- QMVPQBFHUJZJCS-NTKFZFFISA-N 1v8x590xdp Chemical compound O=C1N(NC(CO)CO)C(=O)C(C2=C3[CH]C=C(O)C=C3NC2=C23)=C1C2=C1C=CC(O)=C[C]1N3[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O QMVPQBFHUJZJCS-NTKFZFFISA-N 0.000 description 1
- ROZCIVXTLACYNY-UHFFFAOYSA-N 2,3,4,5,6-pentafluoro-n-(3-fluoro-4-methoxyphenyl)benzenesulfonamide Chemical compound C1=C(F)C(OC)=CC=C1NS(=O)(=O)C1=C(F)C(F)=C(F)C(F)=C1F ROZCIVXTLACYNY-UHFFFAOYSA-N 0.000 description 1
- QXLQZLBNPTZMRK-UHFFFAOYSA-N 2-[(dimethylamino)methyl]-1-(2,4-dimethylphenyl)prop-2-en-1-one Chemical compound CN(C)CC(=C)C(=O)C1=CC=C(C)C=C1C QXLQZLBNPTZMRK-UHFFFAOYSA-N 0.000 description 1
- POAOYUHQDCAZBD-UHFFFAOYSA-N 2-butoxyethanol Chemical compound CCCCOCCO POAOYUHQDCAZBD-UHFFFAOYSA-N 0.000 description 1
- LGEXGKUJMFHVSY-UHFFFAOYSA-N 2-n,4-n,6-n-trimethyl-1,3,5-triazine-2,4,6-triamine Chemical compound CNC1=NC(NC)=NC(NC)=N1 LGEXGKUJMFHVSY-UHFFFAOYSA-N 0.000 description 1
- UZFPOOOQHWICKY-UHFFFAOYSA-N 3-[13-[1-[1-[8,12-bis(2-carboxyethyl)-17-(1-hydroxyethyl)-3,7,13,18-tetramethyl-21,24-dihydroporphyrin-2-yl]ethoxy]ethyl]-18-(2-carboxyethyl)-8-(1-hydroxyethyl)-3,7,12,17-tetramethyl-22,23-dihydroporphyrin-2-yl]propanoic acid Chemical compound N1C(C=C2C(=C(CCC(O)=O)C(C=C3C(=C(C)C(C=C4N5)=N3)CCC(O)=O)=N2)C)=C(C)C(C(C)O)=C1C=C5C(C)=C4C(C)OC(C)C1=C(N2)C=C(N3)C(C)=C(C(O)C)C3=CC(C(C)=C3CCC(O)=O)=NC3=CC(C(CCC(O)=O)=C3C)=NC3=CC2=C1C UZFPOOOQHWICKY-UHFFFAOYSA-N 0.000 description 1
- WEVYNIUIFUYDGI-UHFFFAOYSA-N 3-[6-[4-(trifluoromethoxy)anilino]-4-pyrimidinyl]benzamide Chemical compound NC(=O)C1=CC=CC(C=2N=CN=C(NC=3C=CC(OC(F)(F)F)=CC=3)C=2)=C1 WEVYNIUIFUYDGI-UHFFFAOYSA-N 0.000 description 1
- AOJJSUZBOXZQNB-VTZDEGQISA-N 4'-epidoxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-VTZDEGQISA-N 0.000 description 1
- CLPFFLWZZBQMAO-UHFFFAOYSA-N 4-(5,6,7,8-tetrahydroimidazo[1,5-a]pyridin-5-yl)benzonitrile Chemical compound C1=CC(C#N)=CC=C1C1N2C=NC=C2CCC1 CLPFFLWZZBQMAO-UHFFFAOYSA-N 0.000 description 1
- AKJHMTWEGVYYSE-AIRMAKDCSA-N 4-HPR Chemical compound C=1C=C(O)C=CC=1NC(=O)/C=C(\C)/C=C/C=C(C)C=CC1=C(C)CCCC1(C)C AKJHMTWEGVYYSE-AIRMAKDCSA-N 0.000 description 1
- TVZGACDUOSZQKY-LBPRGKRZSA-N 4-aminofolic acid Chemical compound C1=NC2=NC(N)=NC(N)=C2N=C1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 TVZGACDUOSZQKY-LBPRGKRZSA-N 0.000 description 1
- NMUSYJAQQFHJEW-UHFFFAOYSA-N 5-Azacytidine Natural products O=C1N=C(N)N=CN1C1C(O)C(O)C(CO)O1 NMUSYJAQQFHJEW-UHFFFAOYSA-N 0.000 description 1
- XAUDJQYHKZQPEU-KVQBGUIXSA-N 5-aza-2'-deoxycytidine Chemical compound O=C1N=C(N)N=CN1[C@@H]1O[C@H](CO)[C@@H](O)C1 XAUDJQYHKZQPEU-KVQBGUIXSA-N 0.000 description 1
- NMUSYJAQQFHJEW-KVTDHHQDSA-N 5-azacytidine Chemical compound O=C1N=C(N)N=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 NMUSYJAQQFHJEW-KVTDHHQDSA-N 0.000 description 1
- HFEKDTCAMMOLQP-RRKCRQDMSA-N 5-fluorodeoxyuridine monophosphate Chemical compound O1[C@H](COP(O)(O)=O)[C@@H](O)C[C@@H]1N1C(=O)NC(=O)C(F)=C1 HFEKDTCAMMOLQP-RRKCRQDMSA-N 0.000 description 1
- FEIQOMCWGDNMHM-UHFFFAOYSA-N 5-phenylpenta-2,4-dienoic acid Chemical compound OC(=O)C=CC=CC1=CC=CC=C1 FEIQOMCWGDNMHM-UHFFFAOYSA-N 0.000 description 1
- WYWHKKSPHMUBEB-UHFFFAOYSA-N 6-Mercaptoguanine Natural products N1C(N)=NC(=S)C2=C1N=CN2 WYWHKKSPHMUBEB-UHFFFAOYSA-N 0.000 description 1
- VVIAGPKUTFNRDU-UHFFFAOYSA-N 6S-folinic acid Natural products C1NC=2NC(N)=NC(=O)C=2N(C=O)C1CNC1=CC=C(C(=O)NC(CCC(O)=O)C(O)=O)C=C1 VVIAGPKUTFNRDU-UHFFFAOYSA-N 0.000 description 1
- VHRSUDSXCMQTMA-PJHHCJLFSA-N 6alpha-methylprednisolone Chemical compound C([C@@]12C)=CC(=O)C=C1[C@@H](C)C[C@@H]1[C@@H]2[C@@H](O)C[C@]2(C)[C@@](O)(C(=O)CO)CC[C@H]21 VHRSUDSXCMQTMA-PJHHCJLFSA-N 0.000 description 1
- MKBLHFILKIKSQM-UHFFFAOYSA-N 9-methyl-3-[(2-methyl-1h-imidazol-3-ium-3-yl)methyl]-2,3-dihydro-1h-carbazol-4-one;chloride Chemical compound Cl.CC1=NC=CN1CC1C(=O)C(C=2C(=CC=CC=2)N2C)=C2CC1 MKBLHFILKIKSQM-UHFFFAOYSA-N 0.000 description 1
- 229930024421 Adenine Natural products 0.000 description 1
- GFFGJBXGBJISGV-UHFFFAOYSA-N Adenine Chemical compound NC1=NC=NC2=C1N=CN2 GFFGJBXGBJISGV-UHFFFAOYSA-N 0.000 description 1
- OGSPWJRAVKPPFI-UHFFFAOYSA-N Alendronic Acid Chemical compound NCCCC(O)(P(O)(O)=O)P(O)(O)=O OGSPWJRAVKPPFI-UHFFFAOYSA-N 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 239000005995 Aluminium silicate Substances 0.000 description 1
- MLDQJTXFUGDVEO-UHFFFAOYSA-N BAY-43-9006 Chemical compound C1=NC(C(=O)NC)=CC(OC=2C=CC(NC(=O)NC=3C=C(C(Cl)=CC=3)C(F)(F)F)=CC=2)=C1 MLDQJTXFUGDVEO-UHFFFAOYSA-N 0.000 description 1
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- COVZYZSDYWQREU-UHFFFAOYSA-N Busulfan Chemical compound CS(=O)(=O)OCCCCOS(C)(=O)=O COVZYZSDYWQREU-UHFFFAOYSA-N 0.000 description 1
- FVLVBPDQNARYJU-XAHDHGMMSA-N C[C@H]1CCC(CC1)NC(=O)N(CCCl)N=O Chemical compound C[C@H]1CCC(CC1)NC(=O)N(CCCl)N=O FVLVBPDQNARYJU-XAHDHGMMSA-N 0.000 description 1
- 102000055006 Calcitonin Human genes 0.000 description 1
- 108060001064 Calcitonin Proteins 0.000 description 1
- GAGWJHPBXLXJQN-UORFTKCHSA-N Capecitabine Chemical compound C1=C(F)C(NC(=O)OCCCCC)=NC(=O)N1[C@H]1[C@H](O)[C@H](O)[C@@H](C)O1 GAGWJHPBXLXJQN-UORFTKCHSA-N 0.000 description 1
- GAGWJHPBXLXJQN-UHFFFAOYSA-N Capecitabine Natural products C1=C(F)C(NC(=O)OCCCCC)=NC(=O)N1C1C(O)C(O)C(C)O1 GAGWJHPBXLXJQN-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- DLGOEMSEDOSKAD-UHFFFAOYSA-N Carmustine Chemical compound ClCCNC(=O)N(N=O)CCCl DLGOEMSEDOSKAD-UHFFFAOYSA-N 0.000 description 1
- 229920001661 Chitosan Polymers 0.000 description 1
- JWBOIMRXGHLCPP-UHFFFAOYSA-N Chloditan Chemical compound C=1C=CC=C(Cl)C=1C(C(Cl)Cl)C1=CC=C(Cl)C=C1 JWBOIMRXGHLCPP-UHFFFAOYSA-N 0.000 description 1
- 208000035473 Communicable disease Diseases 0.000 description 1
- CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical compound ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 description 1
- UHDGCWIWMRVCDJ-CCXZUQQUSA-N Cytarabine Chemical compound O=C1N=C(N)C=CN1[C@H]1[C@@H](O)[C@H](O)[C@@H](CO)O1 UHDGCWIWMRVCDJ-CCXZUQQUSA-N 0.000 description 1
- 108010092160 Dactinomycin Proteins 0.000 description 1
- 108010019673 Darbepoetin alfa Proteins 0.000 description 1
- GJKXGJCSJWBJEZ-XRSSZCMZSA-N Deslorelin Chemical compound CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H]1NC(=O)CC1)CC1=CNC2=CC=CC=C12 GJKXGJCSJWBJEZ-XRSSZCMZSA-N 0.000 description 1
- 235000019739 Dicalciumphosphate Nutrition 0.000 description 1
- CYQFCXCEBYINGO-DLBZAZTESA-N Dronabinol Natural products C1=C(C)CC[C@H]2C(C)(C)OC3=CC(CCCCC)=CC(O)=C3[C@H]21 CYQFCXCEBYINGO-DLBZAZTESA-N 0.000 description 1
- 206010059866 Drug resistance Diseases 0.000 description 1
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 1
- 102000012199 E3 ubiquitin-protein ligase Mdm2 Human genes 0.000 description 1
- 108050002772 E3 ubiquitin-protein ligase Mdm2 Proteins 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- HTIJFSOGRVMCQR-UHFFFAOYSA-N Epirubicin Natural products COc1cccc2C(=O)c3c(O)c4CC(O)(CC(OC5CC(N)C(=O)C(C)O5)c4c(O)c3C(=O)c12)C(=O)CO HTIJFSOGRVMCQR-UHFFFAOYSA-N 0.000 description 1
- 108010074604 Epoetin Alfa Proteins 0.000 description 1
- 108090000394 Erythropoietin Proteins 0.000 description 1
- 102000003951 Erythropoietin Human genes 0.000 description 1
- RSEPBGGWRJCQGY-RBRWEJTLSA-N Estradiol valerate Chemical compound C1CC2=CC(O)=CC=C2[C@@H]2[C@@H]1[C@@H]1CC[C@H](OC(=O)CCCC)[C@@]1(C)CC2 RSEPBGGWRJCQGY-RBRWEJTLSA-N 0.000 description 1
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 description 1
- BFPYWIDHMRZLRN-SLHNCBLASA-N Ethinyl estradiol Chemical compound OC1=CC=C2[C@H]3CC[C@](C)([C@](CC4)(O)C#C)[C@@H]4[C@@H]3CCC2=C1 BFPYWIDHMRZLRN-SLHNCBLASA-N 0.000 description 1
- 239000001856 Ethyl cellulose Substances 0.000 description 1
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 description 1
- 239000005977 Ethylene Substances 0.000 description 1
- DBVJJBKOTRCVKF-UHFFFAOYSA-N Etidronic acid Chemical compound OP(=O)(O)C(O)(C)P(O)(O)=O DBVJJBKOTRCVKF-UHFFFAOYSA-N 0.000 description 1
- 239000004606 Fillers/Extenders Substances 0.000 description 1
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 description 1
- VWUXBMIQPBEWFH-WCCTWKNTSA-N Fulvestrant Chemical compound OC1=CC=C2[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3[C@H](CCCCCCCCCS(=O)CCCC(F)(F)C(F)(F)F)CC2=C1 VWUXBMIQPBEWFH-WCCTWKNTSA-N 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 108010069236 Goserelin Proteins 0.000 description 1
- BLCLNMBMMGCOAS-URPVMXJPSA-N Goserelin Chemical compound C([C@@H](C(=O)N[C@H](COC(C)(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCN=C(N)N)C(=O)N1[C@@H](CCC1)C(=O)NNC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H]1NC(=O)CC1)C1=CC=C(O)C=C1 BLCLNMBMMGCOAS-URPVMXJPSA-N 0.000 description 1
- 102100039619 Granulocyte colony-stimulating factor Human genes 0.000 description 1
- 102100028999 High mobility group protein HMGI-C Human genes 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 101000987586 Homo sapiens Eosinophil peroxidase Proteins 0.000 description 1
- 101000920686 Homo sapiens Erythropoietin Proteins 0.000 description 1
- 101000986379 Homo sapiens High mobility group protein HMGI-C Proteins 0.000 description 1
- 101001033249 Homo sapiens Interleukin-1 beta Proteins 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 108091069885 IAP family Proteins 0.000 description 1
- 102000040104 IAP family Human genes 0.000 description 1
- MPBVHIBUJCELCL-UHFFFAOYSA-N Ibandronate Chemical compound CCCCCN(C)CCC(O)(P(O)(O)=O)P(O)(O)=O MPBVHIBUJCELCL-UHFFFAOYSA-N 0.000 description 1
- XDXDZDZNSLXDNA-TZNDIEGXSA-N Idarubicin Chemical compound C1[C@H](N)[C@H](O)[C@H](C)O[C@H]1O[C@@H]1C2=C(O)C(C(=O)C3=CC=CC=C3C3=O)=C3C(O)=C2C[C@@](O)(C(C)=O)C1 XDXDZDZNSLXDNA-TZNDIEGXSA-N 0.000 description 1
- XDXDZDZNSLXDNA-UHFFFAOYSA-N Idarubicin Natural products C1C(N)C(O)C(C)OC1OC1C2=C(O)C(C(=O)C3=CC=CC=C3C3=O)=C3C(O)=C2CC(O)(C(C)=O)C1 XDXDZDZNSLXDNA-UHFFFAOYSA-N 0.000 description 1
- 108010078049 Interferon alpha-2 Proteins 0.000 description 1
- 108010079944 Interferon-alpha2b Proteins 0.000 description 1
- 108090000467 Interferon-beta Proteins 0.000 description 1
- 102000003996 Interferon-beta Human genes 0.000 description 1
- 102000008070 Interferon-gamma Human genes 0.000 description 1
- 108010074328 Interferon-gamma Proteins 0.000 description 1
- 102000013462 Interleukin-12 Human genes 0.000 description 1
- 108010065805 Interleukin-12 Proteins 0.000 description 1
- 108010002350 Interleukin-2 Proteins 0.000 description 1
- 102000000588 Interleukin-2 Human genes 0.000 description 1
- 108010063738 Interleukins Proteins 0.000 description 1
- 102000015696 Interleukins Human genes 0.000 description 1
- SHGAZHPCJJPHSC-NUEINMDLSA-N Isotretinoin Chemical compound OC(=O)C=C(C)/C=C/C=C(C)C=CC1=C(C)CCCC1(C)C SHGAZHPCJJPHSC-NUEINMDLSA-N 0.000 description 1
- FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 0.000 description 1
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 description 1
- 239000005411 L01XE02 - Gefitinib Substances 0.000 description 1
- 239000005551 L01XE03 - Erlotinib Substances 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 229920001491 Lentinan Polymers 0.000 description 1
- 240000007472 Leucaena leucocephala Species 0.000 description 1
- 235000010643 Leucaena leucocephala Nutrition 0.000 description 1
- HLFSDGLLUJUHTE-SNVBAGLBSA-N Levamisole Chemical compound C1([C@H]2CN3CCSC3=N2)=CC=CC=C1 HLFSDGLLUJUHTE-SNVBAGLBSA-N 0.000 description 1
- 241000408529 Libra Species 0.000 description 1
- GQYIWUVLTXOXAJ-UHFFFAOYSA-N Lomustine Chemical compound ClCCN(N=O)C(=O)NC1CCCCC1 GQYIWUVLTXOXAJ-UHFFFAOYSA-N 0.000 description 1
- 229940124761 MMP inhibitor Drugs 0.000 description 1
- 240000003183 Manihot esculenta Species 0.000 description 1
- 235000016735 Manihot esculenta subsp esculenta Nutrition 0.000 description 1
- XOGTZOOQQBDUSI-UHFFFAOYSA-M Mesna Chemical compound [Na+].[O-]S(=O)(=O)CCS XOGTZOOQQBDUSI-UHFFFAOYSA-M 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 1
- LKJPYSCBVHEWIU-UHFFFAOYSA-N N-[4-cyano-3-(trifluoromethyl)phenyl]-3-[(4-fluorophenyl)sulfonyl]-2-hydroxy-2-methylpropanamide Chemical compound C=1C=C(C#N)C(C(F)(F)F)=CC=1NC(=O)C(O)(C)CS(=O)(=O)C1=CC=C(F)C=C1 LKJPYSCBVHEWIU-UHFFFAOYSA-N 0.000 description 1
- 108010021717 Nafarelin Proteins 0.000 description 1
- 240000007594 Oryza sativa Species 0.000 description 1
- 235000007164 Oryza sativa Nutrition 0.000 description 1
- 239000012828 PI3K inhibitor Substances 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 241000282373 Panthera pardus Species 0.000 description 1
- 108010067902 Peptide Library Proteins 0.000 description 1
- 239000001888 Peptone Substances 0.000 description 1
- 108010080698 Peptones Proteins 0.000 description 1
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
- HFVNWDWLWUCIHC-GUPDPFMOSA-N Prednimustine Chemical compound O=C([C@@]1(O)CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)[C@@H](O)C[C@@]21C)COC(=O)CCCC1=CC=C(N(CCCl)CCCl)C=C1 HFVNWDWLWUCIHC-GUPDPFMOSA-N 0.000 description 1
- 229940079156 Proteasome inhibitor Drugs 0.000 description 1
- 108010090931 Proto-Oncogene Proteins c-bcl-2 Proteins 0.000 description 1
- 102000013535 Proto-Oncogene Proteins c-bcl-2 Human genes 0.000 description 1
- 102000016971 Proto-Oncogene Proteins c-kit Human genes 0.000 description 1
- 108010014608 Proto-Oncogene Proteins c-kit Proteins 0.000 description 1
- YJDYDFNKCBANTM-QCWCSKBGSA-N SDZ PSC 833 Chemical compound C\C=C\C[C@@H](C)C(=O)[C@@H]1N(C)C(=O)[C@H](C(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)N(C)C(=O)CN(C)C(=O)[C@H](C(C)C)NC1=O YJDYDFNKCBANTM-QCWCSKBGSA-N 0.000 description 1
- 240000004808 Saccharomyces cerevisiae Species 0.000 description 1
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 1
- 244000061456 Solanum tuberosum Species 0.000 description 1
- 235000002595 Solanum tuberosum Nutrition 0.000 description 1
- 241000191940 Staphylococcus Species 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- SSZBUIDZHHWXNJ-UHFFFAOYSA-N Stearinsaeure-hexadecylester Natural products CCCCCCCCCCCCCCCCCC(=O)OCCCCCCCCCCCCCCCC SSZBUIDZHHWXNJ-UHFFFAOYSA-N 0.000 description 1
- 241000194017 Streptococcus Species 0.000 description 1
- 108700011582 TER 286 Proteins 0.000 description 1
- CYQFCXCEBYINGO-UHFFFAOYSA-N THC Natural products C1=C(C)CCC2C(C)(C)OC3=CC(CCCCC)=CC(O)=C3C21 CYQFCXCEBYINGO-UHFFFAOYSA-N 0.000 description 1
- DRHKJLXJIQTDTD-OAHLLOKOSA-N Tamsulosine Chemical compound CCOC1=CC=CC=C1OCCN[C@H](C)CC1=CC=C(OC)C(S(N)(=O)=O)=C1 DRHKJLXJIQTDTD-OAHLLOKOSA-N 0.000 description 1
- NAVMQTYZDKMPEU-UHFFFAOYSA-N Targretin Chemical compound CC1=CC(C(CCC2(C)C)(C)C)=C2C=C1C(=C)C1=CC=C(C(O)=O)C=C1 NAVMQTYZDKMPEU-UHFFFAOYSA-N 0.000 description 1
- BPEGJWRSRHCHSN-UHFFFAOYSA-N Temozolomide Chemical compound O=C1N(C)N=NC2=C(C(N)=O)N=CN21 BPEGJWRSRHCHSN-UHFFFAOYSA-N 0.000 description 1
- CBPNZQVSJQDFBE-FUXHJELOSA-N Temsirolimus Chemical compound C1C[C@@H](OC(=O)C(C)(CO)CO)[C@H](OC)C[C@@H]1C[C@@H](C)[C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@](O)(O2)[C@H](C)CC[C@H]2C[C@H](OC)/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C1 CBPNZQVSJQDFBE-FUXHJELOSA-N 0.000 description 1
- PDMMFKSKQVNJMI-BLQWBTBKSA-N Testosterone propionate Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H](OC(=O)CC)[C@@]1(C)CC2 PDMMFKSKQVNJMI-BLQWBTBKSA-N 0.000 description 1
- FOCVUCIESVLUNU-UHFFFAOYSA-N Thiotepa Chemical compound C1CN1P(N1CC1)(=S)N1CC1 FOCVUCIESVLUNU-UHFFFAOYSA-N 0.000 description 1
- AYFVYJQAPQTCCC-UHFFFAOYSA-N Threonine Natural products CC(O)C(N)C(O)=O AYFVYJQAPQTCCC-UHFFFAOYSA-N 0.000 description 1
- 239000004473 Threonine Substances 0.000 description 1
- 108010046075 Thymosin Proteins 0.000 description 1
- 102000007501 Thymosin Human genes 0.000 description 1
- 102000011923 Thyrotropin Human genes 0.000 description 1
- 108010061174 Thyrotropin Proteins 0.000 description 1
- DKJJVAGXPKPDRL-UHFFFAOYSA-N Tiludronic acid Chemical compound OP(O)(=O)C(P(O)(O)=O)SC1=CC=C(Cl)C=C1 DKJJVAGXPKPDRL-UHFFFAOYSA-N 0.000 description 1
- IVTVGDXNLFLDRM-HNNXBMFYSA-N Tomudex Chemical compound C=1C=C2NC(C)=NC(=O)C2=CC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)S1 IVTVGDXNLFLDRM-HNNXBMFYSA-N 0.000 description 1
- QHMBSVQNZZTUGM-UHFFFAOYSA-N Trans-Cannabidiol Natural products OC1=CC(CCCCC)=CC(O)=C1C1C(C(C)=C)CCC(C)=C1 QHMBSVQNZZTUGM-UHFFFAOYSA-N 0.000 description 1
- 102000000887 Transcription factor STAT Human genes 0.000 description 1
- 108050007918 Transcription factor STAT Proteins 0.000 description 1
- 108010050144 Triptorelin Pamoate Proteins 0.000 description 1
- 102000004142 Trypsin Human genes 0.000 description 1
- 108090000631 Trypsin Proteins 0.000 description 1
- 108091008605 VEGF receptors Proteins 0.000 description 1
- 102000005789 Vascular Endothelial Growth Factors Human genes 0.000 description 1
- 108010019530 Vascular Endothelial Growth Factors Proteins 0.000 description 1
- 102100033177 Vascular endothelial growth factor receptor 2 Human genes 0.000 description 1
- JXLYSJRDGCGARV-WWYNWVTFSA-N Vinblastine Natural products O=C(O[C@H]1[C@](O)(C(=O)OC)[C@@H]2N(C)c3c(cc(c(OC)c3)[C@]3(C(=O)OC)c4[nH]c5c(c4CCN4C[C@](O)(CC)C[C@H](C3)C4)cccc5)[C@@]32[C@H]2[C@@]1(CC)C=CCN2CC3)C JXLYSJRDGCGARV-WWYNWVTFSA-N 0.000 description 1
- 240000008042 Zea mays Species 0.000 description 1
- 235000005824 Zea mays ssp. parviglumis Nutrition 0.000 description 1
- 235000002017 Zea mays subsp mays Nutrition 0.000 description 1
- HPPONSCISKROOD-OYLNGHKZSA-N acetic acid;(2s)-n-[(2s)-1-[[(2s)-1-[[(2s)-1-[[(2s)-1-[[(2r)-1-[[(2s)-1-[[(2s)-1-[(2s)-2-[(2-amino-2-oxoethyl)carbamoyl]pyrrolidin-1-yl]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-3-(1h-indol-3-yl)-1-oxopropan-2-y Chemical compound CC(O)=O.C([C@@H](C(=O)N[C@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCN=C(N)N)C(=O)N1[C@@H](CCC1)C(=O)NCC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H]1NC(=O)CC1)C1=CC=C(O)C=C1 HPPONSCISKROOD-OYLNGHKZSA-N 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- DUYNJNWVGIWJRI-LJAQVGFWSA-N acolbifene Chemical compound C1=CC([C@H]2C(=C(C3=CC=C(O)C=C3O2)C)C=2C=CC(O)=CC=2)=CC=C1OCCN1CCCCC1 DUYNJNWVGIWJRI-LJAQVGFWSA-N 0.000 description 1
- 229950002421 acolbifene Drugs 0.000 description 1
- RJURFGZVJUQBHK-IIXSONLDSA-N actinomycin D Chemical compound C[C@H]1OC(=O)[C@H](C(C)C)N(C)C(=O)CN(C)C(=O)[C@@H]2CCCN2C(=O)[C@@H](C(C)C)NC(=O)[C@H]1NC(=O)C1=C(N)C(=O)C(C)=C2OC(C(C)=CC=C3C(=O)N[C@@H]4C(=O)N[C@@H](C(N5CCC[C@H]5C(=O)N(C)CC(=O)N(C)[C@@H](C(C)C)C(=O)O[C@@H]4C)=O)C(C)C)=C3N=C21 RJURFGZVJUQBHK-IIXSONLDSA-N 0.000 description 1
- 239000012190 activator Substances 0.000 description 1
- 229960000643 adenine Drugs 0.000 description 1
- 210000000577 adipose tissue Anatomy 0.000 description 1
- 239000003463 adsorbent Substances 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- GZCGUPFRVQAUEE-SLPGGIOYSA-N aldehydo-D-glucose Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C=O GZCGUPFRVQAUEE-SLPGGIOYSA-N 0.000 description 1
- 229960005310 aldesleukin Drugs 0.000 description 1
- 108700025316 aldesleukin Proteins 0.000 description 1
- 229960004343 alendronic acid Drugs 0.000 description 1
- 239000000783 alginic acid Substances 0.000 description 1
- 229960001126 alginic acid Drugs 0.000 description 1
- 150000004781 alginic acids Chemical class 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- SHGAZHPCJJPHSC-YCNIQYBTSA-N all-trans-retinoic acid Chemical compound OC(=O)\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C SHGAZHPCJJPHSC-YCNIQYBTSA-N 0.000 description 1
- 229960003459 allopurinol Drugs 0.000 description 1
- OFCNXPDARWKPPY-UHFFFAOYSA-N allopurinol Chemical compound OC1=NC=NC2=C1C=NN2 OFCNXPDARWKPPY-UHFFFAOYSA-N 0.000 description 1
- 229960003235 allopurinol sodium Drugs 0.000 description 1
- 229960000473 altretamine Drugs 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 235000012211 aluminium silicate Nutrition 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 229960003437 aminoglutethimide Drugs 0.000 description 1
- ROBVIMPUHSLWNV-UHFFFAOYSA-N aminoglutethimide Chemical compound C=1C=C(N)C=CC=1C1(CC)CCC(=O)NC1=O ROBVIMPUHSLWNV-UHFFFAOYSA-N 0.000 description 1
- 229960003896 aminopterin Drugs 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 229960002550 amrubicin Drugs 0.000 description 1
- VJZITPJGSQKZMX-XDPRQOKASA-N amrubicin Chemical compound O([C@H]1C[C@](CC2=C(O)C=3C(=O)C4=CC=CC=C4C(=O)C=3C(O)=C21)(N)C(=O)C)[C@H]1C[C@H](O)[C@H](O)CO1 VJZITPJGSQKZMX-XDPRQOKASA-N 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 229960002932 anastrozole Drugs 0.000 description 1
- YBBLVLTVTVSKRW-UHFFFAOYSA-N anastrozole Chemical compound N#CC(C)(C)C1=CC(C(C)(C#N)C)=CC(CN2N=CN=C2)=C1 YBBLVLTVTVSKRW-UHFFFAOYSA-N 0.000 description 1
- 239000004037 angiogenesis inhibitor Substances 0.000 description 1
- 229940121369 angiogenesis inhibitor Drugs 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 230000002022 anti-cellular effect Effects 0.000 description 1
- 230000001028 anti-proliverative effect Effects 0.000 description 1
- 229940124350 antibacterial drug Drugs 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 229940045988 antineoplastic drug protein kinase inhibitors Drugs 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 229960001372 aprepitant Drugs 0.000 description 1
- ATALOFNDEOCMKK-OITMNORJSA-N aprepitant Chemical compound O([C@@H]([C@@H]1C=2C=CC(F)=CC=2)O[C@H](C)C=2C=C(C=C(C=2)C(F)(F)F)C(F)(F)F)CCN1CC1=NNC(=O)N1 ATALOFNDEOCMKK-OITMNORJSA-N 0.000 description 1
- 239000008365 aqueous carrier Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 229940115115 aranesp Drugs 0.000 description 1
- UVJYAKBJSGRTHA-ZCRGAIPPSA-N arglabin Chemical compound C1C[C@H]2C(=C)C(=O)O[C@@H]2[C@@H]2C(C)=CC[C@]32O[C@]31C UVJYAKBJSGRTHA-ZCRGAIPPSA-N 0.000 description 1
- UVJYAKBJSGRTHA-UHFFFAOYSA-N arglabin Natural products C1CC2C(=C)C(=O)OC2C2C(C)=CCC32OC31C UVJYAKBJSGRTHA-UHFFFAOYSA-N 0.000 description 1
- GOLCXWYRSKYTSP-UHFFFAOYSA-N arsenic trioxide Inorganic materials O1[As]2O[As]1O2 GOLCXWYRSKYTSP-UHFFFAOYSA-N 0.000 description 1
- 229950003620 asoprisnil Drugs 0.000 description 1
- GJMNAFGEUJBOCE-MEQIQULJSA-N asoprisnil Chemical compound C1([C@@H]2C3=C4CCC(=O)C=C4CC[C@H]3[C@@H]3CC[C@]([C@]3(C2)C)(COC)OC)=CC=C(\C=N\O)C=C1 GJMNAFGEUJBOCE-MEQIQULJSA-N 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- PEPMWUSGRKINHX-TXTPUJOMSA-N atamestane Chemical compound C1C[C@@H]2[C@@]3(C)C(C)=CC(=O)C=C3CC[C@H]2[C@@H]2CCC(=O)[C@]21C PEPMWUSGRKINHX-TXTPUJOMSA-N 0.000 description 1
- 229950004810 atamestane Drugs 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- MOTJMGVDPWRKOC-QPVYNBJUSA-N atrasentan Chemical compound C1([C@H]2[C@@H]([C@H](CN2CC(=O)N(CCCC)CCCC)C=2C=C3OCOC3=CC=2)C(O)=O)=CC=C(OC)C=C1 MOTJMGVDPWRKOC-QPVYNBJUSA-N 0.000 description 1
- 229950010993 atrasentan Drugs 0.000 description 1
- 229940120638 avastin Drugs 0.000 description 1
- 229960002756 azacitidine Drugs 0.000 description 1
- KLNFSAOEKUDMFA-UHFFFAOYSA-N azanide;2-hydroxyacetic acid;platinum(2+) Chemical compound [NH2-].[NH2-].[Pt+2].OCC(O)=O KLNFSAOEKUDMFA-UHFFFAOYSA-N 0.000 description 1
- VSRXQHXAPYXROS-UHFFFAOYSA-N azanide;cyclobutane-1,1-dicarboxylic acid;platinum(2+) Chemical compound [NH2-].[NH2-].[Pt+2].OC(=O)C1(C(O)=O)CCC1 VSRXQHXAPYXROS-UHFFFAOYSA-N 0.000 description 1
- 229960002170 azathioprine Drugs 0.000 description 1
- LMEKQMALGUDUQG-UHFFFAOYSA-N azathioprine Chemical compound CN1C=NC([N+]([O-])=O)=C1SC1=NC=NC2=C1NC=N2 LMEKQMALGUDUQG-UHFFFAOYSA-N 0.000 description 1
- 244000052616 bacterial pathogen Species 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- DRTQHJPVMGBUCF-PSQAKQOGSA-N beta-L-uridine Natural products O[C@H]1[C@@H](O)[C@H](CO)O[C@@H]1N1C(=O)NC(=O)C=C1 DRTQHJPVMGBUCF-PSQAKQOGSA-N 0.000 description 1
- 229940064804 betadine Drugs 0.000 description 1
- 229960002537 betamethasone Drugs 0.000 description 1
- UREBDLICKHMUKA-DVTGEIKXSA-N betamethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O UREBDLICKHMUKA-DVTGEIKXSA-N 0.000 description 1
- 229960004648 betamethasone acetate Drugs 0.000 description 1
- AKUJBENLRBOFTD-QZIXMDIESA-N betamethasone acetate Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@H](C)[C@@](C(=O)COC(C)=O)(O)[C@@]1(C)C[C@@H]2O AKUJBENLRBOFTD-QZIXMDIESA-N 0.000 description 1
- 229960005354 betamethasone sodium phosphate Drugs 0.000 description 1
- PLCQGRYPOISRTQ-LWCNAHDDSA-L betamethasone sodium phosphate Chemical compound [Na+].[Na+].C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@H](C)[C@@](C(=O)COP([O-])([O-])=O)(O)[C@@]1(C)C[C@@H]2O PLCQGRYPOISRTQ-LWCNAHDDSA-L 0.000 description 1
- 229960002938 bexarotene Drugs 0.000 description 1
- 238000007664 blowing Methods 0.000 description 1
- RJTANRZEWTUVMA-UHFFFAOYSA-N boron;n-methylmethanamine Chemical compound [B].CNC RJTANRZEWTUVMA-UHFFFAOYSA-N 0.000 description 1
- GXJABQQUPOEUTA-RDJZCZTQSA-N bortezomib Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)B(O)O)NC(=O)C=1N=CC=NC=1)C1=CC=CC=C1 GXJABQQUPOEUTA-RDJZCZTQSA-N 0.000 description 1
- 229960001467 bortezomib Drugs 0.000 description 1
- 210000000481 breast Anatomy 0.000 description 1
- 239000006172 buffering agent Substances 0.000 description 1
- 229960002092 busulfan Drugs 0.000 description 1
- 235000019437 butane-1,3-diol Nutrition 0.000 description 1
- BBBFJLBPOGFECG-VJVYQDLKSA-N calcitonin Chemical compound N([C@H](C(=O)N[C@@H](CC(C)C)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)NCC(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H]([C@@H](C)O)C(=O)N1[C@@H](CCC1)C(N)=O)C(C)C)C(=O)[C@@H]1CSSC[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)O)C(=O)N1 BBBFJLBPOGFECG-VJVYQDLKSA-N 0.000 description 1
- 229960004015 calcitonin Drugs 0.000 description 1
- GMRQFYUYWCNGIN-NKMMMXOESA-N calcitriol Chemical compound C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@@H](CCCC(C)(C)O)C)=C\C=C1\C[C@@H](O)C[C@H](O)C1=C GMRQFYUYWCNGIN-NKMMMXOESA-N 0.000 description 1
- 235000010216 calcium carbonate Nutrition 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- KVUAALJSMIVURS-ZEDZUCNESA-L calcium folinate Chemical compound [Ca+2].C1NC=2NC(N)=NC(=O)C=2N(C=O)C1CNC1=CC=C(C(=O)N[C@@H](CCC([O-])=O)C([O-])=O)C=C1 KVUAALJSMIVURS-ZEDZUCNESA-L 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 1
- 235000013539 calcium stearate Nutrition 0.000 description 1
- 239000008116 calcium stearate Substances 0.000 description 1
- QHMBSVQNZZTUGM-ZWKOTPCHSA-N cannabidiol Chemical compound OC1=CC(CCCCC)=CC(O)=C1[C@H]1[C@H](C(C)=C)CCC(C)=C1 QHMBSVQNZZTUGM-ZWKOTPCHSA-N 0.000 description 1
- 229950011318 cannabidiol Drugs 0.000 description 1
- ZTGXAWYVTLUPDT-UHFFFAOYSA-N cannabidiol Natural products OC1=CC(CCCCC)=CC(O)=C1C1C(C(C)=C)CC=C(C)C1 ZTGXAWYVTLUPDT-UHFFFAOYSA-N 0.000 description 1
- 229960004117 capecitabine Drugs 0.000 description 1
- 239000001569 carbon dioxide Substances 0.000 description 1
- 229910002092 carbon dioxide Inorganic materials 0.000 description 1
- 229960004562 carboplatin Drugs 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 229960005243 carmustine Drugs 0.000 description 1
- 229940097647 casodex Drugs 0.000 description 1
- 239000004359 castor oil Substances 0.000 description 1
- 235000019438 castor oil Nutrition 0.000 description 1
- 229920006317 cationic polymer Polymers 0.000 description 1
- 150000001768 cations Chemical class 0.000 description 1
- 229940047495 celebrex Drugs 0.000 description 1
- RZEKVGVHFLEQIL-UHFFFAOYSA-N celecoxib Chemical compound C1=CC(C)=CC=C1C1=CC(C(F)(F)F)=NN1C1=CC=C(S(N)(=O)=O)C=C1 RZEKVGVHFLEQIL-UHFFFAOYSA-N 0.000 description 1
- 230000012820 cell cycle checkpoint Effects 0.000 description 1
- 230000030833 cell death Effects 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 239000006285 cell suspension Substances 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 235000010980 cellulose Nutrition 0.000 description 1
- 229920002301 cellulose acetate Polymers 0.000 description 1
- 229960005395 cetuximab Drugs 0.000 description 1
- 229960000541 cetyl alcohol Drugs 0.000 description 1
- JCKYGMPEJWAADB-UHFFFAOYSA-N chlorambucil Chemical compound OC(=O)CCCC1=CC=C(N(CCCl)CCCl)C=C1 JCKYGMPEJWAADB-UHFFFAOYSA-N 0.000 description 1
- 229960004316 cisplatin Drugs 0.000 description 1
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 1
- 229940001468 citrate Drugs 0.000 description 1
- 229960002286 clodronic acid Drugs 0.000 description 1
- ACSIXWWBWUQEHA-UHFFFAOYSA-N clodronic acid Chemical compound OP(O)(=O)C(Cl)(Cl)P(O)(O)=O ACSIXWWBWUQEHA-UHFFFAOYSA-N 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 229940000425 combination drug Drugs 0.000 description 1
- 239000013065 commercial product Substances 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- 235000005822 corn Nutrition 0.000 description 1
- 235000012343 cottonseed oil Nutrition 0.000 description 1
- 239000002385 cottonseed oil Substances 0.000 description 1
- 229940111134 coxibs Drugs 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 229940043378 cyclin-dependent kinase inhibitor Drugs 0.000 description 1
- 239000003255 cyclooxygenase 2 inhibitor Substances 0.000 description 1
- 229960004397 cyclophosphamide Drugs 0.000 description 1
- 229960000684 cytarabine Drugs 0.000 description 1
- 210000000805 cytoplasm Anatomy 0.000 description 1
- 239000000824 cytostatic agent Substances 0.000 description 1
- 239000002254 cytotoxic agent Substances 0.000 description 1
- 229960003901 dacarbazine Drugs 0.000 description 1
- 229960000640 dactinomycin Drugs 0.000 description 1
- 230000034994 death Effects 0.000 description 1
- 229960003603 decitabine Drugs 0.000 description 1
- 239000007857 degradation product Substances 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- CYQFCXCEBYINGO-IAGOWNOFSA-N delta1-THC Chemical compound C1=C(C)CC[C@H]2C(C)(C)OC3=CC(CCCCC)=CC(O)=C3[C@@H]21 CYQFCXCEBYINGO-IAGOWNOFSA-N 0.000 description 1
- 108700025485 deslorelin Proteins 0.000 description 1
- 229960005408 deslorelin Drugs 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- LRCZQSDQZJBHAF-PUBGEWHCSA-N dha-paclitaxel Chemical compound N([C@H]([C@@H](OC(=O)CC\C=C/C\C=C/C\C=C/C\C=C/C\C=C/C\C=C/CC)C(=O)O[C@@H]1C(=C2[C@@H](OC(C)=O)C(=O)[C@]3(C)[C@@H](O)C[C@H]4OC[C@]4([C@H]3[C@H](OC(=O)C=3C=CC=CC=3)[C@](C2(C)C)(O)C1)OC(C)=O)C)C=1C=CC=CC=1)C(=O)C1=CC=CC=C1 LRCZQSDQZJBHAF-PUBGEWHCSA-N 0.000 description 1
- NEFBYIFKOOEVPA-UHFFFAOYSA-K dicalcium phosphate Chemical compound [Ca+2].[Ca+2].[O-]P([O-])([O-])=O NEFBYIFKOOEVPA-UHFFFAOYSA-K 0.000 description 1
- 229940038472 dicalcium phosphate Drugs 0.000 description 1
- 229910000390 dicalcium phosphate Inorganic materials 0.000 description 1
- RGLYKWWBQGJZGM-ISLYRVAYSA-N diethylstilbestrol Chemical compound C=1C=C(O)C=CC=1C(/CC)=C(\CC)C1=CC=C(O)C=C1 RGLYKWWBQGJZGM-ISLYRVAYSA-N 0.000 description 1
- 229960000452 diethylstilbestrol Drugs 0.000 description 1
- 229940063123 diflucan Drugs 0.000 description 1
- PCXRACLQFPRCBB-ZWKOTPCHSA-N dihydrocannabidiol Natural products OC1=CC(CCCCC)=CC(O)=C1[C@H]1[C@H](C(C)C)CCC(C)=C1 PCXRACLQFPRCBB-ZWKOTPCHSA-N 0.000 description 1
- 229940008099 dimethicone Drugs 0.000 description 1
- 235000013870 dimethyl polysiloxane Nutrition 0.000 description 1
- 239000004205 dimethyl polysiloxane Substances 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 239000003534 dna topoisomerase inhibitor Substances 0.000 description 1
- 229960003668 docetaxel Drugs 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
- ZWAOHEXOSAUJHY-ZIYNGMLESA-N doxifluridine Chemical compound O[C@@H]1[C@H](O)[C@@H](C)O[C@H]1N1C(=O)NC(=O)C(F)=C1 ZWAOHEXOSAUJHY-ZIYNGMLESA-N 0.000 description 1
- 229950005454 doxifluridine Drugs 0.000 description 1
- 229960004242 dronabinol Drugs 0.000 description 1
- 239000000890 drug combination Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- JWJOTENAMICLJG-QWBYCMEYSA-N dutasteride Chemical compound O=C([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)N[C@@H]4CC3)C)CC[C@@]21C)NC1=CC(C(F)(F)F)=CC=C1C(F)(F)F JWJOTENAMICLJG-QWBYCMEYSA-N 0.000 description 1
- 229960004199 dutasteride Drugs 0.000 description 1
- 229950001287 edotecarin Drugs 0.000 description 1
- VLCYCQAOQCDTCN-UHFFFAOYSA-N eflornithine Chemical compound NCCCC(N)(C(F)F)C(O)=O VLCYCQAOQCDTCN-UHFFFAOYSA-N 0.000 description 1
- 229960002759 eflornithine Drugs 0.000 description 1
- 229940121647 egfr inhibitor Drugs 0.000 description 1
- 230000009881 electrostatic interaction Effects 0.000 description 1
- 230000001804 emulsifying effect Effects 0.000 description 1
- 108010048367 enhanced green fluorescent protein Proteins 0.000 description 1
- 239000002702 enteric coating Substances 0.000 description 1
- 238000009505 enteric coating Methods 0.000 description 1
- 229960001904 epirubicin Drugs 0.000 description 1
- 229960003265 epirubicin hydrochloride Drugs 0.000 description 1
- 229960003388 epoetin alfa Drugs 0.000 description 1
- AAKJLRGGTJKAMG-UHFFFAOYSA-N erlotinib Chemical compound C=12C=C(OCCOC)C(OCCOC)=CC2=NC=NC=1NC1=CC=CC(C#C)=C1 AAKJLRGGTJKAMG-UHFFFAOYSA-N 0.000 description 1
- 229940105423 erythropoietin Drugs 0.000 description 1
- 229930182833 estradiol Natural products 0.000 description 1
- 229960004766 estradiol valerate Drugs 0.000 description 1
- IIUMCNJTGSMNRO-VVSKJQCTSA-L estramustine sodium phosphate Chemical compound [Na+].[Na+].ClCCN(CCCl)C(=O)OC1=CC=C2[C@H]3CC[C@](C)([C@H](CC4)OP([O-])([O-])=O)[C@@H]4[C@@H]3CCC2=C1 IIUMCNJTGSMNRO-VVSKJQCTSA-L 0.000 description 1
- 229940011871 estrogen Drugs 0.000 description 1
- 239000000262 estrogen Substances 0.000 description 1
- 239000002834 estrogen receptor modulator Substances 0.000 description 1
- JKKFKPJIXZFSSB-CBZIJGRNSA-N estrone 3-sulfate Chemical compound OS(=O)(=O)OC1=CC=C2[C@H]3CC[C@](C)(C(CC4)=O)[C@@H]4[C@@H]3CCC2=C1 JKKFKPJIXZFSSB-CBZIJGRNSA-N 0.000 description 1
- 229960002568 ethinylestradiol Drugs 0.000 description 1
- 235000019325 ethyl cellulose Nutrition 0.000 description 1
- 229920001249 ethyl cellulose Polymers 0.000 description 1
- 229940009626 etidronate Drugs 0.000 description 1
- VJJPUSNTGOMMGY-MRVIYFEKSA-N etoposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@H](C)OC[C@H]4O3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 VJJPUSNTGOMMGY-MRVIYFEKSA-N 0.000 description 1
- 229960005420 etoposide Drugs 0.000 description 1
- 229950011548 fadrozole Drugs 0.000 description 1
- 229950003662 fenretinide Drugs 0.000 description 1
- 239000012091 fetal bovine serum Substances 0.000 description 1
- 229960004177 filgrastim Drugs 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 229960004039 finasteride Drugs 0.000 description 1
- DBEPLOCGEIEOCV-WSBQPABSSA-N finasteride Chemical compound N([C@@H]1CC2)C(=O)C=C[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H](C(=O)NC(C)(C)C)[C@@]2(C)CC1 DBEPLOCGEIEOCV-WSBQPABSSA-N 0.000 description 1
- 229960004884 fluconazole Drugs 0.000 description 1
- 229960000390 fludarabine Drugs 0.000 description 1
- GIUYCYHIANZCFB-FJFJXFQQSA-N fludarabine phosphate Chemical compound C1=NC=2C(N)=NC(F)=NC=2N1[C@@H]1O[C@H](COP(O)(O)=O)[C@@H](O)[C@@H]1O GIUYCYHIANZCFB-FJFJXFQQSA-N 0.000 description 1
- 229960002949 fluorouracil Drugs 0.000 description 1
- YLRFCQOZQXIBAB-RBZZARIASA-N fluoxymesterone Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1CC[C@](C)(O)[C@@]1(C)C[C@@H]2O YLRFCQOZQXIBAB-RBZZARIASA-N 0.000 description 1
- 229960001751 fluoxymesterone Drugs 0.000 description 1
- 229960002074 flutamide Drugs 0.000 description 1
- MKXKFYHWDHIYRV-UHFFFAOYSA-N flutamide Chemical compound CC(C)C(=O)NC1=CC=C([N+]([O-])=O)C(C(F)(F)F)=C1 MKXKFYHWDHIYRV-UHFFFAOYSA-N 0.000 description 1
- 239000011888 foil Substances 0.000 description 1
- 235000008191 folinic acid Nutrition 0.000 description 1
- 239000011672 folinic acid Substances 0.000 description 1
- 229960002258 fulvestrant Drugs 0.000 description 1
- 108010074605 gamma-Globulins Proteins 0.000 description 1
- 229920000370 gamma-poly(glutamate) polymer Polymers 0.000 description 1
- XGALLCVXEZPNRQ-UHFFFAOYSA-N gefitinib Chemical compound C=12C=C(OCCCN3CCOCC3)C(OC)=CC2=NC=NC=1NC1=CC=C(F)C(Cl)=C1 XGALLCVXEZPNRQ-UHFFFAOYSA-N 0.000 description 1
- 229960005277 gemcitabine Drugs 0.000 description 1
- SDUQYLNIPVEERB-QPPQHZFASA-N gemcitabine Chemical compound O=C1N=C(N)C=CN1[C@H]1C(F)(F)[C@H](O)[C@@H](CO)O1 SDUQYLNIPVEERB-QPPQHZFASA-N 0.000 description 1
- 229960000578 gemtuzumab Drugs 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 235000001727 glucose Nutrition 0.000 description 1
- 229960001031 glucose Drugs 0.000 description 1
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 description 1
- 229940075507 glyceryl monostearate Drugs 0.000 description 1
- 229960002913 goserelin Drugs 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 125000005842 heteroatom Chemical group 0.000 description 1
- BXWNKGSJHAJOGX-UHFFFAOYSA-N hexadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCO BXWNKGSJHAJOGX-UHFFFAOYSA-N 0.000 description 1
- UUVWYPNAQBNQJQ-UHFFFAOYSA-N hexamethylmelamine Chemical compound CN(C)C1=NC(N(C)C)=NC(N(C)C)=N1 UUVWYPNAQBNQJQ-UHFFFAOYSA-N 0.000 description 1
- 231100000086 high toxicity Toxicity 0.000 description 1
- 229960004931 histamine dihydrochloride Drugs 0.000 description 1
- PPZMYIBUHIPZOS-UHFFFAOYSA-N histamine dihydrochloride Chemical compound Cl.Cl.NCCC1=CN=CN1 PPZMYIBUHIPZOS-UHFFFAOYSA-N 0.000 description 1
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 1
- 229960002885 histidine Drugs 0.000 description 1
- 102000044890 human EPO Human genes 0.000 description 1
- 229960000890 hydrocortisone Drugs 0.000 description 1
- 239000000017 hydrogel Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
- 229920003063 hydroxymethyl cellulose Polymers 0.000 description 1
- 229940031574 hydroxymethyl cellulose Drugs 0.000 description 1
- 229960005236 ibandronic acid Drugs 0.000 description 1
- 229960000908 idarubicin Drugs 0.000 description 1
- HOMGKSMUEGBAAB-UHFFFAOYSA-N ifosfamide Chemical compound ClCCNP1(=O)OCCCN1CCCl HOMGKSMUEGBAAB-UHFFFAOYSA-N 0.000 description 1
- 229960001101 ifosfamide Drugs 0.000 description 1
- 238000003384 imaging method Methods 0.000 description 1
- 229960003685 imatinib mesylate Drugs 0.000 description 1
- YLMAHDNUQAMNNX-UHFFFAOYSA-N imatinib methanesulfonate Chemical compound CS(O)(=O)=O.C1CN(C)CCN1CC1=CC=C(C(=O)NC=2C=C(NC=3N=C(C=CN=3)C=3C=NC=CC=3)C(C)=CC=2)C=C1 YLMAHDNUQAMNNX-UHFFFAOYSA-N 0.000 description 1
- LFKYBJLFJOOKAE-UHFFFAOYSA-N imidazol-2-ylidenemethanone Chemical compound O=C=C1N=CC=N1 LFKYBJLFJOOKAE-UHFFFAOYSA-N 0.000 description 1
- 150000002466 imines Chemical class 0.000 description 1
- 239000007943 implant Substances 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 239000000411 inducer Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 229940090044 injection Drugs 0.000 description 1
- 102000006495 integrins Human genes 0.000 description 1
- 108010044426 integrins Proteins 0.000 description 1
- 229960003130 interferon gamma Drugs 0.000 description 1
- 229960001388 interferon-beta Drugs 0.000 description 1
- 229940117681 interleukin-12 Drugs 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 229940065638 intron a Drugs 0.000 description 1
- 229940084651 iressa Drugs 0.000 description 1
- UWKQSNNFCGGAFS-XIFFEERXSA-N irinotecan Chemical compound C1=C2C(CC)=C3CN(C(C4=C([C@@](C(=O)OC4)(O)CC)C=4)=O)C=4C3=NC2=CC=C1OC(=O)N(CC1)CCC1N1CCCCC1 UWKQSNNFCGGAFS-XIFFEERXSA-N 0.000 description 1
- 229960004768 irinotecan Drugs 0.000 description 1
- 230000002427 irreversible effect Effects 0.000 description 1
- 229960005280 isotretinoin Drugs 0.000 description 1
- 229960002014 ixabepilone Drugs 0.000 description 1
- FABUFPQFXZVHFB-CFWQTKTJSA-N ixabepilone Chemical compound C/C([C@@H]1C[C@@H]2O[C@]2(C)CCC[C@@H]([C@@H]([C@H](C)C(=O)C(C)(C)[C@H](O)CC(=O)N1)O)C)=C\C1=CSC(C)=N1 FABUFPQFXZVHFB-CFWQTKTJSA-N 0.000 description 1
- NLYAJNPCOHFWQQ-UHFFFAOYSA-N kaolin Chemical compound O.O.O=[Al]O[Si](=O)O[Si](=O)O[Al]=O NLYAJNPCOHFWQQ-UHFFFAOYSA-N 0.000 description 1
- BWHLPLXXIDYSNW-UHFFFAOYSA-N ketorolac tromethamine Chemical compound OCC(N)(CO)CO.OC(=O)C1CCN2C1=CC=C2C(=O)C1=CC=CC=C1 BWHLPLXXIDYSNW-UHFFFAOYSA-N 0.000 description 1
- 108010045069 keyhole-limpet hemocyanin Proteins 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 108010021336 lanreotide Proteins 0.000 description 1
- 229960002437 lanreotide Drugs 0.000 description 1
- GOTYRUGSSMKFNF-UHFFFAOYSA-N lenalidomide Chemical compound C1C=2C(N)=CC=CC=2C(=O)N1C1CCC(=O)NC1=O GOTYRUGSSMKFNF-UHFFFAOYSA-N 0.000 description 1
- 229940115286 lentinan Drugs 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- 229960003881 letrozole Drugs 0.000 description 1
- HPJKCIUCZWXJDR-UHFFFAOYSA-N letrozole Chemical compound C1=CC(C#N)=CC=C1C(N1N=CN=C1)C1=CC=C(C#N)C=C1 HPJKCIUCZWXJDR-UHFFFAOYSA-N 0.000 description 1
- 229960001691 leucovorin Drugs 0.000 description 1
- 229940075961 levoleucovorin calcium pentahydrate Drugs 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 229960002247 lomustine Drugs 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 229960003538 lonidamine Drugs 0.000 description 1
- WDRYRZXSPDWGEB-UHFFFAOYSA-N lonidamine Chemical compound C12=CC=CC=C2C(C(=O)O)=NN1CC1=CC=C(Cl)C=C1Cl WDRYRZXSPDWGEB-UHFFFAOYSA-N 0.000 description 1
- 108010078259 luprolide acetate gel depot Proteins 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 229960004961 mechlorethamine Drugs 0.000 description 1
- HAWPXGHAZFHHAD-UHFFFAOYSA-N mechlorethamine Chemical class ClCCN(C)CCCl HAWPXGHAZFHHAD-UHFFFAOYSA-N 0.000 description 1
- PSGAAPLEWMOORI-PEINSRQWSA-N medroxyprogesterone acetate Chemical compound C([C@@]12C)CC(=O)C=C1[C@@H](C)C[C@@H]1[C@@H]2CC[C@]2(C)[C@@](OC(C)=O)(C(C)=O)CC[C@H]21 PSGAAPLEWMOORI-PEINSRQWSA-N 0.000 description 1
- 229960002985 medroxyprogesterone acetate Drugs 0.000 description 1
- RQZAXGRLVPAYTJ-GQFGMJRRSA-N megestrol acetate Chemical compound C1=C(C)C2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(C)=O)(OC(=O)C)[C@@]1(C)CC2 RQZAXGRLVPAYTJ-GQFGMJRRSA-N 0.000 description 1
- 229960004296 megestrol acetate Drugs 0.000 description 1
- SGDBTWWWUNNDEQ-LBPRGKRZSA-N melphalan Chemical compound OC(=O)[C@@H](N)CC1=CC=C(N(CCCl)CCCl)C=C1 SGDBTWWWUNNDEQ-LBPRGKRZSA-N 0.000 description 1
- 229960001924 melphalan Drugs 0.000 description 1
- 229960001428 mercaptopurine Drugs 0.000 description 1
- 229960004635 mesna Drugs 0.000 description 1
- 230000037353 metabolic pathway Effects 0.000 description 1
- 229960000485 methotrexate Drugs 0.000 description 1
- YUUAYBAIHCDHHD-UHFFFAOYSA-N methyl 5-aminolevulinate Chemical compound COC(=O)CCC(=O)CN YUUAYBAIHCDHHD-UHFFFAOYSA-N 0.000 description 1
- 229960005033 methyl aminolevulinate Drugs 0.000 description 1
- JEWJRMKHSMTXPP-BYFNXCQMSA-M methylcobalamin Chemical compound C[Co+]N([C@]1([H])[C@H](CC(N)=O)[C@]\2(CCC(=O)NC[C@H](C)OP(O)(=O)OC3[C@H]([C@H](O[C@@H]3CO)N3C4=CC(C)=C(C)C=C4N=C3)O)C)C/2=C(C)\C([C@H](C/2(C)C)CCC(N)=O)=N\C\2=C\C([C@H]([C@@]/2(CC(N)=O)C)CCC(N)=O)=N\C\2=C(C)/C2=N[C@]1(C)[C@@](C)(CC(N)=O)[C@@H]2CCC(N)=O JEWJRMKHSMTXPP-BYFNXCQMSA-M 0.000 description 1
- 235000007672 methylcobalamin Nutrition 0.000 description 1
- 239000011585 methylcobalamin Substances 0.000 description 1
- 229960004584 methylprednisolone Drugs 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- JMUHBNWAORSSBD-WKYWBUFDSA-N mifamurtide Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@@H](OC(=O)CCCCCCCCCCCCCCC)COP(O)(=O)OCCNC(=O)[C@H](C)NC(=O)CC[C@H](C(N)=O)NC(=O)[C@H](C)NC(=O)[C@@H](C)O[C@H]1[C@H](O)[C@@H](CO)OC(O)[C@@H]1NC(C)=O JMUHBNWAORSSBD-WKYWBUFDSA-N 0.000 description 1
- 229960005225 mifamurtide Drugs 0.000 description 1
- PQLXHQMOHUQAKB-UHFFFAOYSA-N miltefosine Chemical compound CCCCCCCCCCCCCCCCOP([O-])(=O)OCC[N+](C)(C)C PQLXHQMOHUQAKB-UHFFFAOYSA-N 0.000 description 1
- 229960003775 miltefosine Drugs 0.000 description 1
- DYKFCLLONBREIL-KVUCHLLUSA-N minocycline Chemical compound C([C@H]1C2)C3=C(N(C)C)C=CC(O)=C3C(=O)C1=C(O)[C@@]1(O)[C@@H]2[C@H](N(C)C)C(O)=C(C(N)=O)C1=O DYKFCLLONBREIL-KVUCHLLUSA-N 0.000 description 1
- 229960004023 minocycline Drugs 0.000 description 1
- VMMKGHQPQIEGSQ-UHFFFAOYSA-N minodronic acid Chemical compound C1=CC=CN2C(CC(O)(P(O)(O)=O)P(O)(O)=O)=CN=C21 VMMKGHQPQIEGSQ-UHFFFAOYSA-N 0.000 description 1
- 229950011129 minodronic acid Drugs 0.000 description 1
- CFCUWKMKBJTWLW-BKHRDMLASA-N mithramycin Chemical compound O([C@@H]1C[C@@H](O[C@H](C)[C@H]1O)OC=1C=C2C=C3C[C@H]([C@@H](C(=O)C3=C(O)C2=C(O)C=1C)O[C@@H]1O[C@H](C)[C@@H](O)[C@H](O[C@@H]2O[C@H](C)[C@H](O)[C@H](O[C@@H]3O[C@H](C)[C@@H](O)[C@@](C)(O)C3)C2)C1)[C@H](OC)C(=O)[C@@H](O)[C@@H](C)O)[C@H]1C[C@@H](O)[C@H](O)[C@@H](C)O1 CFCUWKMKBJTWLW-BKHRDMLASA-N 0.000 description 1
- 239000002829 mitogen activated protein kinase inhibitor Substances 0.000 description 1
- 229960004857 mitomycin Drugs 0.000 description 1
- 229960000350 mitotane Drugs 0.000 description 1
- KKZJGLLVHKMTCM-UHFFFAOYSA-N mitoxantrone Chemical compound O=C1C2=C(O)C=CC(O)=C2C(=O)C2=C1C(NCCNCCO)=CC=C2NCCNCCO KKZJGLLVHKMTCM-UHFFFAOYSA-N 0.000 description 1
- 229960001156 mitoxantrone Drugs 0.000 description 1
- 238000002715 modification method Methods 0.000 description 1
- 239000001788 mono and diglycerides of fatty acids Substances 0.000 description 1
- CQDGTJPVBWZJAZ-UHFFFAOYSA-N monoethyl carbonate Chemical compound CCOC(O)=O CQDGTJPVBWZJAZ-UHFFFAOYSA-N 0.000 description 1
- VMGAPWLDMVPYIA-HIDZBRGKSA-N n'-amino-n-iminomethanimidamide Chemical compound N\N=C\N=N VMGAPWLDMVPYIA-HIDZBRGKSA-N 0.000 description 1
- RWHUEXWOYVBUCI-ITQXDASVSA-N nafarelin Chemical compound C([C@@H](C(=O)N[C@H](CC=1C=C2C=CC=CC2=CC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCN=C(N)N)C(=O)N1[C@@H](CCC1)C(=O)NCC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H]1NC(=O)CC1)C1=CC=C(O)C=C1 RWHUEXWOYVBUCI-ITQXDASVSA-N 0.000 description 1
- 229960002333 nafarelin Drugs 0.000 description 1
- 230000017074 necrotic cell death Effects 0.000 description 1
- 229950007221 nedaplatin Drugs 0.000 description 1
- CTMCWCONSULRHO-UHQPFXKFSA-N nemorubicin Chemical compound C1CO[C@H](OC)CN1[C@@H]1[C@H](O)[C@H](C)O[C@@H](O[C@@H]2C3=C(O)C=4C(=O)C5=C(OC)C=CC=C5C(=O)C=4C(O)=C3C[C@](O)(C2)C(=O)CO)C1 CTMCWCONSULRHO-UHQPFXKFSA-N 0.000 description 1
- 229950010159 nemorubicin Drugs 0.000 description 1
- 229940029345 neupogen Drugs 0.000 description 1
- XWXYUMMDTVBTOU-UHFFFAOYSA-N nilutamide Chemical compound O=C1C(C)(C)NC(=O)N1C1=CC=C([N+]([O-])=O)C(C(F)(F)F)=C1 XWXYUMMDTVBTOU-UHFFFAOYSA-N 0.000 description 1
- 229960002653 nilutamide Drugs 0.000 description 1
- 238000010899 nucleation Methods 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 229960000770 ondansetron hydrochloride Drugs 0.000 description 1
- 229940100688 oral solution Drugs 0.000 description 1
- 229960001756 oxaliplatin Drugs 0.000 description 1
- DWAFYCQODLXJNR-BNTLRKBRSA-L oxaliplatin Chemical compound O1C(=O)C(=O)O[Pt]11N[C@@H]2CCCC[C@H]2N1 DWAFYCQODLXJNR-BNTLRKBRSA-L 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- OLDRWYVIKMSFFB-SSPJITILSA-N palonosetron hydrochloride Chemical compound Cl.C1N(CC2)CCC2[C@@H]1N1C(=O)C(C=CC=C2CCC3)=C2[C@H]3C1 OLDRWYVIKMSFFB-SSPJITILSA-N 0.000 description 1
- 229960003359 palonosetron hydrochloride Drugs 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 244000052769 pathogen Species 0.000 description 1
- HQQSBEDKMRHYME-UHFFFAOYSA-N pefloxacin mesylate Chemical compound [H+].CS([O-])(=O)=O.C1=C2N(CC)C=C(C(O)=O)C(=O)C2=CC(F)=C1N1CCN(C)CC1 HQQSBEDKMRHYME-UHFFFAOYSA-N 0.000 description 1
- 229960001744 pegaspargase Drugs 0.000 description 1
- 108010001564 pegaspargase Proteins 0.000 description 1
- 229940002988 pegasys Drugs 0.000 description 1
- 108010044644 pegfilgrastim Proteins 0.000 description 1
- 229960001373 pegfilgrastim Drugs 0.000 description 1
- 108010092853 peginterferon alfa-2a Proteins 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- 229960002340 pentostatin Drugs 0.000 description 1
- FPVKHBSQESCIEP-JQCXWYLXSA-N pentostatin Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(N=CNC[C@H]2O)=C2N=C1 FPVKHBSQESCIEP-JQCXWYLXSA-N 0.000 description 1
- 235000019319 peptone Nutrition 0.000 description 1
- 239000002304 perfume Substances 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 150000002994 phenylalanines Chemical class 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 229940043441 phosphoinositide 3-kinase inhibitor Drugs 0.000 description 1
- 229960004838 phosphoric acid Drugs 0.000 description 1
- 230000004962 physiological condition Effects 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 229940096701 plain lipid modifying drug hmg coa reductase inhibitors Drugs 0.000 description 1
- 229960003171 plicamycin Drugs 0.000 description 1
- 229920000435 poly(dimethylsiloxane) Polymers 0.000 description 1
- 125000003367 polycyclic group Chemical group 0.000 description 1
- 229920000136 polysorbate Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 229960004293 porfimer sodium Drugs 0.000 description 1
- OXCMYAYHXIHQOA-UHFFFAOYSA-N potassium;[2-butyl-5-chloro-3-[[4-[2-(1,2,4-triaza-3-azanidacyclopenta-1,4-dien-5-yl)phenyl]phenyl]methyl]imidazol-4-yl]methanol Chemical compound [K+].CCCCC1=NC(Cl)=C(CO)N1CC1=CC=C(C=2C(=CC=CC=2)C2=N[N-]N=N2)C=C1 OXCMYAYHXIHQOA-UHFFFAOYSA-N 0.000 description 1
- 229960004694 prednimustine Drugs 0.000 description 1
- 229940063238 premarin Drugs 0.000 description 1
- 239000013630 prepared media Substances 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- CPTBDICYNRMXFX-UHFFFAOYSA-N procarbazine Chemical compound CNNCC1=CC=C(C(=O)NC(C)C)C=C1 CPTBDICYNRMXFX-UHFFFAOYSA-N 0.000 description 1
- 229960000624 procarbazine Drugs 0.000 description 1
- RJKFOVLPORLFTN-UHFFFAOYSA-N progesterone acetate Natural products C1CC2=CC(=O)CCC2(C)C2C1C1CCC(C(=O)C)C1(C)CC2 RJKFOVLPORLFTN-UHFFFAOYSA-N 0.000 description 1
- 235000013772 propylene glycol Nutrition 0.000 description 1
- 239000003207 proteasome inhibitor Substances 0.000 description 1
- 239000003197 protein kinase B inhibitor Substances 0.000 description 1
- 239000003909 protein kinase inhibitor Substances 0.000 description 1
- 238000010926 purge Methods 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 239000010453 quartz Substances 0.000 description 1
- 150000003856 quaternary ammonium compounds Chemical class 0.000 description 1
- 229960004622 raloxifene Drugs 0.000 description 1
- GZUITABIAKMVPG-UHFFFAOYSA-N raloxifene Chemical compound C1=CC(O)=CC=C1C1=C(C(=O)C=2C=CC(OCCN3CCCCC3)=CC=2)C2=CC=C(O)C=C2S1 GZUITABIAKMVPG-UHFFFAOYSA-N 0.000 description 1
- 229960004432 raltitrexed Drugs 0.000 description 1
- 229960000424 rasburicase Drugs 0.000 description 1
- 108010084837 rasburicase Proteins 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- BOLDJAUMGUJJKM-LSDHHAIUSA-N renifolin D Natural products CC(=C)[C@@H]1Cc2c(O)c(O)ccc2[C@H]1CC(=O)c3ccc(O)cc3O BOLDJAUMGUJJKM-LSDHHAIUSA-N 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- WUAPFZMCVAUBPE-IGMARMGPSA-N rhenium-186 Chemical compound [186Re] WUAPFZMCVAUBPE-IGMARMGPSA-N 0.000 description 1
- 235000009566 rice Nutrition 0.000 description 1
- 229960004641 rituximab Drugs 0.000 description 1
- 239000003419 rna directed dna polymerase inhibitor Substances 0.000 description 1
- 229960005399 satraplatin Drugs 0.000 description 1
- 190014017285 satraplatin Chemical compound 0.000 description 1
- 239000000849 selective androgen receptor modulator Substances 0.000 description 1
- 229960003440 semustine Drugs 0.000 description 1
- 239000011257 shell material Substances 0.000 description 1
- 150000004760 silicates Chemical class 0.000 description 1
- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicon dioxide Inorganic materials O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- PTJRZVJXXNYNLN-UHFFFAOYSA-M sodium;2h-pyrazolo[3,4-d]pyrimidin-1-id-4-one Chemical compound [Na+].[O-]C1=NC=NC2=C1C=NN2 PTJRZVJXXNYNLN-UHFFFAOYSA-M 0.000 description 1
- 229960003787 sorafenib Drugs 0.000 description 1
- 239000002594 sorbent Substances 0.000 description 1
- 239000003549 soybean oil Substances 0.000 description 1
- 235000012424 soybean oil Nutrition 0.000 description 1
- 238000011895 specific detection Methods 0.000 description 1
- 235000013599 spices Nutrition 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 238000009168 stem cell therapy Methods 0.000 description 1
- 238000009580 stem-cell therapy Methods 0.000 description 1
- 229960001052 streptozocin Drugs 0.000 description 1
- ZSJLQEPLLKMAKR-GKHCUFPYSA-N streptozocin Chemical compound O=NN(C)C(=O)N[C@H]1[C@@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O ZSJLQEPLLKMAKR-GKHCUFPYSA-N 0.000 description 1
- 229910052712 strontium Inorganic materials 0.000 description 1
- CIOAGBVUUVVLOB-UHFFFAOYSA-N strontium atom Chemical compound [Sr] CIOAGBVUUVVLOB-UHFFFAOYSA-N 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000010414 supernatant solution Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 229960002613 tamsulosin Drugs 0.000 description 1
- 229940120982 tarceva Drugs 0.000 description 1
- 229940063683 taxotere Drugs 0.000 description 1
- 229960004964 temozolomide Drugs 0.000 description 1
- 229960000235 temsirolimus Drugs 0.000 description 1
- NRUKOCRGYNPUPR-QBPJDGROSA-N teniposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@@H](OC[C@H]4O3)C=3SC=CC=3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 NRUKOCRGYNPUPR-QBPJDGROSA-N 0.000 description 1
- 229960001278 teniposide Drugs 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 229960003604 testosterone Drugs 0.000 description 1
- 229960001712 testosterone propionate Drugs 0.000 description 1
- 229960001196 thiotepa Drugs 0.000 description 1
- LCJVIYPJPCBWKS-NXPQJCNCSA-N thymosin Chemical compound SC[C@@H](N)C(=O)N[C@H](CO)C(=O)N[C@H](CC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](C)C(=O)N[C@H](C(C)C)C(=O)N[C@H](CC(O)=O)C(=O)N[C@H](C(C)C)C(=O)N[C@H](CO)C(=O)N[C@H](CO)C(=O)N[C@H](CCC(O)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@H]([C@H](C)O)C(=O)N[C@H](C(C)C)C(=O)N[C@H](CCCCN)C(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(C)C)C(=O)N[C@H](CCCCN)C(=O)N[C@H](CCC(O)=O)C(=O)N[C@H](CCCCN)C(=O)N[C@H](CCCCN)C(=O)N[C@H](CCC(O)=O)C(=O)N[C@H](C(C)C)C(=O)N[C@H](C(C)C)C(=O)N[C@H](CCC(O)=O)C(=O)N[C@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@H](CCC(O)=O)C(O)=O LCJVIYPJPCBWKS-NXPQJCNCSA-N 0.000 description 1
- 229960000874 thyrotropin Drugs 0.000 description 1
- 230000001748 thyrotropin Effects 0.000 description 1
- 229960005324 tiludronic acid Drugs 0.000 description 1
- 229960003087 tioguanine Drugs 0.000 description 1
- MNRILEROXIRVNJ-UHFFFAOYSA-N tioguanine Chemical compound N1C(N)=NC(=S)C2=NC=N[C]21 MNRILEROXIRVNJ-UHFFFAOYSA-N 0.000 description 1
- 229950009158 tipifarnib Drugs 0.000 description 1
- PLHJCIYEEKOWNM-HHHXNRCGSA-N tipifarnib Chemical compound CN1C=NC=C1[C@](N)(C=1C=C2C(C=3C=C(Cl)C=CC=3)=CC(=O)N(C)C2=CC=1)C1=CC=C(Cl)C=C1 PLHJCIYEEKOWNM-HHHXNRCGSA-N 0.000 description 1
- 229950002376 tirapazamine Drugs 0.000 description 1
- QVMPZNRFXAKISM-UHFFFAOYSA-N tirapazamine Chemical compound C1=CC=C2[N+]([O-])=NC(=N)N(O)C2=C1 QVMPZNRFXAKISM-UHFFFAOYSA-N 0.000 description 1
- 238000000954 titration curve Methods 0.000 description 1
- 229940044693 topoisomerase inhibitor Drugs 0.000 description 1
- UCFGDBYHRUNTLO-QHCPKHFHSA-N topotecan Chemical compound C1=C(O)C(CN(C)C)=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 UCFGDBYHRUNTLO-QHCPKHFHSA-N 0.000 description 1
- 229960000303 topotecan Drugs 0.000 description 1
- 229960005267 tositumomab Drugs 0.000 description 1
- 239000003558 transferase inhibitor Substances 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 230000001131 transforming effect Effects 0.000 description 1
- 229960000575 trastuzumab Drugs 0.000 description 1
- 229960001727 tretinoin Drugs 0.000 description 1
- UAEJRRZPRZCUBE-UHFFFAOYSA-N trimethoxyalumane Chemical compound [Al+3].[O-]C.[O-]C.[O-]C UAEJRRZPRZCUBE-UHFFFAOYSA-N 0.000 description 1
- UCPYLLCMEDAXFR-UHFFFAOYSA-N triphosgene Chemical compound ClC(Cl)(Cl)OC(=O)OC(Cl)(Cl)Cl UCPYLLCMEDAXFR-UHFFFAOYSA-N 0.000 description 1
- 229960000434 triptorelin acetate Drugs 0.000 description 1
- 229960000294 triptorelin pamoate Drugs 0.000 description 1
- 239000012588 trypsin Substances 0.000 description 1
- 125000000430 tryptophan group Chemical group [H]N([H])C(C(=O)O*)C([H])([H])C1=C([H])N([H])C2=C([H])C([H])=C([H])C([H])=C12 0.000 description 1
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 1
- KIGCDEJCMKDBHU-NIQQUOCOSA-K ukrain Chemical compound [OH-].[OH-].[OH-].C([C@H](O)[C@@H]1C2=CC=C3OCOC3=C2C2)C3=CC=4OCOC=4C=C3[C@H]1[N+]2(C)CCNP(=S)(NCC[N+]1(C)[C@@H]2C3=CC=4OCOC=4C=C3C[C@H](O)[C@@H]2C2=CC=C3OCOC3=C2C1)NCC[N+]1(C)[C@@H]2C3=CC(OCO4)=C4C=C3C[C@H](O)[C@@H]2C2=CC=C3OCOC3=C2C1 KIGCDEJCMKDBHU-NIQQUOCOSA-K 0.000 description 1
- DRTQHJPVMGBUCF-UHFFFAOYSA-N uracil arabinoside Natural products OC1C(O)C(CO)OC1N1C(=O)NC(=O)C=C1 DRTQHJPVMGBUCF-UHFFFAOYSA-N 0.000 description 1
- 229940045145 uridine Drugs 0.000 description 1
- 229960000653 valrubicin Drugs 0.000 description 1
- ZOCKGBMQLCSHFP-KQRAQHLDSA-N valrubicin Chemical compound O([C@H]1C[C@](CC2=C(O)C=3C(=O)C4=CC=CC(OC)=C4C(=O)C=3C(O)=C21)(O)C(=O)COC(=O)CCCC)[C@H]1C[C@H](NC(=O)C(F)(F)F)[C@H](O)[C@H](C)O1 ZOCKGBMQLCSHFP-KQRAQHLDSA-N 0.000 description 1
- 229950010938 valspodar Drugs 0.000 description 1
- 108010082372 valspodar Proteins 0.000 description 1
- 229960002730 vapreotide Drugs 0.000 description 1
- 108700029852 vapreotide Proteins 0.000 description 1
- 229950000578 vatalanib Drugs 0.000 description 1
- YCOYDOIWSSHVCK-UHFFFAOYSA-N vatalanib Chemical compound C1=CC(Cl)=CC=C1NC(C1=CC=CC=C11)=NN=C1CC1=CC=NC=C1 YCOYDOIWSSHVCK-UHFFFAOYSA-N 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 229960003895 verteporfin Drugs 0.000 description 1
- ZQFGRJWRSLZCSQ-ZSFNYQMMSA-N verteporfin Chemical compound C=1C([C@@]2([C@H](C(=O)OC)C(=CC=C22)C(=O)OC)C)=NC2=CC(C(=C2C=C)C)=NC2=CC(C(=C2CCC(O)=O)C)=NC2=CC2=NC=1C(C)=C2CCC(=O)OC ZQFGRJWRSLZCSQ-ZSFNYQMMSA-N 0.000 description 1
- 229960003048 vinblastine Drugs 0.000 description 1
- JXLYSJRDGCGARV-XQKSVPLYSA-N vincaleukoblastine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 JXLYSJRDGCGARV-XQKSVPLYSA-N 0.000 description 1
- 229960004528 vincristine Drugs 0.000 description 1
- OGWKCGZFUXNPDA-UHFFFAOYSA-N vincristine Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(OC(C)=O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-UHFFFAOYSA-N 0.000 description 1
- NMDYYWFGPIMTKO-HBVLKOHWSA-N vinflunine Chemical compound C([C@@](C1=C(C2=CC=CC=C2N1)C1)(C2=C(OC)C=C3N(C)[C@@H]4[C@@]5(C3=C2)CCN2CC=C[C@]([C@@H]52)([C@H]([C@]4(O)C(=O)OC)OC(C)=O)CC)C(=O)OC)[C@H]2C[C@@H](C(C)(F)F)CN1C2 NMDYYWFGPIMTKO-HBVLKOHWSA-N 0.000 description 1
- 229960000922 vinflunine Drugs 0.000 description 1
- GBABOYUKABKIAF-GHYRFKGUSA-N vinorelbine Chemical compound C1N(CC=2C3=CC=CC=C3NC=22)CC(CC)=C[C@H]1C[C@]2(C(=O)OC)C1=CC([C@]23[C@H]([C@]([C@H](OC(C)=O)[C@]4(CC)C=CCN([C@H]34)CC2)(O)C(=O)OC)N2C)=C2C=C1OC GBABOYUKABKIAF-GHYRFKGUSA-N 0.000 description 1
- 229960002066 vinorelbine Drugs 0.000 description 1
- 229960004276 zoledronic acid Drugs 0.000 description 1
- XRASPMIURGNCCH-UHFFFAOYSA-N zoledronic acid Chemical compound OP(=O)(O)C(P(O)(O)=O)(O)CN1C=CN=C1 XRASPMIURGNCCH-UHFFFAOYSA-N 0.000 description 1
- ZAFYATHCZYHLPB-UHFFFAOYSA-N zolpidem Chemical compound N1=C2C=CC(C)=CN2C(CC(=O)N(C)C)=C1C1=CC=C(C)C=C1 ZAFYATHCZYHLPB-UHFFFAOYSA-N 0.000 description 1
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
- A61K47/59—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes
- A61K47/60—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
Definitions
- the invention relates to the technical fields of polymer materials and medicines, in particular to a pH-sensitive membrane-breaking polypeptide and its application.
- Some amphiphilic polymers with cationic groups can kill pathogens such as tumor cells and bacteria by destroying cell membranes. This form of killing that does not rely on metabolic pathways has the advantages of broad-spectrum killing effects and is not easy to produce drug resistance. It has broad application prospects in the treatment of infectious diseases.
- the interaction between the membrane-breaking polymer material and the cell membrane is mainly through electrostatic and hydrophobic interactions. First, the cationic domain of the polymer and the negatively charged cell membrane electrostatic interaction are used to bind to the surface of the cell membrane, and then the hydrophobic domain of the polymer is inserted into the lipid layer of the cell membrane. , forming irreparable membrane damage on the cell membrane, thereby killing the cell.
- amphiphilic conformation composed of cationic groups and hydrophobic groups is the key structure for the interaction between macromolecular materials and cell membranes, and it is also an important cause of cytotoxicity to normal tissue cells.
- the ratio of the two structures is very important for its interaction with the cell membrane.
- pure cationic polymers are easy to bind to the cell membrane but difficult to insert into the cell membrane, while polymers with a hydrophobic structure are difficult to bind to the surface of the cell membrane and cannot effectively damage the cell membrane.
- the research group has previously prepared a polymethacrylate polymer material with a tertiary amine side chain that has membrane-breaking activity.
- the main chain of polymethacrylate is difficult to degrade, and long-term use can easily cause toxicity when accumulated in the body.
- the present invention provides a pH-sensitive membrane-breaking polypeptide material with side groups containing tertiary amines and hydrophobic groups.
- the macromolecular material is hydrophobic and electrically neutral at normal physiological pH, and its interaction with cell membranes Weak; under slightly acidic pH conditions, it can be protonated to form an amphiphilic structure composed of a hydrophobic domain and a cationic domain, which has a strong interaction with the cell membrane and has strong membrane breaking activity, so it can kill efficiently and selectively Tumor cells or bacteria.
- the present invention includes the following technical solutions.
- R is selected from: -R 3 -N(R 4 R 5 ), -R 3 -R',
- R' is selected from:
- R 1 is selected from: alkylene
- R 2 is selected from: C 1 -C 12 alkyl, C 6 -C 14 aryl, C 1 -C 12 alkyl substituted by C 6 -C 14 aryl, C 1 -C 12 alkyl substituted by benzyloxycarbonyl , 5-10 membered heteroaryl substituted C 1 -C 12 alkyl;
- R 3 is selected from: alkylene, C 6 -C 14 aryl substituted alkylene;
- R 4 and R 5 are independently selected from: alkyl, C 6 -C 14 aryl substituted alkyl, or R 3 , R 4 and the nitrogen atom connected to them together form a heterocycloalkyl;
- y is selected from: 2-150;
- R 6 is selected from: C 1 -C 15 alkyl, C 6 -C 14 aryl, C 6 -C 14 aryl substituted C 1 -C 15 alkyl;
- n+m is greater than 0, and n is not 0;
- q is selected from: 0, 1, 2, 3, 4.
- the present invention also provides a membrane-breaking polypeptide nanoparticle, including the following technical solutions.
- a membrane-breaking polypeptide nanoparticle is formed by self-assembling the above-mentioned membrane-breaking polypeptide in an aqueous medium.
- the present invention also provides a method for preparing membrane-disrupting polypeptide nanoparticles, including the following technical solutions.
- a method for preparing membrane-breaking polypeptide nanoparticles comprising the following steps: dissolving the membrane-breaking polypeptide in an organic solvent or a hydrochloric acid solution with a pH of 1.5-2.5, and then adding the obtained solution dropwise into water under stirring , continue stirring, low-temperature dialysis to remove the solvent, and obtain the membrane-breaking polypeptide nanoparticles.
- the present invention also provides the application of the above-mentioned membrane-breaking polypeptide or membrane-breaking polypeptide nanoparticles, including the following technical solutions.
- membrane-breaking polypeptide or its stereoisomer or its pharmaceutically acceptable salt in the preparation of drugs for preventing and/or treating tumors.
- membrane-breaking polypeptide nanoparticle in the preparation of drugs for preventing and/or treating tumors.
- membrane-breaking polypeptide or its stereoisomer or its pharmaceutically acceptable salt in combination with an immune checkpoint inhibitor in the preparation of a drug for preventing and/or treating tumors.
- membrane-breaking polypeptide or its stereoisomer or its pharmaceutically acceptable salt in the preparation of anti-bacterial infection medicine.
- the present invention also provides a drug for preventing and/or treating tumors, including the following technical solutions.
- a drug for preventing and/or treating tumors prepared from active ingredients and pharmaceutically acceptable adjuvants and/or carriers, the active ingredients include the membrane-breaking polypeptide or its stereoisomer or its pharmaceutical Acceptable salts, and/or the membrane-breaking polypeptide nanoparticles.
- the present invention also provides a combined drug for preventing and/or treating tumors, including the following technical solutions.
- a combined drug for preventing and/or treating tumors the active ingredients of which include:
- Component 1 the membrane-breaking polypeptide or its stereoisomer or pharmaceutically acceptable salt thereof, and/or the membrane-breaking polypeptide nanoparticles;
- Component 2 Antineoplastic drugs other than Component 1;
- the component 1 and component 2 respectively become independent administration units, or the components 1 and 2 jointly form a combined administration unit.
- the present invention also provides a drug for antibacterial infection, including the following technical solutions.
- a drug against bacterial infection prepared from an active ingredient and a pharmaceutically acceptable adjuvant and/or carrier, the active ingredient includes the membrane-breaking polypeptide or its stereoisomer or its pharmaceutically acceptable salt, and/or the membrane-breaking polypeptide nanoparticles.
- the present invention provides a membrane-breaking polypeptide material modified by tertiary amines.
- the macromolecular material is hydrophobic and electrically neutral at normal physiological pH, and the polypeptide fragments are hydrophobic, and the interaction with the cell membrane is weak, so that it can It has the advantage of low toxicity to normal tissues during circulation in the body; under the slightly acidic pH conditions of tumor tissue or bacterial infection, the tertiary amine part of the macromolecular material will be protonated, so that the polypeptide fragments form hydrophobic domains and cations
- the amphiphilic structure composed of domains makes it have a strong interaction with the cell membrane and a strong membrane breaking activity, so that it can kill tumor cells and bacteria efficiently and selectively.
- the present invention also finds that the selectivity of the polypeptide containing the benzene ring structure can be improved.
- the membrane-breaking polypeptide macromolecular material of the present invention can be used to prepare antitumor or antibacterial drugs, and has the advantages of good antitumor and antibacterial effects, high selectivity and low toxicity. And because the polymerized polypeptide has the advantages of degradability and no biotoxicity of the degradation product, it will have a wider range of biomedical applications.
- Figure 1 is the gel permeation chromatogram of mPEG 44 -PLys(Z) 33 .
- Figure 2 is the H NMR spectrum of mPEG 44 -PLys(Z) 33 .
- Figure 3 is the H NMR spectrum of mPEG 44 -PLys 33 .
- Figure 4 is the H NMR spectrum of DE-CDI.
- Figure 5 is the H NMR spectrum of mPEG 44 -PLys-DE 33 .
- Fig. 6 is the protonation curve (A) and the helicity change curve (B) of the tertiary amine-modified polypeptide in Example 1.
- Fig. 7 is the H NMR spectra of peptides modified with different alkylene groups as R3 .
- Fig. 8 is the protonation curve (A) and the helicity change curve (B) of R3 being different alkylene modified polypeptides.
- Fig. 9 is a gel permeation chromatogram of DE tertiary amine-modified different polyethylene glycol-triggered polypeptides.
- Figure 10 is the H NMR spectra of different polyethylene glycol-triggered peptides modified by DE tertiary amines.
- Figure 11 is the protonation curves of PEG-initiated peptides with different degrees of polymerization.
- Figure 12 is the H NMR spectra of mPEG 44 -PLys 86 modified with different tertiary amines.
- Figure 13 is the protonation curve (A) and helicity curve (B) of mPEG 44 -PLys 86 modified with different tertiary amines.
- Fig. 14 is a gel permeation chromatogram of peptides with different degrees of polymerization obtained by triggering Lys(Z)-NCA with mPEG 44 -NH 2 .
- Figure 15 is the H NMR spectra of polylysine with different degrees of polymerization.
- Fig. 16 is the protonation curve (A) and the helicity change curve (B) of the polypeptide mPEG 44 -PLys n -DB with different degrees of polymerization.
- Fig. 17 is the H NMR spectra of C5P2 tertiary amine-modified polypeptides with different degrees of polymerization.
- Fig. 18 is the H NMR spectra of C5P tertiary amine-modified polypeptides with different degrees of polymerization.
- Figure 19 is the H NMR spectra of C6P tertiary amine-modified polypeptides with different degrees of polymerization.
- Figure 20 is the H NMR spectra of DB tertiary amine modified polypeptides with different degrees of polymerization.
- Fig. 21 is the H NMR spectra of DMP2 tertiary amine-modified polypeptides with different degrees of polymerization.
- Figure 22 is the H NMR spectra of DMP tertiary amine modified polypeptides with different degrees of polymerization.
- Figure 23 is the H NMR spectrum of mPEG 44 -PLys-CC6 86 .
- Figure 24 is the protonation rate curve of mPEG 44 -PLys-CC6 86 .
- FIG. 25 is a gel permeation chromatogram of mPEG 44 -PBLG 30 .
- Figure 26 is the H NMR spectrum of mPEG 44 -PBLG 30 .
- Figure 27 is the H NMR spectrum of mPEG 44 -PLG-DB 30 .
- Fig. 28 is the protonation rate curve of mPEG 44 -PLG-DB 30 .
- Figure 29 shows the hemolytic activity of polypeptides modified with different tertiary amines with different degrees of polymerization.
- Fig. 32 is the 24h cell killing curves of mPEG 44 -PLys-C6P 10 on MC38 (A) and Panc02 (B) at different pHs.
- Figure 33 is the 4h cell killing curves of mPEG 44 -PLys-DB 86 on MC38 (A) and Panc02 (B) at different pH.
- Figure 35 is the in vivo tumor therapeutic effect of mPEG 44 -PLys-DB 86 and its combined therapeutic effect with ⁇ PD1; wherein, A is a schematic diagram of the dosage regimen; B is the in vivo tumor therapeutic effect of mPEG 44 -PLys-DB 86 at different doses ; C is the combined treatment effect of mPEG 44 -PLys-DB 86 and ⁇ PD1.
- Figure 36 shows the antibacterial activity of polypeptides modified with different tertiary amines with different degrees of polymerization.
- Figure 37 shows the antibacterial activity of mPEG 44 -PLys-C5P 33 at different pHs.
- Fig. 38 is a gel permeation chromatogram of a polypeptide obtained by copolymerization of leucine and lysine (protected by benzyloxycarbonyl) in different ratios.
- Figure 39 is the H NMR spectrum of the polypeptide obtained by copolymerization of leucine and lysine in different proportions.
- Figure 40 is the H NMR spectrum of the peptide obtained by copolymerization of N-hydroxyethylpiperidine modified leucine and lysine in different proportions.
- Fig. 41 is the H NMR spectrum of the polypeptide obtained by copolymerization of 2-(hexamethyleneimine) ethanol-modified leucine and lysine in different proportions.
- Figure 42 is the protonation rate curve (A) and helicity curve (B) of the polypeptide obtained by copolymerization of N-hydroxyethylpiperidine modified leucine and lysine in different proportions.
- Figure 43 is the protonation rate curve (A) and helicity curve (B) of the polypeptide obtained by copolymerization of 2-(hexamethyleneimine) ethanol-modified leucine and lysine in different proportions.
- Fig. 44 is the gel permeation chromatogram of the peptide obtained by the copolymerization of phenylalanine and lysine (protected by benzyloxycarbonyl group) with different ratios initiated by mPEG 44 -NH 2 .
- Figure 45 is the H NMR spectrum of the peptide obtained by the copolymerization of phenylalanine and lysine (protected by benzyloxycarbonyl group) with different ratios initiated by mPEG 44 -NH 2 .
- Figure 46 is the NMR spectrum of the peptide obtained by N-hydroxyethylpiperidine modification of phenylalanine and lysine in different proportions of copolymerization.
- Figure 47 is the H NMR spectrum of the polypeptide obtained by copolymerization of 2-(hexamethyleneimine) ethanol-modified phenylalanine and lysine in different proportions.
- Figure 48 is the protonation rate curve of the peptide obtained by copolymerization of N-hydroxyethylpiperidine (A) and 2-(hexamethyleneimine) ethanol (B) modified in different proportions of phenylalanine and lysine.
- Fig. 49 is the gel permeation chromatogram of the peptide obtained by the copolymerization of phenylalanine and lysine (protected by benzyloxycarbonyl group) with different ratios initiated by mPEG 112 -NH 2 .
- Figure 50 is the H NMR spectrum of the peptide obtained by the copolymerization of phenylalanine and lysine in different proportions initiated by mPEG 112 -NH 2 .
- Figure 51 is the NMR spectrum of the peptide obtained by the copolymerization of phenylalanine and lysine in different proportions initiated by N-hydroxyethylpiperidine-modified mPEG 112 -NH 2 .
- Figure 52 is the protonation rate curve of the peptide obtained by the copolymerization of phenylalanine and lysine with different proportions initiated by N-hydroxyethylpiperidine-modified mPEG 112 -NH 2 .
- Fig. 53 is a gel permeation chromatogram of a peptide obtained by copolymerization of norleucine and lysine (benzyloxycarbonyl protected) in different ratios.
- Figure 54 is the H NMR spectra of the peptides obtained by copolymerization of norleucine and lysine (benzyloxycarbonyl protected) in different ratios.
- Figure 55 is the H NMR spectrum of the peptide obtained by copolymerization of norleucine and lysine in different proportions.
- Figure 56 is the NMR spectrum of the peptide obtained by copolymerization of N-hydroxyethylpiperidine-modified norleucine and lysine in different proportions.
- Figure 57 is the NMR spectrum of the peptide obtained by copolymerization of N-hydroxyethylpiperidine-modified L-aminocaprylic acid and lysine in different proportions.
- Figure 58 is the NMR spectrum of the peptide obtained by the 1:1 copolymerization of tryptophan and lysine modified by N-hydroxyethylpiperidine.
- Figure 59 shows the hemolytic activity of copolylysine with different hydrophobic amino acids modified by C6 tertiary amine.
- Figure 60 shows the selective killing of tumors by C6 tertiary amine-modified polylysine with different hydrophobic amino acids.
- Figure 61 shows the selective killing of tumors by C6 tertiary amine-modified tryptophan and lysine copolypeptides at different pHs.
- Fig. 62 shows that mPEG 44 -P(Lys-C6 50 -co-Trp 50 ) induces cell membrane damage to release LDH.
- Figure 63 is the tumor treatment effect of mPEG 44 -P(Lys-C6 50 -co-Trp 50 ) in vivo; where A is a schematic diagram of the dosage regimen, and B is the effect of mPEG 44 -P(Lys-C6 50 -co-Trp 50 ). Tumor treatment effect.
- the "plurality” mentioned in the present invention means two or more.
- “And/or” describes the association relationship of associated objects, indicating that there may be three types of relationships, for example, A and/or B may indicate: A exists alone, A and B exist simultaneously, and B exists independently.
- the character “/” generally indicates that the contextual objects are an "or” relationship.
- any variable eg, R1 , R2, etc.
- its definition at each occurrence is independent of its definition at each other occurrence.
- combinations of substituents and variables are permissible only if such combinations render the compounds stable.
- a line drawn from a substituent into a ring system indicates that the indicated bond may be attached to any substitutable ring atom. If the ring system is polycyclic it means that such bonds are only to any suitable carbon atoms of adjacent rings. It is understood that one of ordinary skill in the art can select substituents and substitution patterns on the compounds of the present invention to provide compounds that are chemically stable and can be readily synthesized from readily available starting materials by skill in the art and by methods set forth below. If a substituent is itself substituted with more than one group, it is understood that these groups may be on the same carbon atom or on different carbon atoms, so long as the structure is stabilized.
- alkyl is meant to include both branched and straight chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms.
- the definition of “C 1 -C 6 " in “C 1 -C 6 alkyl” includes groups having 1, 2, 3, 4, 5 or 6 carbon atoms arranged in a linear or branched chain.
- “C 1 -C 6 alkyl” specifically includes methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, pentyl, hexyl.
- alkylene refers to a group having one less hydrogen on the basis of "alkyl”, for example, -CH2- , -CH2CH2- , -CH2CH2CH2- , -CH2CH2 CH 2 CH 2 -etc.
- heterocycloalkyl is a saturated monocyclic cyclic substituent in which one or more ring atoms are heteroatoms selected from N, O or S(O)m (wherein m is an integer from 0 to 2), and the rest
- ring atoms are carbon, for example: piperidinyl, pyrrolidinyl and the like.
- One embodiment of the present invention provides a membrane-breaking polypeptide having a structure represented by formula (I) or its stereoisomer or its pharmaceutically acceptable salt:
- R is selected from: -R 3 -N(R 4 R 5 ), -R 3 -R',
- R' is selected from:
- R 1 is selected from: alkylene
- R 2 is selected from: C 1 -C 12 alkyl, C 6 -C 14 aryl, C 1 -C 12 alkyl substituted by C 6 -C 14 aryl, C 1 -C 12 alkyl substituted by benzyloxycarbonyl , 5-10 membered heteroaryl substituted C 1 -C 12 alkyl;
- R 3 is selected from: alkylene, C 6 -C 14 aryl substituted alkylene;
- R 4 and R 5 are independently selected from: alkyl, C 6 -C 14 aryl substituted alkyl, or R 3 , R 4 and the nitrogen atom connected to them together form a heterocycloalkyl;
- y is selected from: 2-150;
- R 6 is selected from: C 1 -C 15 alkyl, C 6 -C 14 aryl, C 6 -C 14 aryl substituted C 1 -C 15 alkyl;
- n+m is greater than 0, and n is not 0;
- q is selected from: 0, 1, 2, 3, 4.
- R 1 is selected from: C 1 -C 6 alkylene.
- R 1 is selected from: -(CH 2 ) x -, wherein, x is selected from: 1, 2, 3, 4, 5, 6.
- the membrane-breaking polypeptide has the structure shown in the following formula (II):
- X is: -O- or none.
- the membrane-breaking polypeptide has the structure shown in the following formula (III):
- R is selected from: -R 3 -N(R 4 R 5 ),
- R 3 is selected from: C 1 -C 6 alkylene, C 1 -C 6 alkylene substituted by phenyl.
- R 3 is selected from: -(CH 2 ) x -, -(CH 2 ) x substituted by phenyl; wherein, x is selected from: 1, 2, 3, 4, 5, 6.
- R 4 and R 5 are independently selected from: C 1 -C 12 alkyl, C 1 -C 6 alkyl substituted by phenyl, C 1 -C 6 alkyl substituted by naphthyl, Or R 4 , R 5 and the nitrogen atom connected to them together form a 5-10 membered heterocycloalkyl group.
- R 4 and R 5 are independently selected from: C 1 -C 6 alkyl, C 1 -C 3 alkyl substituted by phenyl, C 1 -C 3 alkyl substituted by naphthyl, Or R 4 , R 5 and the nitrogen atom connected to them together form a 5-8 membered heterocycloalkyl group.
- R 4 , R 5 and the nitrogen atom connected to them together form the following group:
- R 6 is selected from: C 1 -C 6 alkyl, phenyl, naphthyl, phenyl substituted C 1 -C 6 alkyl.
- R is selected from: -R 3 -N(R 4 R 5 ),
- R 3 is selected from: -CH 2 -CH 2 -, -CH 2 -CH 2 -CH 2 -, -CH 2 -(CH 2 ) 3 -CH 2 -, R 4 , R 5 and the nitrogen atom connected to them together form the following group:
- R 6 is benzyl
- R is selected from: C 1 -C 8 alkyl, phenyl, naphthyl, C 1 -C 6 alkyl substituted by phenyl, C 1 -C 6 alkyl substituted by benzyloxycarbonyl , 5-10 membered heteroaryl substituted C 1 -C 6 alkyl.
- R is selected from: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, pentyl, hexyl, heptyl, octyl, nonyl, Decyl, undecyl, dodecyl, phenyl, naphthyl, benzyl, benzyloxycarbonyl substituted ethyl, benzopyrrole substituted ethyl.
- y is selected from: 5-120.
- y is selected from: 30-120.
- y is selected from: 40-48 or 108-116.
- y is selected from: 9, 44, 112.
- n+m is not less than 5, more preferably not less than 10.
- n+m is 10-200, more preferably 10-150, more preferably 10-110.
- m is 0-60% of n+m, more preferably 0-50%.
- m is 0-30% of n+m.
- m is 0-25% of n+m.
- m is 10-23% of n+m.
- m is 15-25% of n+m.
- m is 25-35% of n+m.
- m is 35-45% of n+m.
- m is 40-50% of n+m.
- m is 45-50% of n+m.
- R is selected from: -R 3 -N(R 4 R 5 ),
- R 3 is -CH 2 -CH 2 -;
- R 4 , R 5 and the nitrogen atom connected to them together form the following group:
- R 6 is benzyl; y is 40-48.
- R is selected from: -R 3 -N(R 4 R 5 );
- R 3 is selected from: -CH 2 -CH 2 -; R 4 , R 5 and the nitrogen atom connected to them together form the following group:
- R2 is selected from: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, pentyl, hexyl, heptyl, octyl, nonyl, decanyl, undecane radical, dodecyl, phenyl, naphthyl, benzyl, ethyl substituted by benzyloxycarbonyl, ethyl substituted by benzopyrrole.
- the membrane-breaking polypeptide is selected from the following polymers:
- Another embodiment of the present invention also provides a membrane-disrupting polypeptide nanoparticle formed by self-assembly of the membrane-disrupting polypeptide in an aqueous medium.
- Another embodiment of the present invention also provides the preparation method of the membrane-breaking polypeptide nanoparticles, including the following steps: dissolving the membrane-breaking polypeptide in an organic solvent or a hydrochloric acid solution with a pH of 1.5-2.5 , and then add the obtained solution dropwise into water under stirring, continue to stir, and remove the solvent by low-temperature dialysis to obtain the membrane-breaking polypeptide nanoparticles.
- the organic solvent is N,N-dimethylformamide.
- the proportion of the membrane-breaking polypeptide, the organic solvent or hydrochloric acid solution, and the water is 10 mg-30 mg: 1 mL: 4-6 mL.
- the preparation method of the membrane-disrupting polypeptide nanoparticles comprises the following steps: dissolving the membrane-disrupting polypeptide in N, N-dimethylformamide at a ratio of 10 mg to 30 mg: 1 mL, and then Add the resulting solution dropwise into water under stirring at a speed of 400-800 rpm, continue stirring at a speed of 200-600 rpm for 8-20 minutes, and dialyze in water using a dialysis bag with a molecular weight cut-off of 10,000-20,000 The solvent is removed to obtain the membrane-breaking polypeptide nanoparticles.
- Another embodiment of the present invention also provides the use of the membrane-breaking polypeptide or its stereoisomer or its pharmaceutically acceptable salt in the preparation of drugs for preventing and/or treating tumors.
- Another embodiment of the present invention also provides the application of membrane-breaking polypeptide nanoparticles in the preparation of drugs for preventing and/or treating tumors.
- Another embodiment of the present invention also provides the use of the membrane-breaking polypeptide or its stereoisomer or its pharmaceutically acceptable salt in combination with immune checkpoint inhibitors in the preparation of drugs for preventing and/or treating tumors.
- Another embodiment of the present invention also provides the application of the membrane-breaking polypeptide nanoparticles combined with immune checkpoint inhibitors in the preparation of drugs for preventing and/or treating tumors.
- the immune checkpoint inhibitor is a PD-1 inhibitor.
- the tumor is pancreatic cancer, melanoma, colorectal cancer, colon cancer, lung cancer, squamous cell carcinoma of the tongue, cervical cancer, ovarian cancer, osteosarcoma, liver cancer, breast cancer, bladder cancer, ovarian epithelial cancer .
- Another embodiment of the present invention also provides the use of the membrane-breaking polypeptide or its stereoisomer or its pharmaceutically acceptable salt in the preparation of anti-bacterial infection medicine.
- Another embodiment of the present invention also provides the application of the membrane-breaking polypeptide nanoparticles in the preparation of anti-bacterial infection drugs.
- the bacteria are Gram-negative bacilli, Gram-negative Pseudomonas, Gram-positive Staphylococcus, Gram-positive cocci, Gram-positive cocci, and Streptococcus.
- the bacteria are Escherichia coli, Salmonella, Staphylococcus aureus, Klebsiella pneumoniae, Pseudomonas aeruginosa, Enterococcus faecalis, Streptococcus pyogenes, Streptococcus pneumoniae, Acinetobacter baumannii bacillus, pneumococcus, pseudomonas aeruginosa.
- a drug for preventing and/or treating tumors which is prepared from active ingredients and pharmaceutically acceptable adjuvants and/or carriers, the active ingredients include the membrane-breaking The polypeptide or its stereoisomer or its pharmaceutically acceptable salt, and/or the membrane-breaking polypeptide nanoparticles.
- a combination drug for preventing and/or treating tumors is provided, the active ingredients of which include:
- Component 1 the membrane-breaking polypeptide or its stereoisomer or pharmaceutically acceptable salt thereof, and/the membrane-breaking polypeptide nanoparticles;
- Component 2 Antineoplastic drugs other than Component 1;
- the component 1 and component 2 respectively become independent administration units, or the components 1 and 2 jointly form a combined administration unit.
- the component 2 is an immune checkpoint inhibitor.
- the immune checkpoint inhibitor is a PD-1 inhibitor.
- the compounds of formula (I) to formula (III) of the present invention can be used in combination with other known antitumor drugs.
- formula (I)-formula (III) compound and known medicine can become independent administration unit respectively, or jointly form the administration unit of combination;
- Formula (I)-formula (III) compound can be combined with existing Other known antineoplastic drugs were administered simultaneously or separately.
- Drug combination also includes administration of the compound of formula (I)-formula (III) and one or several other known drugs in overlapping time periods.
- the dosage of the formula (I)-formula (III) compound or the known drug can be the same as that of the single drug, or lower doses than when they are used alone.
- Drugs or active ingredients that can be combined with compounds of formula (I)-formula (III) include but are not limited to: immune checkpoint inhibitors, estrogen receptor modulators, androgen receptor modulators, retinal-like receptor Body regulators, cytotoxic/cytostatic agents, antiproliferative agents, protein transferase inhibitors, HMG-CoA reductase inhibitors, HIV protein kinase inhibitors, reverse transcriptase inhibitors, angiogenesis inhibitors, cell proliferation and survival Signal inhibitors, drugs that interfere with cell cycle checkpoints and inducers of apoptosis, cytotoxic drugs, tyrosine protein inhibitors, EGFR inhibitors, VEGFR inhibitors, serine/threonine protein inhibitors, Bcr-Abl inhibition Agents, c-Kit inhibitors, Met inhibitors, Raf inhibitors, MEK inhibitors, MMP inhibitors, topoisomerase inhibitors, histidine deacetylase inhibitors, proteasome inhibitors, CDK inhibitors, Bcl-2
- the drugs or active ingredients that can be used in combination with the compounds of formula (I) - formula (III) include but are not limited to: aldesleukin, alendronic acid, interferon, atrinoin , allopurinol, allopurinol sodium, palonosetron hydrochloride, hexamethylmelamine, aminoglutethimide, amifostine, amrubicin, anaridine, anastrozole, dolac Joan, aranesp, arglabin, arsenic trioxide, Aroxin, 5-azacytidine, azathioprine, BCG or Tice BCG, betadine, betamethasone acetate, betamethasone sodium phosphate preparations, bexarotene, betamethasone sulfate Leymycin, bromuridine, bortezomib, busulfan, calcitonin, alezolizumab injection, capecitabine, carboplatin, Casod
- an anti-bacterial infection drug which is prepared from an active ingredient and a pharmaceutically acceptable adjuvant and/or carrier, and the active ingredient includes the membrane-breaking polypeptide or Stereoisomers thereof or pharmaceutically acceptable salts thereof, and/or the membrane-disrupting polypeptide nanoparticles.
- the medicament for preventing and/or treating tumor or the medicament for antibacterial infection of the present invention can be used in non-human mammals or humans.
- the pharmaceutically acceptable adjuvant used in the medicine for preventing and/or treating tumor or the medicine for antibacterial infection of the present invention refers to: one or more compatible solid or liquid fillers or gel substances, which It is suitable for human use and must be of sufficient purity and low enough toxicity.
- Compatibility here refers to the ability of each component in the composition to blend with the active ingredient of the present invention (the tertiary amine-modified polypeptide membrane breaking material shown in formula I-III) and between them , without significantly reducing the efficacy of the active ingredient.
- the pharmaceutically acceptable adjuvant used in the medicine for preventing and/or treating tumor of the present invention includes but not limited to one or more of the following materials: solvent, excipient, filler, compatibilizer, binder , humectant, disintegrant, slow agent, absorption accelerator, adsorbent, diluent, solubilizer, emulsifier, lubricant, wetting agent, suspending agent, flavoring agent and spices at least one.
- Examples of pharmaceutically acceptable excipients include cellulose and its derivatives (such as sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid , magnesium stearate), calcium sulfate, vegetable oil (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (such as Tween ), wetting agent (such as sodium lauryl sulfate), coloring agent, flavoring agent, stabilizer, antioxidant, preservative, pyrogen-free water, etc.
- cellulose and its derivatives such as sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.
- gelatin such as talc
- solid lubricants such as stearic acid , magnesium stearate
- the administration method of the active ingredient or pharmaceutical composition of the present invention is not particularly limited, and representative administration methods include (but not limited to): oral, rectal, parenteral (intravenous, intramuscular or subcutaneous) and the like.
- Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules.
- the active ingredient is admixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with:
- fillers or extenders such as starch, lactose, sucrose, glucose, mannitol and silicic acid;
- binders such as hydroxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia;
- humectants for example, glycerin
- disintegrants such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate;
- absorption accelerators for example, quaternary ammonium compounds
- humectants for example, cetyl alcohol and glyceryl monostearate
- Lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, or mixtures thereof.
- the dosage form may also contain buffering agents.
- the solid dosage form can also be prepared with coatings and shell materials, such as enteric coatings and other materials known in the art. They may contain opacifying agents and the release of the active ingredient from such compositions may be in a certain part of the alimentary canal in a delayed manner.
- coatings and shell materials such as enteric coatings and other materials known in the art. They may contain opacifying agents and the release of the active ingredient from such compositions may be in a certain part of the alimentary canal in a delayed manner.
- examples of usable embedding components are polymeric substances and waxy substances.
- Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures.
- liquid dosage forms may contain inert diluents conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethylformamide and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances, etc.
- the compositions can also contain adjuvants, such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
- Suspensions in addition to the active ingredient, may contain suspending agents, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, mixtures of these substances, and the like.
- suspending agents for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, mixtures of these substances, and the like.
- compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions.
- Suitable aqueous and non-aqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols, and suitable mixtures thereof.
- peptides were synthesized by mPEG-NH 2- initiated copolymerization of R 1a -NCA and R 2 -NCA, and tertiary amines were introduced through the side chain reaction of R 1a to obtain a series of membrane-breaking peptide polymers Material.
- the reaction formula and corresponding abbreviation are as follows:
- mPEG-NH 2 is the initiator
- R 1a -NCA is the N-carboxylic anhydride of the amino acid monomer whose side chain can be modified
- R 2 -NCA is the N-carboxylic anhydride of the hydrophobic amino acid monomer
- -N(R 4 R 5 ) is a tertiary amine structure that can undergo protonation with pH changes.
- R 1a -NCA is Lys(Z)-NCA, it needs to be deprotected with TFA/HBr/CH 3 COOH before modification of the side chain.
- Alcohols (R-OH) containing tertiary amine structures used for side chain modification are all commercial products available in the market. R-OH is first reacted with carbonylimidazole (CDI) to prepare R-CDI, and then used for side chain modification. chain modification.
- R-CDI is prepared by reacting R-OH and CDI in dichloromethane. After the reaction, deionized water is added to remove unreacted CDI, extracted and separated by dichloromethane, and dried with anhydrous magnesium sulfate to obtain R-CDI in dichloromethane. solution, and drained.
- the side chain modification method is as follows: dissolve the deprotected polypeptide in N,N-dimethylformamide (DMF), add R-CDI (2-fold excess) with a syringe, and add triethylamine to stir the reaction for 24h , precipitated in ether, drained, dissolved in deionized water, dialyzed in deionized water for 24 hours with a dialysis bag with a molecular weight cut-off of 3500, changing the water every 2 hours, and freeze-dried to obtain the membrane-breaking peptide.
- DMF N,N-dimethylformamide
- R 1a -NCA is BLG-NCA, it needs to be deprotected with TFA/HBr/CH 3 COOH before side chain modification.
- the primary ammonia (R-NH 2 ) containing a tertiary amine structure used for side chain modification is a commercial product available in the market.
- the carboxyl group of the side chain of polyglutamic acid is first reacted with BOP-Cl/DMAP, and then reacted with For R-NH 2 reaction, use a dialysis bag with a molecular weight cut-off of 3500 to dialyze in deionized water for 24 hours, change the water every 2 hours, and freeze-dry to obtain the membrane-breaking peptide.
- Embodiment 1 Polyethylene glycol-polylysine copolymer (polypeptide) modified by tertiary amine
- R3 is a polypeptide with different alkylene groups
- R 3 are respectively: ethylene, propylene, pentylene.
- mPEG 44 -Lys 33 and mPEG 44 -Lys 33 in Example 1 are the same batch of polypeptides.
- Dissolve mPEG 44 -PLys 33 in DMF add R-CDI (over 2 times) with a syringe, add triethylamine (equal to lysine side chain amino group), react for 24 hours, add dropwise to anhydrous ether to precipitate , remove ether, drain, dissolve with DMSO, load with 3500 dialysis bag, dialyze in deionized water for 24h, change water once every 2h, and freeze-dry to obtain R3 respectively ethylene, propylene, and pentylene.
- C 2 /C 3 /C 5 is expressed as ethylene, propylene, and pentylene.
- PEG-NH 2 with different molecular weights was selected as the initiator to obtain polylysine with a similar degree of polymerization, and a tertiary amine modification with a structure of N,N-diethylethanol was selected to study the effect of PEG with different molecular weights on the modified polylysine. Effect of amino acid pKa and helical structure.
- the reaction equation is as follows:
- mPEG-NH 2 is respectively: mPEG 9 -NH 2 , mPEG 44 -NH 2 , mPEG 112 -NH 2 .
- step (3) Weigh 2.0 g of the polymer prepared in step (2), dissolve it in 3 mL of CF 3 COOH, add 3.0 mL of HBr/CH 3 COOH, react for 4 hours, drain the solution with an oil pump, add DMF to dissolve, and precipitate into ether. Remove the supernatant, drain and dissolve in deionized water, dialyze in deionized water with a dialysis bag with a molecular weight cut-off of 3500 for 24 hours, change the water every 2 hours, freeze-dry for later use.
- y is the degree of PEG polymerization.
- R-OH is one of the following structures:
- n 10/33/61/86/128.
- each polymer has Monodispersity.
- tertiary amine groups can also be introduced by reacting tertiary amines containing carboxyl groups with amino groups on the side chains of polylysine.
- Amines take the reaction of 1-piperidine acetic acid and polylysine as an example.
- Its nuclear magnetic spectrum is shown in Figure 23, which proves that the structure is correct; through titration, its pKa is 7.15, as shown in Figure 24.
- tertiary amine groups are introduced into the side chain of the polypeptide by means of side chain carboxyl reaction, etc.
- the reaction of N,N-dibutylethylamine and polyglutamic acid is used as an example to prepare tertiary amine-modified polyethylene glycol - polyglutamic acid copolymers.
- the cytotoxicity of the polypeptide at pH 7.4 was determined by erythrocyte hemolysis assay.
- the specific detection method is as follows:
- Polypeptide stock solution preparation Dissolve the polypeptide into a 10mg/ml stock solution with deionized water, and adjust the pH to pH 7.4;
- the absorbance value of the experimental group incubated with the drug is defined as the I experimental group
- the absorbance value of the control group incubated with PBS and red blood cells is defined as the I negative control
- the absorbance of the control group incubated with red blood cells with Triton-X100 at a final concentration of 0.1% is defined as I positive control ; then according to the formula [(I experimental group -I negative control )/(I positive control -I negative control )] ⁇ 100%, calculate the erythrocyte hemolysis rate.
- DMP2 tertiary amine-modified polypeptides have higher hemolytic activity, which may be due to the higher pKa of this series of polypeptides; while other tertiary amine-modified polypeptides containing benzene rings have lower hemolytic activity, which may be due to The benzene ring makes the nanoparticles more stable; N,N-dibutyl (DB) modified peptides have hemolytic activity at low polymerization degrees, and low hemolytic activity at high polymerization degrees, because at higher polymerization degrees, the peptides With a low pKa, it can be assembled into relatively compact particles and has low hemolysis.
- DB N,N-dibutyl
- Example 4 The pH-responsive anticancer activity of tertiary amine-modified polyethylene glycol-polypeptide (polylysine or polyglutamic acid)
- Tumor cells are plated in 96-well plates at 10,000 cells per well, and used after culturing overnight;
- the results show that the polypeptide mPEG 44 -PLys-C6P 10 has a better pH for tumor cells in 4h Selectivity ( FIG. 32 ), the peptide mPEG 44 -PLys-DB 86 has good pH selectivity for tumor cells at 24 hours ( FIG. 33 ).
- the cell-killing mode of the polypeptide is studied through high-content, and the specific steps are as follows:
- Cell seeding plate seed in a high-content 96-well plate at a density of 15,000 cells/well, and culture overnight in a 37°C, 5% carbon dioxide incubator.
- the peptides were prepared in each pH medium, a total of 12 pH (pH 7.4-6.3). For the convenience of dosing, first configure in a 96-well plate for bacteria, add 120 ⁇ L of medium with corresponding pH to each well, then add 4.8 ⁇ L of material (5 mg/ml) and mix evenly with a row gun.
- Drug treatment absorb the original medium in the high-content 96-well plate, and use a discharge gun to absorb 100 ⁇ L of the pre-prepared medium of each pH of the peptide and gently add it to the high-content 96-well plate.
- Embodiment 6 anti-tumor effect in vivo
- the anti-tumor effect is evaluated by an in vivo tumor-inhibiting experiment, and the specific steps are as follows:
- EMT6 tumor cells were amplified and cultured in DMEM medium (Gibco) containing 10% fetal bovine serum;
- Mouse orthotopic EMT6 breast cancer tumor model resuspend in serum-free medium and adjust the concentration of EMT6 cells to 6.0 ⁇ 10 6 cells/mL; inject 50 ⁇ L of cell suspension into the fat pad of the right second breast of female BABL/C mice ;
- the tumor-bearing mice were randomly divided into 3 groups. Inject into the tail vein according to the following groups: PBS, 30mg/kg, 60mg/kg of the drug to be evaluated.
- mPEG 44 -PLys-DB 86 showed a significant dose-dependent, 60mg/kg dose can well inhibit tumor growth without causing obvious toxicity, and showed and anti-cellular programming Antibodies to death ligand 1 ( ⁇ PD1) have combined therapeutic effects.
- Example 7 The pH-responsive antibacterial activity of polyethylene glycol-polypeptide modified by tertiary amines
- peptides in the peptide library prepared in Example 1 have relatively low hemolytic activity, and besides antitumor activity, they also have antibacterial activity.
- the bacterial strains used in the antibacterial experiment of this embodiment include Gram-negative bacteria (Escherichia coli, ATCC35218, Pseudomonas aeruginosa, P.aeruginosa ATCC27853).
- the bacteria used in all experiments should be used after the following treatments: wash 3 times with sterile 1 ⁇ PBS (centrifugation condition: 10,000rpm, 1min), re-use sterile 1 ⁇ PBS after the last centrifugation
- To suspend bacteria take 100 ⁇ L of the above bacterial solution and add it to 900 ⁇ L sterile PBS (10-fold dilution), take the 10-fold diluted bacterial solution into a quartz cuvette, subtract the background with 1 ⁇ sterile PBS, and test the bacterial solution at 600 nm According to the absorbance of bacteria, calculate the bacterial concentration of the original bacterial liquid.
- the plateau bacterial solution was diluted to 1 ⁇ 10 6 CFU/mL with pH 6.5 M9 medium; The bacteria were mixed in equal volume, and the control group was mixed with equal volume of blank M9 medium and bacteria. Incubate all systems at 37°C for 2 hours; vortex fully and spread the plate, place the agar plate in the incubator for overnight culture, and compare each The number of colonies between the material groups, and compared with the blank control group, the less the number of colonies, the better the antibacterial effect.
- the plateau bacterial solution was diluted to 1 ⁇ 10 6 CFU/mL with M9 medium with pH 7.4, 7.2, 7.0, 6.8, 6.6, 6.4, 6.2, and 6.0, respectively , use the M9 medium with pH 7.4, 7.2, 7.0, 6.8, 6.6, 6.4, 6.2, 6.0 to prepare 32 ⁇ g/mL polypeptide solution, incubate the polypeptide solution with equal volumes of bacteria, and the blank control is equal volumes of different pH M9 medium, incubate at 37°C for 4 hours, dilute 10 times and 100 times with cold LB, vortex fully, take the diluted solution to spread on the plate, place the agar plate in the incubator for overnight culture, and count the number of colonies.
- Example 8 Polypeptides doped with hydrophobic groups
- mPEG 44 -NH 2 was selected to initiate the copolymerization of Lys(Z)-NCA and Leu-NCA in different proportions to obtain a polymer mPEG-P(Lys(Z)-co-Leu-NCA) with a total degree of polymerization (n+m) close to ), and deprotected in HBr/CH 3 COOH to obtain mPEG-P(Lys-co-Leu), respectively modified polylysine side chains with N-hydroxyethylpiperidine and 2-(hexamethyleneimine) ethanol , to study the effect of hydrophobic leucine doping ratio on the pKa and helical structure of the polypeptide.
- the reaction equation is as follows:
- R-OH is: That is, R 4 , R 5 and the nitrogen atom connected to them together form the following structure:
- Azeotrope mPEG 44 -NH 2 with toluene to remove a small amount of water vapor, drain it with an oil pump, and transfer it to a glove box for later use.
- step (3) Dissolve the polymer prepared in step (2) in 2 mL of CF 3 COOH, add 2.0 mL of HBr/CH 3 COOH, react for 4 hours, drain the solution with an oil pump, add DMF to dissolve, precipitate into ether, and remove the supernatant , dissolved in deionized water after draining, dialyzed in deionized water for 24 hours with a dialysis bag with a molecular weight cut-off of 3500, changing the water every 2 hours, and freeze-dried for later use.
- the NMR characterization proved that the structure was correct and completely deprotected, as shown in Figure 39.
- the obtained modified polymer was titrated to obtain a protonation curve and a helicity curve (the method is the same as in Example 1).
- PD represents the protonation rate, and the specific data are shown in the following table:
- mPEG 44 -NH 2 (mPEG 2k -NH 2 ) was selected to initiate the copolymerization of Lys(Z)-NCA and Phe-NCA in different proportions to obtain polymers with close total polymerization degrees (n+m), and the HBr/ mPEG-P(Lys-co-Phe) was obtained by deprotection in CH 3 COOH, the polylysine side chain was modified with N-hydroxyethylpiperidine and 2-(hexamethyleneimine) ethanol respectively, and the hydrophobicity of styrene-acrylic acid was studied.
- the effect of amino acid doping ratio on the pKa and helical structure of polypeptides is as follows:
- R-OH is: That is, R 4 , R 5 and the nitrogen atom connected to them together form the following structure:
- the resulting unmodified polymer mPEG-P (Lys(Z)-co-Phe) is characterized by gel permeation chromatography, as shown in Figure 44, which is a unimodal distribution; its NMR spectrum is shown in Figure 45, and the degree of polymerization is calculated .
- Figure 44 the NMR of the polypeptide modified by N-hydroxyethylpiperidine
- Figure 47 The NMR of the polypeptide modified by 2-(hexamethyleneimine) ethanol is shown in Figure 47, which has been completely modified.
- titration as shown in Figure 48, as the proportion of phenylalanine increases, the pKa of the polypeptide decreases gradually.
- Example (2) Replace mPEG 44 -NH 2 in Example (2) with mPEG 112 -NH 2 to synthesize Lys(Z)-NCA and Phe-NCA copolymerized in different proportions.
- the synthesis steps are the same as those in Example (1) )same.
- the specific feeding ratio is as follows:
- the resulting polymer was characterized by gel permeation chromatography, as shown in Figure 49, as a unimodal distribution.
- the H NMR spectrum characterization after deprotection is shown in Figure 50, and the complete deprotection is modified by N-hydroxyethylpiperidine to obtain a polypeptide product.
- the H NMR spectrum characterization is shown in Figure 51, which is completely modified.
- the protonation rate curve was obtained, as shown in Figure 52, it can be seen that with the increase of the proportion of phenylalanine, the pKa of the polypeptide gradually decreased, and the pKa of the polypeptide was lower than that of mPEG 44 -NH 2 .
- the pKa of the polymer is too high.
- the polypeptide mPEG 44 -P (Lys-C6 50 -co-Trp 50 ) was obtained when the hydrophobic amino acid was tryptophan and the doping ratio was 50%. NMR results As shown in Figure 58, the proof structure is correct.
- the pKa of the peptide was titrated in a sodium chloride system containing 150mM, and the results are shown in the table below: as the doping ratio of the hydrophobic monomer increases, the pKa of the peptide decreases.
- the cytotoxicity of the series of copolymerized polypeptide macromolecular materials prepared in this example was tested at the characteristic pH of normal tissues and tumor tissues, and the specific experimental methods were the same as those in Examples 3 and 4.
- the hemolytic toxicity results of the polypeptide are shown in Figure 59.
- the hemolytic activity of the polypeptide is not only related to pKa, but also related to the hydrophobicity of the hydrophobic monomer.
- the results show that the polypeptide containing phenylalanine copolymer has a lower hemolytic activity. , which may be related to the ⁇ -sheet structure.
- Polypeptides doped with hydrophobic groups have better tumor killing selectivity, and among them, polypeptides containing benzene ring structure have better tumor killing Selectivity and lower hemolytic toxicity, which may be because the benzene ring structure is more conducive to the stability of nanoparticles.
- lactate dehydrogenase lactate dehydrogenase
- LDH lactate dehydrogenase
- the polypeptide of the present invention has an amphiphilic structure and can kill cells by interacting with the plasma membrane of cells. Taking mPEG 44 -P(Lys-C6 50 -co-Trp 50 ) as an example, to measure the release of LDH during cell death, the specific method is as follows:
- LDH release reagent was added to the maximum enzyme activity control well, the amount added was 10% of the volume of the original culture solution, repeated blowing several times to mix well, and then continued to incubate in the cell culture incubator.
- the cell culture plate is centrifuged at 400 g for 5 min with a multi-well plate centrifuge. Take 80 ⁇ L of the supernatant from each well, add it into the corresponding well of a new 96-well plate, and then carry out the sample determination.
- mPEG 44 -P(Lys-C6 50 -co-Trp 50 ) can be well Inhibits tumor growth.
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Organic Chemistry (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Oncology (AREA)
- Genetics & Genomics (AREA)
- Communicable Diseases (AREA)
- Biochemistry (AREA)
- Gastroenterology & Hepatology (AREA)
- Molecular Biology (AREA)
- Biophysics (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Epidemiology (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Peptides Or Proteins (AREA)
Abstract
提供了一种具有式(I)所示结构的pH敏感的破膜聚肽或者其立体异构体或者其药学上可接受的盐,及其应用。该大分子材料在正常生理pH下,呈疏水电中性,可自组装成纳米颗粒,组装紧密,与细胞膜的相互作用弱;在微酸的pH条件下,可以质子化,形成疏水结构域和阳离子结构域组成的两亲性结构,与细胞膜具有强相互作用并且具有强破膜活性,因而可以高效、高选择性杀伤肿瘤细胞或细菌。
Description
本发明涉及高分子材料和药物技术领域,具体涉及一种pH敏感的破膜聚肽及其应用。
一些具有阳离子基团的两亲性高分子可通过破坏细胞膜的方式杀伤肿瘤细胞及细菌等病原体,这种不依赖代谢途径的杀伤形式,具有广谱杀伤效果、不易产生耐药等优点,在肿瘤及感染性疾病的治疗中具有广阔应用前景。破膜高分子材料与细胞膜作用主要通过静电和疏水相互作用,首先利用高分子的阳离子结构域和负电荷细胞膜静电相互作用结合到细胞膜表面,然后高分子的疏水结构域插入到细胞膜脂质层中,在细胞膜上形成不可修复的膜损伤,从而杀伤细胞。由阳离子基团和疏水基团组成的两亲性构象是大分子材料与细胞膜作用的关键结构,同时也是对正常组织细胞造成细胞毒性的重要原因。两者结构比例对其与细胞膜相互作用非常重要。通常来说,单纯阳离子高分子易与细胞膜结合但不易插入细胞膜,而疏水结构聚合物难以结合到细胞膜表面,无法有效破坏细胞膜。因此,设计高分子材料使其在正常组织呈现阳离子或疏水结构,而在病变部位转变为阳离子结构域和疏水结构域组成的两亲性构象,以解决破膜高分子材料毒性大的问题,具有重要的意义。
课题组前期制备了具有破膜活性的含有三级胺侧链的聚甲基丙烯酸酯高分子材料,通过侧链的三级胺质子化可控制在不同pH下实现破膜活性的激活,并且通过共聚引入疏水链接,可以实现在pH=7.4下具有较低的溶血和杀伤,而在微酸环境下可以实现破膜活性的精准激活,对肿瘤细胞膜不可逆的损伤,实现高选择性杀伤肿瘤细胞。但聚甲基丙烯酸酯主链难以降解,长期使用在体内累积容易产生毒性。
发明内容
基于此,本发明提供了一种侧基含三级胺及疏水基团的pH敏感的破膜聚肽材料,该大分子材料在正常生理pH下,呈疏水电中性,与细胞膜的相互作用弱;在微酸的pH条件下,可以质子化,形成疏水结构域和阳离子结构域组成的两亲性结构,与细胞膜具有强相互作用并且具有强破膜活性,因而可以高效、高选择性杀伤肿瘤细胞或细菌。本发明包括如下技术方案。
一种具有式(I)所示结构的破膜聚肽或者其立体异构体或者其药学上可接受的盐:
L选自:-NH-C(=O)O-、-NH-C(=O)-、-C(=O)-NH-、-C(=O)-O-;
R
1选自:亚烷基;
R
2选自:C
1-C
12烷基、C
6-C
14芳基、C
6-C
14芳基取代的C
1-C
12烷基、苄氧羰基取代的C
1-C
12烷基、5-10元杂芳基取代的C
1-C
12烷基;
R
3选自:亚烷基、C
6-C
14芳基取代的亚烷基;
R
4、R
5分别独立地选自:烷基、C
6-C
14芳基取代的烷基,或者R
3、R
4和与其相连的氮原子一起形成杂环烷基;
y选自:2-150;
R
6选自:C
1-C
15烷基、C
6-C
14芳基、C
6-C
14芳基取代的C
1-C
15烷基;
n+m大于0,并且n不为0;
q选自:0、1、2、3、4。
另一方面,本发明还提供了一种破膜聚肽纳米颗粒,包括如下技术方案。
一种破膜聚肽纳米颗粒,由上述破膜聚肽在水介质中自组装形成。
另一方面,本发明还提供了一种破膜聚肽纳米颗粒的制备方法,包括如下技术方案。
一种破膜聚肽纳米颗粒的制备方法,包括如下步骤:将所述破膜聚肽溶于有机溶剂或者pH为1.5-2.5的盐酸溶液中,然后将所得溶液在搅拌状态下逐滴加入水中,继续搅拌,低温透析除去溶剂,即得所述的破膜聚肽纳米颗粒。
另一方面,本发明还提供了上述破膜聚肽或者破膜聚肽纳米颗粒的应用,包括如下技术方案。
所述破膜聚肽或者其立体异构体或者其药学上可接受的盐在制备预防和/或治疗肿瘤的药物中的应用。
所述破膜聚肽纳米颗粒在制备预防和/或治疗肿瘤的药物中的应用。
所述破膜聚肽或者其立体异构体或者其药学上可接受的盐联合免疫检查点抑制剂在制备预防和/或治疗肿瘤的药物中的应用。
所述破膜聚肽纳米颗粒联合免疫检查点抑制剂在制备预防和/或治疗肿瘤的药物中的应用。
所述破膜聚肽或者其立体异构体或者其药学上可接受的盐在制备抗细菌感染的药物中的应用。
所述破膜聚肽纳米颗粒在制备抗细菌感染的药物中的应用。
另一方面,本发明还提供了一种预防和/或治疗肿瘤的药物,包括如下技术方案。
一种预防和/或治疗肿瘤的药物,由活性成分和药学上可接受的辅料和/或载体制备得到,所述活性成分包括所述的破膜聚肽或者其立体异构体或者其药学上可接受的盐,和/或所述的破膜聚肽纳米颗粒。
另一方面,本发明还提供了一种预防和/或治疗肿瘤的联合用药物,包括如下技术方案。
一种预防和/或治疗肿瘤的联合用药物,其活性成分包括:
组分1:所述的破膜聚肽或者其立体异构体或者其药学上可接受的盐,和/或所述的破膜聚肽纳米颗粒;以及
组分2:组分1之外的抗肿瘤药物;
所述组分1和组分2分别成为独立的给药单元,或所述组分1和组分2共同形成组合的给药单元。
另一方面,本发明还提供了一种抗细菌感染的药物,包括如下技术方案。
一种抗细菌感染的药物,由活性成分和药学上可接受的辅料和/或载体制备得到,所述活性成分包括所述的破膜聚肽或者其立体异构体或者其药学上可接受的盐,和/或所述的破膜聚肽纳米颗粒。
本发明提供了一种三级胺修饰的破膜聚肽材料,该大分子材料在正常生理pH下呈疏水电中性,聚肽片段呈疏水性,与细胞膜的相互作用弱,从而使其在体内循环时具有对正常组织毒性小的优点;在肿瘤组织或者细菌感染微酸的pH条件下,该大分子材料的三级胺部分会发生质子化,从而使聚肽片段形成疏水结构域和阳离子结构域组成的两亲性结构,从而使其与细胞膜具有极强的相互作用以及很强的破膜活性,从而可以高效、高选择性地杀伤肿瘤细胞及细菌。本发明还发现含有苯环结构的聚肽可以提高其选择性。本发明的破膜聚肽大分子材料能够用于制备抗肿瘤或者抗菌药物,具有抗肿瘤和抗菌效果好,选择性高,毒性小的 优点。并且由于聚合多肽具有可降解性及降解产物无生物毒性的优点,因而将具有更广泛的生物医学应用。
图1为mPEG
44-PLys(Z)
33的凝胶渗透色谱图。
图2为mPEG
44-PLys(Z)
33的核磁氢谱图。
图3为mPEG
44-PLys
33的核磁氢谱图。
图4为DE-CDI的核磁氢谱图。
图5为mPEG
44-PLys-DE
33的核磁氢谱图。
图6为实施例1中的三级胺修饰聚肽前后的质子化曲线(A)和螺旋度变化曲线(B)。
图7为R
3为不同亚烷基修饰聚肽的核磁氢谱图。
图8为R
3为不同亚烷基修饰聚肽的质子化曲线(A)和螺旋度变化曲线(B)。
图9为DE三级胺修饰不同聚乙二醇引发聚肽的凝胶渗透色谱图。
图10为DE三级胺修饰不同聚乙二醇引发聚肽的核磁氢谱图。
图11为不同聚合度的PEG引发的聚肽的质子化曲线。
图12为不同三级胺修饰mPEG
44-PLys
86的核磁氢谱图。
图13为不同三级胺修饰mPEG
44-PLys
86的质子化曲线(A)和螺旋度变化曲线(B)。
图14为mPEG
44-NH
2引发Lys(Z)-NCA得到的不同聚合度的聚肽的凝胶渗透色谱图。
图15为不同聚合度聚赖氨酸的核磁氢谱图。
图16为不同聚合度聚肽mPEG
44-PLys
n-DB的质子化曲线(A)和螺旋度变化曲线(B)。
图17为C5P2三级胺修饰不同聚合度聚肽的核磁氢谱图。
图18为C5P三级胺修饰不同聚合度聚肽的核磁氢谱图。
图19为C6P三级胺修饰不同聚合度聚肽的核磁氢谱图。
图20为DB三级胺修饰不同聚合度聚肽的核磁氢谱图。
图21为DMP2三级胺修饰不同聚合度聚肽的核磁氢谱图。
图22为DMP三级胺修饰不同聚合度聚肽的核磁氢谱图。
图23为mPEG
44-PLys-CC6
86的核磁氢谱图。
图24为mPEG
44-PLys-CC6
86的质子化率曲线。
图25为mPEG
44-PBLG
30的凝胶渗透色谱图。
图26为mPEG
44-PBLG
30的核磁氢谱图。
图27为mPEG
44-PLG-DB
30的核磁氢谱图。
图28为mPEG
44-PLG-DB
30的质子化率曲线。
图29为不同三级胺修饰不同聚合度的聚肽的溶血活性。
图30为不同三级胺修饰不同聚合度的聚肽在Panc02细胞器中pH=6.8下24h的细胞杀伤曲线。
图31为不同三级胺修饰不同聚合度的聚肽在MC38细胞器中pH=6.8下24h的细胞杀伤曲线。
图32为mPEG
44-PLys-C6P
10在不同pH下对MC38(A)及Panc02(B)的24h细胞杀伤曲线。
图33为mPEG
44-PLys-DB
86在不同pH下对MC38(A)及Panc02(B)的4h细胞杀伤曲线。
图34为mPEG
44-PLys-DB
86在Panc02细胞器中pH=6.8下的破膜活性。
图35为mPEG
44-PLys-DB
86的体内肿瘤治疗效果及其与αPD1的联合治疗效果;其中,A为给药方案示意图;B为不同剂量下mPEG
44-PLys-DB
86的体内肿瘤治疗效果;C为mPEG
44-PLys-DB
86与αPD1联合治疗效果。
图36为不同三级胺修饰不同聚合度的聚肽的抗菌活性。
图37为mPEG
44-PLys-C5P
33在不同pH下的抗菌活性。
图38为亮氨酸和赖氨酸(苄氧羰基保护)以不同比例共聚所得聚肽的凝胶渗透色谱图。
图39为亮氨酸和赖氨酸不同比例共聚所得聚肽的核磁氢谱图。
图40为N-羟基乙基哌啶修饰的亮氨酸和赖氨酸不同比例共聚所得聚肽的核磁氢谱图。
图41为2-(六甲撑亚胺)乙醇修饰的亮氨酸和赖氨酸不同比例共聚所得聚肽的核磁氢谱图。
图42为N-羟基乙基哌啶修饰的亮氨酸和赖氨酸不同比例共聚所得聚肽的质子化率曲线(A)和螺旋度曲线(B)。
图43为2-(六甲撑亚胺)乙醇修饰的亮氨酸和赖氨酸不同比例共聚所得聚肽的质子化率曲线(A)和螺旋度曲线(B)。
图44为mPEG
44-NH
2引发苯丙氨酸和赖氨酸(苄氧羰基保护)不同比例共聚所得聚肽的凝胶渗透色谱图。
图45为mPEG
44-NH
2引发苯丙氨酸和赖氨酸(苄氧羰基保护)不同比例共聚所得聚肽的核磁氢谱图。
图46为N-羟基乙基哌啶修饰苯丙氨酸和赖氨酸不同比例共聚所得聚肽的核磁氢谱图。
图47为2-(六甲撑亚胺)乙醇修饰的苯丙氨酸和赖氨酸不同比例共聚所得聚肽的核磁氢谱图。
图48为N-羟基乙基哌啶(A)和2-(六甲撑亚胺)乙醇(B)修饰的苯丙氨酸和赖氨酸不同比例共聚所得聚肽的质子化率曲线。
图49为mPEG
112-NH
2引发苯丙氨酸和赖氨酸(苄氧羰基保护)不同比例共聚所得聚肽的凝胶渗透色谱图。
图50为mPEG
112-NH
2引发苯丙氨酸和赖氨酸不同比例共聚所得聚肽的核磁氢谱图。
图51为N-羟基乙基哌啶修饰的mPEG
112-NH
2引发的苯丙氨酸和赖氨酸不同比例共聚所得聚肽的核磁氢谱图。
图52为N-羟基乙基哌啶修饰的mPEG
112-NH
2引发的苯丙氨酸和赖氨酸不同比例共聚所得聚肽的质子化率曲线。
图53为正亮氨酸和赖氨酸(苄氧羰基保护)以不同比例共聚所得聚肽的凝胶渗透色谱图。
图54为正亮氨酸和赖氨酸(苄氧羰基保护)以不同比例共聚所得聚肽的核磁氢谱图。
图55为正亮氨酸和赖氨酸不同比例共聚所得聚肽的核磁氢谱图。
图56为N-羟基乙基哌啶修饰的正亮氨酸和赖氨酸不同比例共聚所得聚肽的核磁氢谱图。
图57为N-羟基乙基哌啶修饰的L-氨基辛酸和赖氨酸不同比例共聚所得聚肽的核磁氢谱图。
图58为N-羟基乙基哌啶修饰的色氨酸和赖氨酸1:1共聚所得聚肽的核磁氢谱图。
图59为C6三级胺修饰的不同疏水氨基酸共聚赖氨酸的溶血活性。
图60为C6三级胺修饰的不同疏水氨基酸共聚赖氨酸的肿瘤选择性杀伤。
图61为C6三级胺修饰的色氨酸和赖氨酸共聚聚肽在不同pH下的肿瘤选择性杀伤。
图62为mPEG
44-P(Lys-C6
50-co-Trp
50)诱导细胞膜破损释放LDH。
图63为mPEG
44-P(Lys-C6
50-co-Trp
50)的体内肿瘤治疗效果;其中A为给药方案示意图,B为mPEG
44-P(Lys-C6
50-co-Trp
50)的肿瘤治疗效果。
本发明下列实施例中未注明具体条件的实验方法,通常按照常规条件,或按照制造厂商所建议的条件。实施例中所用到的各种常用化学试剂,均为市售产品。
除非另有定义,本发明所使用的所有的技术和科学术语与属于本发明的技术领域的技术人员通常理解的含义相同。本发明的说明书中所使用的术语只是为了描述具体的实施例的目的,不用于限制本发明。
本发明的术语“包括”和“具有”以及它们任何变形,意图在于覆盖不排他的包含。例如包含了一系列步骤的过程、方法、装置、产品或设备没有限定于已列出的步骤或模块,而是可选地还包括没有列出的步骤,或可选地还包括对于这些过程、方法、产品或设备固有的其它 步骤。
在本发明中提及的“多个”是指两个或两个以上。“和/或”,描述关联对象的关联关系,表示可以存在三种关系,例如,A和/或B,可以表示:单独存在A,同时存在A和B,单独存在B这三种情况。字符“/”一般表示前后关联对象是一种“或”的关系。
本发明所述化合物中,当任何变量(例如R
1、R
2等)在任何组分中出现超过一次,则其每次出现的定义独立于其它每次出现的定义。同样,允许取代基及变量的组合,只要这种组合使化合物稳定。自取代基划入环系统的线表示所指的键可连接到任何能取代的环原子上。如果环系统为多环,其意味着这种键仅连接到邻近环的任何适当的碳原子上。要理解本领域普通技术人员可选择本发明化合物的取代基及取代型式而提供化学上稳定的并可通过本领域技术和下列提出的方法自可容易获得的原料容易合成的化合物。如果取代基自身被超过一个基团取代,应理解这些基团可在相同碳原子上或不同碳原子上,只要使结构稳定。
术语“烷基”意指包括具有特定碳原子数目的支链的和直链的饱和脂肪烃基。例如,“C
1-C
6烷基”中“C
1-C
6”的定义包括以直链或支链排列的具有1、2、3、4、5或6个碳原子的基团。例如,“C
1-C
6烷基”具体包括甲基、乙基、正丙基、异丙基、正丁基、叔丁基、异丁基、戊基、己基。
术语“亚烷基”是指在“烷基”基础上少一个氢的基团,例如,-CH
2-、-CH
2CH
2-、-CH
2CH
2CH
2-、-CH
2CH
2CH
2CH
2-等。
术语“杂环烷基”为饱和的单环环状取代基,其中一个或多个环原子选自N、O或S(O)m(其中m是0-2的整数)的杂原子,其余环原子为碳,例如:哌啶基、吡咯烷基等。
本发明的一实施方式中提供了一种具有式(I)所示结构的破膜聚肽或者其立体异构体或者其药学上可接受的盐:
L选自:-NH-C(=O)O-、-NH-C(=O)-、-C(=O)-NH-、-C(=O)-O-;
R
1选自:亚烷基;
R
2选自:C
1-C
12烷基、C
6-C
14芳基、C
6-C
14芳基取代的C
1-C
12烷基、苄氧羰基取代的C
1-C
12烷基、5-10元杂芳基取代的C
1-C
12烷基;
R
3选自:亚烷基、C
6-C
14芳基取代的亚烷基;
R
4、R
5分别独立地选自:烷基、C
6-C
14芳基取代的烷基,或者R
3、R
4和与其相连的氮原子一起形成杂环烷基;
y选自:2-150;
R
6选自:C
1-C
15烷基、C
6-C
14芳基、C
6-C
14芳基取代的C
1-C
15烷基;
n+m大于0,并且n不为0;
q选自:0、1、2、3、4。
在其中一些实施例中,R
1选自:C
1-C
6亚烷基。
在其中一些实施例中,R
1选自:-(CH
2)
x-,其中,x选自:1、2、3、4、5、6。
在其中一些实施例中,所述破膜聚肽具有如下式(II)所示结构:
其中,X为:-O-或者没有。
在其中一些实施例中,所述破膜聚肽具有如下式(III)所示结构:
在其中一些实施例中,R
3选自:C
1-C
6亚烷基、苯基取代的C
1-C
6亚烷基。
在其中一些实施例中,R
3选自:-(CH
2)
x-、苯基取代的-(CH
2)
x;其中,x选自:1、2、3、4、5、6。
在其中一些实施例中,R
4、R
5分别独立地选自:C
1-C
12烷基、苯基取代的C
1-C
6烷基、萘基取代的C
1-C
6烷基,或者R
4、R
5和与其相连的氮原子一起形成5-10元杂环烷基。
在其中一些实施例中,R
4、R
5分别独立地选自:C
1-C
6烷基、苯基取代的C
1-C
3烷基、萘基取代的C
1-C
3烷基,或者R
4、R
5和与其相连的氮原子一起形成5-8元杂环烷基。
在其中一些实施例中,R
4、R
5和与其相连的氮原子一起形成如下基团:
在其中一些实施例中,R
6选自:C
1-C
6烷基、苯基、萘基、苯基取代的C
1-C
6烷基。
R
6为苄基。
在其中一些实施例中,R
2选自:C
1-C
8烷基、苯基、萘基、苯基取代的C
1-C
6烷基、苄氧羰基取代的C
1-C
6烷基、5-10元杂芳基取代的C
1-C
6烷基。
在其中一些实施例中,R
2选自:甲基、乙基、正丙基、异丙基、正丁基、异丁基、戊烷基、己基、庚基、辛基、壬烷基、癸烷基、十一烷基、十二烷基、苯基、萘基、苄基、苄氧羰基取代的乙基、苯并吡咯取代的乙基。
在其中一些实施例中,y选自:5-120。
在其中一些实施例中,y选自:30-120。
在其中一些实施例中,y选自:40-48或者108-116。
在其中一些实施例中,y选自:9、44、112。
在其中一些实施例中,n+m不小于5,更优选为不小于10。
在其中一些实施例中,n+m为10-200,更优选为10-150,更优选为10-110。
在其中一些实施例中,m为0;n为5-200,优选为10-150,优选为10-110。
在其中一些实施例中,m为0;n为10-15、30-35、60-65、80-90、或者120-130。
在其中一些实施例中,m为0;n为10、30、33、61、86、128。
在其中一些实施例中,m为n+m的0-60%,更优选为0-50%。
在其中一些实施例中,m为n+m的0-30%。
在其中一些实施例中,m为n+m的0-25%。
在其中一些实施例中,m为n+m的10-23%。
在其中一些实施例中,m为n+m的15-25%。
在其中一些实施例中,m为n+m的25-35%。
在其中一些实施例中,m为n+m的35-45%。
在其中一些实施例中,m为n+m的40-50%。
在其中一些实施例中,m为n+m的45-50%。
其中,R
3为-CH
2-CH
2-;R
4、R
5和与其相连的氮原子一起形成如下基团:
R
6为苄基;y为40-48。
在其中一些实施例中,R选自:-R
3-N(R
4R
5);
其中,R
3选自:-CH
2-CH
2-;R
4、R
5和与其相连的氮原子一起形成如下基团:
R
2选自:甲基、乙基、正丙基、异丙基、正丁基、异丁基、戊烷基、己基、庚基、辛基、壬烷基、癸烷基、十一烷基、十二烷基、苯基、萘基、苄基、苄氧羰基取代的乙基、苯并吡咯取代的乙基。
在其中一些实施例中,所述的破膜聚肽选自如下聚合物:
在本发明的另一实施方式中还提供了一种破膜聚肽纳米颗粒,由所述的破膜聚肽在水介质中自组装形成。
在本发明的另一实施方式中还提供了所述的破膜聚肽纳米颗粒的制备方法,包括如下步骤:将所述破膜聚肽溶于有机溶剂或者pH为1.5-2.5的盐酸溶液中,然后将所得溶液在搅拌状态下逐滴加入水中,继续搅拌,低温透析除去溶剂,即得所述的破膜聚肽纳米颗粒。
在其中一些实施例中,所述有机溶剂为N,N-二甲基甲酰胺。
在其中一些实施例中,所述破膜聚肽、所述有机溶剂或盐酸溶液、与所述水的配比为10mg~30mg:1mL:4-6mL。
在其中一些实施例中,所述破膜聚肽纳米颗粒的制备方法包括如下步骤:将所述破膜聚肽按配比10mg~30mg:1mL溶于N,N-二甲基甲酰胺中,然后将所得溶液在转速为400~800转/分钟的搅拌状态下逐滴加入水中,继续以200~600转/分钟的转速搅拌8~20分钟,使用截留分子量为10000~20000的透析袋在水中透析除去溶剂,即得所述破膜聚肽纳米颗粒。
在本发明的另一实施方式中还提供了所述的破膜聚肽或者其立体异构体或者其药学上可接受的盐在制备预防和/或治疗肿瘤的药物中的应用。
在本发明的另一实施方式中还提供了破膜聚肽纳米颗粒在制备预防和/或治疗肿瘤的药物中的应用。
在本发明的另一实施方式中还提供了破膜聚肽或者其立体异构体或者其药学上可接受的盐联合免疫检查点抑制剂在制备预防和/或治疗肿瘤的药物中的应用。
在本发明的另一实施方式中还提供了所述的破膜聚肽纳米颗粒联合免疫检查点抑制剂在制备预防和/或治疗肿瘤的药物中的应用。
在其中一些实施例中,所述免疫检查点抑制剂为PD-1抑制剂。
在其中一些实施例中,所述肿瘤为胰腺癌、黑色素瘤、结直肠癌、结肠癌、肺癌、舌鳞癌、宫颈癌、卵巢癌、骨肉瘤、肝癌、乳腺癌、膀胱癌、卵巢上皮癌。
在本发明的另一实施方式中还提供了所述的破膜聚肽或者其立体异构体或者其药学上可接受的盐在制备抗细菌感染的药物中的应用。
在本发明的另一实施方式中还提供了所述的破膜聚肽纳米颗粒在制备抗细菌感染的药物中的应用。
在其中一些实施例中,所述细菌为革兰氏阴性杆菌、革兰氏阴性假单胞菌、革兰氏阳性葡萄球菌、革兰氏阳性球菌、革兰氏阳性球杆菌、链球菌。
在其中一些实施例中,所述细菌为大肠杆菌、沙门氏菌、金黄色葡萄球菌、肺炎克雷伯菌、铜绿假单胞菌、粪肠球菌、化脓性链球菌、肺炎链球菌、鲍曼不动杆菌、肺炎双球菌、绿脓杆菌。
在本发明的另一实施方式中还提供了一种预防和/或治疗肿瘤的药物,由活性成分和药学上可接受的辅料和/或载体制备得到,所述活性成分包括所述的破膜聚肽或者其立体异构体或者其药学上可接受的盐,和/或所述的破膜聚肽纳米颗粒。
在本发明的另一实施方式中还提供了一种预防和/或治疗肿瘤的联合用药物,其活性成分包括:
组分1:所述的破膜聚肽或者其立体异构体或者其药学上可接受的盐,和/所述的破膜聚肽纳米颗粒;以及
组分2:组分1之外的抗肿瘤药物;
所述组分1和组分2分别成为独立的给药单元,或所述组分1和组分2共同形成组合的给药单元。
在其中一些实施例中,所述组分2为免疫检查点抑制剂。
在其中一些实施例中,所述免疫检查点抑制剂为PD-1抑制剂。
本发明的式(I)-式(III)化合物可以与已知的其它抗肿瘤药物联用。联合给药时,式(I)-式(III)化合物和已知药物可以分别成为独立的给药单元,或共同形成组合的给药单元;式(I)-式(III)化合物可以与已知的其它抗肿瘤药物同时给药或者分别给药。当式(I)-式(III)化合物与其它一种或几种药物同时服用时,优选使用同时含有一种或几种已知药物和式(I)-式(III)化合物的药用组合物。药物联用也包括在重叠的时间段服用式(I)-式(III)化合物与其它一种或几种已知药物。当式(I)-式(III)化合物与其它一种或几种已知药物进行药物联用时,式(I)-式(III)化合物或已知药物的剂量可以与单独用药剂量相同,也可以比它们单独用药时的剂量更低。
可以与式(I)-式(III)化合物进行药物联用的药物或活性成分包括但不局限为:免疫检查点抑制剂、雌激素受体调节剂、雄激素受体调节剂、视网膜样受体调节剂、细胞毒素/细胞抑制剂、抗增殖剂、蛋白转移酶抑制剂、HMG-CoA还原酶抑制剂、HIV蛋白激酶抑制剂、逆转录酶抑制剂、血管生成抑制剂、细胞增殖及生存信号抑制剂、干扰细胞周期关卡的药物和细胞凋亡诱导剂、细胞毒类药物、酪氨酸蛋白抑制剂、EGFR抑制剂、VEGFR抑制剂、丝氨酸/苏氨酸蛋白抑制剂、Bcr-Abl抑制剂、c-Kit抑制剂、Met抑制剂、Raf抑制剂、MEK抑制剂、MMP抑制剂、拓扑异构酶抑制剂、组氨酸去乙酰化酶抑制剂、蛋白酶体抑制剂、CDK抑制剂,Bcl-2家族蛋白抑制剂、MDM2家族蛋白抑制剂、IAP家族蛋白抑制剂、STAT家族蛋白抑制剂、PI3K抑制剂、AKT抑制剂、整联蛋白阻滞剂、干扰素-α、白介素-12、COX-2抑制剂、p53、p53激活剂、VEGF抗体、EGF抗体等。
在其中一些实施方案中,可以与式(I)-式(III)化合物进行药物联用的药物或活性成分包括但不局限为:阿地白介素、阿仑膦酸、干扰素、阿曲诺英、别嘌醇、别嘌醇钠、帕洛诺司琼盐酸盐、六甲蜜胺、氨基格鲁米特、氨磷汀、氨柔比星、安丫啶、阿纳托唑、多拉司琼、aranesp、arglabin、三氧化二砷、阿诺新、5-氮胞苷、硫唑嘌呤、卡介苗或tice卡介苗、贝他定、醋酸倍他米松、倍他米松磷酸钠制剂、贝沙罗汀、硫酸博来霉素、溴尿甘、bortezomib、白消安、降钙素、阿来佐单抗注射剂、卡培他滨、卡铂、康士得、cefesone、西莫白介素、柔 红霉素、苯丁酸氮芥、顺铂、克拉屈滨、克拉屈滨、氯屈磷酸、环磷酰胺、阿糖胞昔、达卡巴嗪、放线菌素D、柔红霉素脂质体、地塞米松、磷酸地塞米松、戊酸雌二醇、地尼白介素2、狄波美、地洛瑞林、地拉佐生、己烯雌酚、大扶康、多西他奇、去氧氟尿苷、阿霉素、屈大麻酚、钦-166-壳聚糖复合物、eligard、拉布立酶、盐酸表柔比星、阿瑞吡坦、表阿霉素、阿法依伯汀、红细胞生成素、依铂、左旋咪唑片、雌二醇制剂、17-β-雌二醇、雌莫司汀磷酸钠、炔雌醇、氨磷汀、羟磷酸、凡毕复、依托泊甙、法倔唑、他莫昔芬制剂、非格司亭、非那司提、非雷司替、氟尿苷、氟康唑、氟达拉滨、5-氟脱氧尿嘧啶核苷一磷酸盐、5-氟尿嘧啶、氟甲睾酮、氟他胺、福麦斯坦、1-β-D-阿糖呋喃糖胞噻啶-5’-硬脂酰磷酸酯、福莫司汀、氟维司群、丙种球蛋白、吉西他滨、吉妥单抗、甲磺酸伊马替尼、卡氮芥糯米纸胶囊剂、戈舍瑞林、盐酸格拉尼西隆、组氨瑞林、和美新、氢化可的松、赤型-羟基壬基腺嘌呤、羟基脲、替坦异贝莫单抗、伊达比星、异环磷酰胺、干扰素α、干扰素-α2、干扰素α-2A、干扰素α-2B、干扰素α-nl、干扰素α-n3、干扰素β、干扰素γ-la、白细胞介素-2、内含子A、易瑞沙、依立替康、凯特瑞、硫酸香菇多糖、来曲唑、甲酰四氢叶酸、亮丙瑞林、亮丙瑞林醋酸盐、左旋四咪唑、左旋亚叶酸钙盐、左甲状腺素钠、左甲状腺素钠制剂、洛莫司汀、氯尼达明、屈大麻酚、氮芥、甲钴胺、甲羟孕酮醋酸酯、醋酸甲地孕酮、美法仑、酯化雌激素、6-琉基嘌呤、美司钠、氨甲蝶呤、氨基乙酰丙酸甲酯、米替福新、美满霉素、丝裂霉素C、米托坦、米托葱醌、曲洛司坦、柠檬酸阿霉素脂质体、奈达铂、聚乙二醇化非格司亭、奥普瑞白介素、neupogen、尼鲁米特、三苯氧胺、NSC-631570、重组人白细胞介素1-β、奥曲肽、盐酸奥丹西隆、去氢氢化可的松口服溶液剂、奥沙利铂、紫杉醇、泼尼松磷酸钠制剂、培门冬酶、派罗欣、喷司他丁、溶链菌制剂、盐酸匹鲁卡品、毗柔比星、普卡霉素、卟吩姆钠、泼尼莫司汀、司替泼尼松龙、泼尼松、倍美力、丙卡巴脐、重组人类红细胞生成素、雷替曲塞、利比、依替膦酸铼-186、美罗华、力度伸-A、罗莫肽、盐酸毛果芸香碱片剂、奥曲肽、沙莫司亭、司莫司汀、西佐喃、索布佐生、唬钠甲强龙、帕福斯酸、干细胞治疗、链佐星、氯化锶-89、左旋甲状腺素钠、他莫昔芬、坦舒洛辛、他索那明、tastolactone、泰索帝、替西硫津、替莫唑胺、替尼泊苷、丙酸睾酮、甲睾酮、硫鸟嘌呤、噻替哌、促甲状腺激素、替鲁膦酸、拓扑替康、托瑞米芬、托西莫单抗、曲妥珠单抗、曲奥舒凡、维A酸、甲氨喋呤片剂、三甲基密胺、三甲曲沙、乙酸曲普瑞林、双羟萘酸曲普瑞林、优福定、尿苷、戊柔比星、维司力农、长春碱、长春新碱、长春酰胺、长春瑞滨、维鲁利秦、右旋丙亚胺、净司他丁斯酯、枢复宁、紫杉醇蛋白质稳定制剂、acolbifene、干扰素r-lb、affinitak、氨基喋呤、阿佐昔芬、asoprisnil、阿他美坦、阿曲生坦、BAY43-9006、阿瓦斯丁、CCI-779、CDC-501、西乐葆、西妥昔单抗、克立那托、环丙孕酮醋酸酯、地西他滨、DN-101、阿霉素-MTC、dSLIM、度他雄胺、edotecarin、 依氟鸟氨酸、依喜替康、芬维A胺、组胺二盐酸盐、组氨瑞林水凝胶植入物、钬-166DOTMP、伊班膦酸、干扰素γ、内含子-PEG、ixabepilone、匙孔形血蓝蛋白、L-651582、兰乐肽、拉索昔芬、libra、lonafamib、米泼昔芬、米诺屈酸酯、MS-209、脂质体MTP-PE、MX-6、那法瑞林、奈莫柔比星、新伐司他、诺拉曲特、奥利默森、onco-TCS、osidem、紫杉醇聚谷氨酸酯、帛米酸钠、PN-401、QS-21、夸西洋、R-154、雷洛昔芬、豹蛙酶、13-顺维A酸、沙铂、西奥骨化醇、T-138067、tarceva、二十二碳六烯酸紫杉醇、胸腺素αl、嘎唑呋林、tipifarnib、替拉扎明、TLK-286、托瑞米芬、反式MID-lo7R、伐司朴达、伐普肽、vatalanib、维替泊芬、长春氟宁、Z-100和唑来麟酸或它们的组合。
在本发明的另一实施方式中还提供了一种抗细菌感染的药物,由活性成分和药学上可接受的辅料和/或载体制备得到,所述活性成分包括所述的破膜聚肽或者其立体异构体或者其药学上可接受的盐,和/或所述的破膜聚肽纳米颗粒。
本发明的用于预防和/或治疗肿瘤的药物或者抗细菌感染的药物可以用于非人哺乳动物或者人。
本发明的用于预防和/或治疗肿瘤的药物或者抗细菌感染的药物中所用的药学上可接受的辅料指的是:一种或多种相容性固体或液体填料或凝胶物质,它们适合于人使用,而且必须有足够的纯度和足够低的毒性。
“相容性”在此指的是组合物中各组分能和本发明的活性成分(式I-式III所示的三级胺修饰的聚肽破膜材料)以及它们之间相互掺和,而不明显降低活性成分的药效。
本发明的用于预防和/或治疗肿瘤的药物所用的药学上可接受的辅料包括但不限于如下材料中的一种或多种:溶剂、赋形剂、填料、增容剂、粘合剂、保湿剂、崩解剂、缓溶剂、吸收加速剂、吸附剂、稀释剂、增溶剂、乳化剂、润滑剂、润湿剂、悬浮剂、矫味剂和香料中的至少一种。
药学上可以接受的辅料部分例子有纤维素及其衍生物(如羧甲基纤维素钠、乙基纤维素钠、纤维素乙酸酯等)、明胶、滑石、固体润滑剂(如硬脂酸、硬脂酸镁)、硫酸钙、植物油(如豆油、芝麻油、花生油、橄榄油等)、多元醇(如丙二醇、甘油、甘露醇、山梨醇等)、乳化剂(如吐温
)、润湿剂(如十二烷基硫酸钠)、着色剂、调味剂、稳定剂、抗氧化剂、防腐剂、无热原水等。
本发明的活性成分或药物组合物的施用方式没有特别限制,代表性的施用方式包括(但并不限于):口服、直肠、肠胃外(静脉内、肌肉内或皮下)等。
用于口服给药的固体剂型包括胶囊剂、片剂、丸剂、散剂和颗粒剂。
在这些固体剂型中,活性成分与至少一种常规惰性赋形剂(或载体)混合,如柠檬酸钠或 磷酸二钙,或与下述成分混合:
(a)填料或增容剂,例如,淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸;
(b)粘合剂,例如,羟甲基纤维素、藻酸盐、明胶、聚乙烯基吡咯烷酮、蔗糖和阿拉伯胶;
(c)保湿剂,例如,甘油;
(d)崩解剂,例如,琼脂、碳酸钙、马铃薯淀粉或木薯淀粉、藻酸、某些复合硅酸盐、和碳酸钠;
(e)缓溶剂,例如,石蜡;
(f)吸收加速剂,例如,季胺化合物;
(g)润湿剂,例如,鲸蜡醇和单硬脂酸甘油酯;
(h)吸附剂,例如,高岭土;和
(i)润滑剂,例如,滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、十二烷基硫酸钠,或其混合物。胶囊剂、片剂和丸剂中,剂型也可包含缓冲剂。
所述的固体剂型还可采用包衣和壳材制备,如肠衣和其它本领域公知的材料。它们可包含不透明剂,并且,这种组合物中活性成分的释放可以延迟的方式在消化道内的某一部分中释放。可采用的包埋组分的实例是聚合物质和蜡类物质。
用于口服给药的液体剂型包括药学上可接受的乳液、溶液、悬浮液、糖浆或酊剂。除了活性成分外,液体剂型可包含本领域中常规采用的惰性稀释剂,如水或其它溶剂,增溶剂和乳化剂,例知,乙醇、异丙醇、碳酸乙酯、乙酸乙酯、丙二醇、1,3-丁二醇、二甲基甲酰胺以及油,特别是棉籽油、花生油、玉米胚油、橄榄油、蓖麻油和芝麻油或这些物质的混合物等。除了这些惰性稀释剂外,组合物也可包含助剂,如润湿剂、乳化剂和悬浮剂、甜味剂、矫味剂和香料。
除了活性成分外,悬浮液可包含悬浮剂,例如,乙氧基化异十八烷醇、聚氧乙烯山梨醇和脱水山梨醇酯、微晶纤维素、甲醇铝和琼脂或这些物质的混合物等。
用于肠胃外注射的组合物可包含生理上可接受的无菌含水或无水溶液、分散液、悬浮液或乳液,和用于重新溶解成无菌的可注射溶液或分散液的无菌粉末。适宜的含水和非水载体、稀释剂、溶剂或赋形剂包括水、乙醇、多元醇及其适宜的混合物。
以下为具体实施例。
以下实施例中通过mPEG-NH
2引发R
1a-NCA、R
2-NCA共聚的聚合方法合成了聚肽,通过R
1a的侧链反应,引入三级胺,得到一系列破膜聚肽高分子材料。反应式以及相应简称如下:
其中,mPEG-NH
2为引发剂,R
1a-NCA为侧链可修饰的氨基酸单体的N-羧酸酐,R
2-NCA为疏水氨基酸单体的N-羧酸酐,-N(R
4R
5)为可随着pH变化而发生质子化的三级胺结构。
当R
1a-NCA为Lys(Z)-NCA时,侧链修饰前需要用TFA/HBr/CH
3COOH脱保护。用于侧链修饰的含有三级胺结构的醇(R-OH)均是市场可以购买到的商业化产品,R-OH与羰基咪唑(CDI)先反应制备成R-CDI,再用于侧链修饰。
R-CDI是通过R-OH与CDI在二氯甲烷中反应制备,反应结束加入去离子水去掉未反应的CDI,通过二氯甲烷萃取分离,无水硫酸镁干燥得到R-CDI的二氯甲烷溶液,抽干即可。
侧链修饰的方法如下:将脱保护后的聚肽溶解于N,N-二甲基甲酰胺(DMF)中,用注射器加入R-CDI(2倍过量),并加入三乙胺搅拌反应24h,在乙醚中沉淀,抽干,用去离子水溶解,用截留分子量3500的透析袋在去离子水中透析24h,每2h换一次水,冻干,即得破膜聚肽。
当R
1a-NCA为BLG-NCA时,侧链修饰前需要用TFA/HBr/CH
3COOH脱保护。用于侧链修饰的含有三级胺结构的伯氨(R-NH
2)均是市场可以购买到的商业化产品,聚谷氨酸侧链的羧基先和BOP-Cl/DMAP反应,再和R-NH
2反应,用截留分子量3500的透析袋在去离子水中透析24h,每2h换一次水,冻干,即得破膜聚肽。
实施例1:三级胺修饰的聚乙二醇-聚赖氨酸共聚物(聚肽)
(一)N,N-二乙基乙醇修饰的聚肽
y=44,n=33,m=0,R-OH为N,N-二乙基乙醇。当用mPEG
44-NH
2引发Lys(Z)-NCA时,脱保护得到mPEG
44-PLys
33,通过CDI把N,N-二乙基乙醇修饰到聚赖氨酸的侧链,研究三级胺修饰聚赖氨酸侧链对聚赖氨酸pKa和螺旋结构的影响。反应方程式如下:
具体步骤如下:
(1)称取10g的Lys(Z)用油泵抽过夜,转入手套箱中,加入250mL的四氢呋喃(THF),转出,置于冰浴上搅拌,加入11.5g的三光气,接上冷凝管,搅拌约10min,转入油浴中,50℃反应约2.5h,抽干后转入手套箱中,用乙酸乙酯溶解,在正己烷中重结晶三次,抽干,得Lys(N)-NCA,备用。
(2)甲苯共沸除去mPEG
44-NH
2中的水汽,抽干后转入手套箱备用。
(3)称取500mg的mPEG
44-NH
2溶解于5mL的二氯甲烷中,得mPEG
44-NH
2溶液。称取10.0g的Lys(N)-NCA溶于30mL的N,N-二甲基甲酰胺,用注射器一次性将mPEG
44-NH
2溶液加到DMF溶液中,反应24h,抽干反应液体,加入10mL二氯甲烷溶解,滴加到正己烷中沉淀,去掉上清,抽干得到聚合物mPEG
44-PLys(Z)
33,备用。通过凝胶渗透色谱对其表征,如图1,聚合物是PDI=1.12的单峰分布,通过核磁氢谱对其结构进行了表征,如图2,根据核磁的积分面积计算聚合度为33。
(4)称取步骤(3)制备的聚合物mPEG
44-PLys(Z)
335.0g,溶解于5mL的CF
3COOH,加入6.0mLHBr/CH
3COOH,反应4h,用油泵抽干溶液,加入DMF溶解,沉淀到乙醚中,去掉上清,抽干后用去离子水溶解,用截留分子量3500的透析袋在去离子水中透析24h,每2h换一次水,冻干,得到mPEG
44-PLys
33,备用。通过核磁氢谱对其结构进行了表征,如图3,苄氧羰基离去,在5.0ppm和7.25ppm处峰消失,并且g峰有明显的变化,证明已经成功脱保护。
(5)将CDI置于圆底烧瓶中,加入无水二氯甲烷搅拌分散(1.0g CDI加5mL二氯甲烷), 胶塞封口,用注射器缓慢加入N,N-二乙基乙醇(CDI过量2倍),溶液逐渐澄清,反应4h后添加与二氯甲烷等量的去离子水,反应约5min,分液漏斗取下层二氯甲烷相,加入无水硫酸镁干燥1h,过滤去除固体,得到溶液并抽干,即N,N-二乙基乙醇-CDI(DE-CDI)。通过核磁氢谱对其进行表征,如图4,各峰积分面积对应,证明DE-CDI键合成功。
(6)将mPEG
44-PLys
33溶解于DMF中,用注射器加入DE-CDI(过量2倍),加入三乙胺(与赖氨酸侧链氨基等量),反应24h,滴加到无水乙醚中沉淀,去掉乙醚,抽干,用DMSO溶解,用3.5k的透析袋装载,在去离子水透析24h,2h换一次水,冻干,得到用N,N-二乙基乙醇修饰的mPEG
44-PLys
33备用(mPEG
44-PLys-DE
33)。通过核磁氢谱对其结构进行表征,如图5,修饰后g峰明显向低场位移,通过计算证明已经完全键合。
(7)取100μL浓盐酸(37%,12mol)加入100mL的去离子水中,充分溶解得到澄清透明溶液。用10mL盐酸溶液溶解10mg步骤(6)制备的聚合物材料(mPEG
44-PLys-DE
33),并将pH探头伸入液面下,搅拌状态下(搅拌速度Mot=3),使用0.5M的氢氧化钠滴定液滴定。待pH计稳定后记录读数,同时在一些pH值时取液体测圆二色谱,测完放回,并继续滴定。直到滴定结果为pH=11结束。通过对滴定曲线求导得到极值点,定为质子化率为1和0点,建立pH和质子化率曲线,如图6中的A,可以看出,当三级胺修饰聚赖氨酸侧链氨基后,聚肽的pKa明显降低。通过对圆二色谱图的计算分析得到聚合物螺旋度和pH的关系曲线,如图6中的B,可以看出,当三级胺修饰聚赖氨酸侧链氨基后,聚肽的螺旋转变的临界pH明显降低。结果如下表:
聚肽 | pKa | 螺旋转变临界pH |
mPEG 44-PLys 33 | 9.47 | 9.98 |
mPEG 44-PLys-DE 33 | 7.89 | 7.4 |
从结果可以看出,三级胺修饰可以明显降低聚赖氨酸的pKa,有望实现在pH=7.4环境下实现低质子化,从而降低其在生理条件下的破膜活性。
(二)R
3为不同亚烷基的聚肽
y=44,n=33,m=0,即引发剂为mPEG
44-NH
2(分子量2000),赖氨酸聚合度为33,R
4和R
5为乙基,与氮原子构成的结构为:
研究R
3为不同的亚烷基对聚赖氨酸pKa和螺旋结构的影响。具体反应方程式如下:
其中R-OH的结构分别如下:
即R
3分别为:亚乙基、亚丙基、亚戊基。
具体步骤如下:
mPEG
44-Lys
33和实施例1中的mPEG
44-Lys
33是同一批次聚肽。
将CDI置于圆底烧瓶中,加入无水二氯甲烷搅拌分散(1g CDI加5mL二氯甲烷),胶塞封口,用注射器缓慢加入R-OH(CDI过量2倍),溶液逐渐澄清,反应4h后添加与二氯甲烷等量的去离子水,反应约5min,分液漏斗取下层二氯甲烷相,加入无水硫酸镁干燥1h,过滤去除固体,得到溶液并抽干,即R-CDI。将mPEG
44-PLys
33溶解于DMF中,用注射器加入R-CDI(过量2倍),加入三乙胺(与赖氨酸侧链氨基等量),反应24h,滴加到无水乙醚中沉淀,去掉乙醚,抽干,用DMSO溶解,用3500的透析袋装载,在去离子水中透析24h,2h换一次水,冻干,得到R
3分别为亚乙基、亚丙基、亚戊基的三级胺修饰mPEG
44-PLys
33(分别记为mPEG
44-PLys-DE
33、mPEG
44-PLys-C
3-DE
33、mPEG
44-PLys-C
5-DE
33),核磁氢谱如图7所示。
同(一)的方法滴定三个聚肽的pKa和圆二色谱,结果如图8中的A和B所示,当R
3从亚乙基增加到亚戊基时,三级胺的中心氮原子离主链越来越远,pKa也越来越大,螺旋转变的临界pH也越来越大。详细结果如下表:
R 3 | 聚肽 | pKa | 螺旋转变临界pH |
C 2 | mPEG 44-PLys-DE 33 | 7.89 | 7.40 |
C 3 | mPEG 44-PLys-C 3-DE 33 | 8.20 | 7.83 |
C 5 | mPEG 44-PLys-C 5-DE 33 | 8.69 | 8.20 |
注:C
2/C
3/C
5表示为亚乙基、亚丙基、亚戊基。
(三)PEG分子量对聚肽pH响应性的影响
选择不同分子量的PEG-NH
2为引发剂,得到相近聚合度的聚赖氨酸,选择结构为N,N- 二乙基乙醇的三级胺修饰,研究不同分子量的PEG对修饰后的聚赖氨酸pKa和螺旋结构的影响。反应方程式如下:
其中mPEG-NH
2分别为:mPEG
9-NH
2、mPEG
44-NH
2、mPEG
112-NH
2。
具体步骤如下:
(1)甲苯共沸除去mPEG
9-NH
2、mPEG
44-NH
2、mPEG
112-NH
2中的水汽,油泵抽过夜,转入手套箱。
(2)在手套箱中称取Lys(Z)-NCA于圆底烧瓶中,按照35倍于引发剂(mPEG
9-NH
2、mPEG
44-NH
2、mPEG
112-NH
2)的量称取,并加入DMF溶解,称取引发剂溶解于3mL二氯甲烷,并加到Lys(Z)-NCA溶液中搅拌反应24h,红外示踪,反应结束后抽掉溶剂,用3mL二氯甲烷溶解,滴到乙醚和正己烷(V:V=1:1)中沉淀,去掉上清,沉淀2次,抽干,如图9所示,聚合物都是单峰分布。
(3)称取步骤(2)制备的聚合物2.0g,溶解于3mL的CF
3COOH,加入3.0mLHBr/CH
3COOH,反应4h,用油泵抽干溶液,加入DMF溶解,沉淀到乙醚中,去掉上清,抽干后用去离子水溶解,用截留分子量3500的透析袋在去离子水中透析24h,每2h换一次水,冻干备用。
(4)将CDI置于圆底烧瓶中,加入无水二氯甲烷搅拌分散(1g CDI加5mL二氯甲烷),胶塞封口,用注射器缓慢加入N,N-二乙基乙醇CDI过量2倍),溶液逐渐澄清,反应4h后添加与二氯甲烷等量的去离子水,反应约5min,分液漏斗取下层二氯甲烷相,加入无水硫酸镁干燥1h,过滤去除固体,得到溶液并抽干,即N,N-二乙基乙醇-CDI。将步骤(3)制备的聚合 物溶解于DMF中,用注射器加入N,N-二乙基乙醇-CDI(过量2倍),加入三乙胺(与赖氨酸侧链氨基等量),反应24h,滴加到无水乙醚中沉淀,去掉乙醚,抽干,用DMSO溶解,用3500的透析袋装载,在去离子水透析24h,2h换一次水,冻干,得到用N,N-二乙基乙醇修饰的聚赖氨酸,备用,核磁氢谱如图10。
同(一)的方法滴定得到三种聚肽的质子化率曲线和螺旋度变化曲线。结果如图11和下表所示,PEG链长越长,pKa越大,但是PEG
9的亲水性比PEG
44差,会导致聚合物组装形成的纳米颗粒的稳定性比PEG
44差。
y | pKa |
9 | 7.45 |
44 | 7.89 |
112 | 7.94 |
注:y为PEG聚合度。
(四)不同三级胺的修饰对聚肽pH响应性的影响
选择mPEG
44-NH
2引发Lys(Z)-NCA聚合,并在HBr/CH
3COOH中脱保护得到mPEG
44-PLys
86,通过CDI将三级胺修饰到聚赖氨酸侧链得到一系列不同三级胺修饰的聚赖氨酸破膜高分子材料,研究不同三级胺结构对聚赖氨酸pKa和螺旋结构的影响。反应方程式如:
其中R-OH为下列结构中的一种:
具体步骤如下:
同(一)的方法大量合成mPEG
44-PLys(Z)
86的聚赖氨酸,通过在HBr/CH
3COOH中脱保护得到mPEG
44-PLys
86,将各含有三级胺结构的醇R-OH通过CDI键合到聚肽mPEG
44-PLys
86的侧链,并用核磁氢谱对其结构进行表征,如图12所示。同(一)的方法滴定得到质子化率曲线和螺旋度变化曲线。
比较6种三级胺修饰对聚肽pKa和螺旋结构的影响,结果如图13所示,随着疏水性的增加,pKa逐渐降低,螺旋转变的临界pH也逐渐降低,其中N,N-二丁基乙二醇修饰聚肽的pKa最低。具体见下表:
R-OH | pKa | 螺旋转变临界pH |
DE | 7.34 | 7.18 |
DiP | 7.32 | 7.18 |
DB | 6.09 | 5.94 |
C5 | 7.76 | 7.40 |
C6 | 7.12 | 7.00 |
C7 | 7.33 | 6.81 |
(五)聚赖氨酸分子量对pH响应性的影响
y=44,m=0,R-OH为N,N-二丁基乙醇。选择mPEG
44-NH
2引发Lys(Z)-NCA,得到不同聚合度的聚肽,并在HBr/CH
3COOH中脱保护得到mPEG-PLys,通过CDI将N,N-二丁基乙二醇修饰到不同聚合度的聚肽侧链,研究不同聚合度对修饰后的聚肽pKa和螺旋结构的影响。
其中n=10/33/61/86/128。
调控引发剂mPEG
44-NH
2和单体Lys(Z)-NCA的比例,聚合得到了不同聚合度的mPEG-PLys(Z),通过GPC对其进行表征,如图14,各聚合物都具有单分散性。
进一步脱保护得到mPEG-PLys(核磁氢谱如图15所示),通过CDI将N,N-二丁基乙二醇修饰到不同聚合度的聚肽侧链,并滴定所得修饰后的聚合物,得到质子化曲线和螺旋度曲线(方法同(一))。结果如图16所示,随着聚合度的增加,三级胺修饰的聚肽的pKa明显下降,螺旋转变的临界pH先下降再升高。具体见下表:
n | pKa | 螺旋转变临界pH |
10 | 7.25 | 6.80 |
33 | 6.85 | 6.20 |
61 | 6.33 | 5.55 |
86 | 6.09 | 5.94 |
128 | 5.85 | 5.81 |
(六)按本实施例同样方法合成了不同分子量、不同三级胺修饰的聚肽库(核磁氢谱如图17-图22所示),其中R-OH为DB或下列结构中的一种:
在含有150mM的NaCl溶液中滴定聚肽的pKa,具体pKa和聚肽分子量关系如下表所示:
主链结构 | C5P2 | DMP | C6P | DMP2 | C5P | DB |
mPEG 112-PLys 30 | 6.21 | 6.56 | 6.52 | 7.20 | 6.22 | 6.61 |
mPEG 44-PLys 10 | 6.50 | 6.77 | 6.64 | 7.31 | 6.48 | 6.76 |
mPEG 44-PLys 33 | 6.0 | 6.02 | 6.35 | 7.05 | 6.30 | 6.59 |
mPEG 44-PLys 86 | 5.97 | 6.08 | 6.03 | 7.05 | 6.25 | 6.48 |
根据pKa结果可以发现,总体而言,随着mPEG分子量的增加,pKa增加;随着聚赖氨酸分子量的增加,pKa降低;随着三级胺疏水性的增加,pKa降低。mPEG
44-PLys-DB
86在含有150mM的NaCl溶液中,聚肽的pKa比在去离子水中高,说明聚肽的pKa也受到盐的影响。
(七)不同方式引入三级胺基团
除了通过含有羟基的三级胺和赖氨酸侧链氨基反应将三级胺基团引入到聚肽侧链,还可以通过含有羧基的三级胺和聚赖氨酸侧链氨基反应引入三级胺,以1-哌啶乙酸和聚赖氨酸反应为例。
将0.7g的1-哌啶乙酸、1.5g的DCC和0.7g的NHS溶于10mL的无水二氯甲烷中反应4h,过滤除去漂浮的杂质DCC,将二氯甲烷溶液抽干,得到活化的中间体。取300mg的mPEG
44-PLys
86溶于5mL的DMF,将溶液加到活化的中间体中,并加入100mg三乙胺,继续反应过夜,用截留分子量为3500的透析袋透析,冻干,得到mPEG
44-PLys-CC6
86。其核磁谱图如图23所示,证明结构正确;通过滴定,得到其pKa为7.15,如图24所示。
实施例2三级胺修饰的聚乙二醇-聚谷氨酸共聚物(聚肽)
除了通过含有羟基的三级胺或者含有羧基的三级胺和赖氨酸侧链氨基反应将三级胺基团引入到聚肽侧链,还可以通过用含有氨基的三级胺和谷氨酸侧链羧基反应等形式将三级胺基团引入到聚肽侧链,本实施例以N,N-二丁基乙胺和聚谷氨酸反应为例制备三级胺修饰的聚乙二醇-聚谷氨酸共聚物。
具体步骤如下:
(1)称取4.0g的BLG于250mL圆底烧瓶中,用油泵抽过夜,转入手套箱中,加入150mL的四氢呋喃(THF),转出,置于冰浴上搅拌,加入6.0g的三光气,接上冷凝管,搅拌约10min,转入油浴中,50℃反应约2.5h,抽干后转入手套箱中,用乙酸乙酯溶解,在正己烷中重结晶三次,抽干,得BLG-NCA,备用。
(2)甲苯共沸除去mPEG
44-NH
2中的水汽,抽干后转入手套箱备用。
(3)称取500mg的mPEG
44-NH
2溶解于5mL的二氯甲烷中,得mPEG
44-NH
2溶液。称取2.0g的BLG-NCA溶于20mL的N,N-二甲基甲酰胺,用注射器一次性将mPEG
44-NH
2溶液加到DMF溶液中,反应24h,抽干反应液体,加入10mL二氯甲烷溶解,滴加到正己烷中沉淀,去掉上清,抽干得到聚合物mPEG
44-PBLG
30,备用。通过凝胶渗透色谱对其表征,如图25,聚合物 是单峰分布,通过核磁氢谱对其结构进行了表征,如图26,根据核磁的积分面积计算聚合度为30。
(4)称取步骤(3)制备的聚合物mPEG
44-PBLG
302.0g,溶解于5mL的CF
3COOH,加入6.0mLHBr/CH
3COOH,反应4h,用油泵抽干溶液,加入DMF溶解,沉淀到乙醚中,去掉上清,抽干后用去离子水溶解,用截留分子量3500的透析袋在去离子水中透析24h,每2h换一次水,冻干,得到mPEG
44-PLG
30,备用。
(5)将mPEG
44-PLG
30(重复单元eq 1)、BOP-Cl(eq 7)、DMAP(eq 0.7)加入到N-甲基吡咯烷酮中,置于冰浴中搅拌,并通入氮气吹洗15min,随后加入2倍过量的N,N-二丁基乙胺,再通入氮气吹洗15mins,之后加入TEA(eq 7),50℃恒温反应72h。反应结束后将产物在超纯水中透析48h,每小时换一次水。透析后产物在超纯水中冻干处理,得到mPEG
44-PLG-DB
30,核磁氢谱如图27所示,结构正确。
(6)取100μL浓盐酸(37%,12mol)加入100mL的去离子水中(含有150mM的NaCl),充分溶解得到澄清透明溶液。用10mL盐酸溶液溶解10mg步骤(5)制备的聚合物材料(mPEG
44-PLG-DB
30),并将pH探头伸入液面下,搅拌状态下(搅拌速度Mot=3),使用0.5M的氢氧化钠滴定液滴定。待pH计稳定后记录读数,同时在一些pH值时取液体测圆二色谱,测完放回,并继续滴定。直到滴定结果为pH=11结束,其pKa为7.86(如图28所示),相比mPEG
44-PLys-DB
33(pKa为6.59),pKa明显增加。
实施例3三级胺修饰的聚乙二醇-聚肽(聚赖氨酸或者聚谷氨酸)在pH 7.4下的细胞毒性
通过红细胞溶血实验测定聚肽在pH 7.4下的细胞毒性。具体检测方法如下:
1)将羊全血轻轻摇匀后,取1mL全血到50mL离心管中,用1×PBS稀释到25mL(即配制4%的羊血),4℃暂存备用;
2)聚肽储备液准备:用去离子水将聚肽溶解成10mg/ml的储备液,并用调节pH到pH 7.4;
3)配置2×药物溶液:用PBS将聚肽储备液稀释至1600μg/mL,随后使用PBS进行梯度稀释,得到各聚肽的一系列2×药物药物储备液;
4)加样:取上述配制好的2×药物溶液于EP管中,再加入等体积的4%的羊血,最终各聚肽的工作液浓度为50-800μg/mL,移液器轻轻吹打混匀;
5)同时,以终浓度0.1%Triton-X100为阳性对照,而PBS溶液为阴性对照;
6)将所有样品放入37℃恒温培养箱中孵育1小时;
7)取出样品,将其置于离心机中,室温下1000rpm离心5分钟;
8)离心后,吸取100μL各样品上清溶液于96孔板;使用酶标仪测试576nm吸光值;
9)将含药物孵育的实验组吸光值定义为I
实验组,PBS与红细胞共孵育的对照组吸光值定义为I
阴性对照,终浓度0.1%的Triton-X100与血红细胞共孵育的对照组吸光值定义为I
阳性对照;再根据公式[(I
实验组-I
阴性对照)/(I
阳性对照-I
阴性对照)]×100%,计算红细胞溶血率。
结果如图29所示:大部分聚肽在800μg/mL的高浓度下也没有明显的溶血活性;当三级胺为DMP2时,聚肽有较强的溶血活性;当三级胺为DB、赖氨酸的聚合度为10或者30左右时,聚肽表现出一定的溶血活性,mPEG
44-PLG-DB
30也具有较高的溶血活性,这可能是由于其pKa较高。DMP2三级胺修饰的聚肽具有较高的溶血活性,可能是由于这一系列聚肽的pKa较高;而其他含苯环的三级胺修饰的聚肽具有较低的溶血活性,可能是苯环让纳米颗粒更稳定;N,N-二丁基(DB)修饰的聚肽在低聚合度时具有溶血活性,高聚合度时溶血活性低,这是因为聚合度较高时,聚肽pKa较低,可以组装成比较紧密的颗粒,溶血较低。
实施例4三级胺修饰的聚乙二醇-聚肽(聚赖氨酸或者聚谷氨酸)的pH响应性抗癌活性
(一)通过MTT法测定聚肽在pH=6.8条件下对肿瘤细胞的杀伤活性:
1)肿瘤细胞按每孔1万个细胞铺于96孔板中,培养过夜后使用;
2)使用pH 6.8的培养基配制系列浓度的聚肽,同时以无药物组作为对照组;
3)取出孔板,除去培养基上清,并按100μL/孔加入对应含药物的培养基,将细胞置于37℃培养箱中培养;
4)在特定时间点,取出细胞,除去上清,再加入含0.5mg/mLMTT的培养基,继续培养2-4小时;
5)弃上清,每孔加入100μLDMSO,在摇床上避光震荡10分钟,使结晶物充分溶解;
6)使用酶标仪测试490nm处的吸光值,将含药物孵育的实验组吸光值定义为I
实验组,无药物和细胞的培养基组吸光值定义为I阴性对照,不加药物的细胞作为阳性对照组,吸光值定义为I
阳性对照;再根据公式[(I
实验组-I
阴性对照)/(I
阳性对照-I
阴性对照)]×100%,计算细胞的存活率,并作图。
结果显示mPEG
44-PLys-DB
86和mPEG
44-PLys-C6P
10以及mPEG
44-PLys-CC6
86聚肽对Panc02细胞(图30)和MC38细胞(图31)都具有较高的杀伤活性。
(二)测试mPEG
44-PLys-DB
86和mPEG
44-PLys-C6P
10两种聚肽在不同pH下对肿瘤细胞的杀伤选择性
用本实施例(一)中的相同方法测试两种聚肽在不同pH下对肿瘤细胞的杀伤选择性,结果显示:聚肽mPEG
44-PLys-C6P
10在4h对肿瘤细胞具有较好的pH选择性(图32),聚肽mPEG
44-PLys-DB
86在24小时对肿瘤细胞具有较好的pH选择性(图33)。
实施例5研究聚肽的细胞杀伤方式
本实施例通过高内涵研究聚肽的细胞杀伤方式,具体步骤如下:
1)细胞种板:按15000cells/well密度种于高内涵96孔板中,37℃、5%二氧化碳培养箱中过夜培养。
2)药物配制:将聚肽分别使用各pH培养基配好,共12个pH(pH 7.4-6.3)。为使加药方便,先配置于细菌用96孔板中,每孔加入120μL相应pH的培养基后加入4.8μL材料(5mg/ml)使用排枪混合均匀。
3)药物处理:吸取高内涵96孔板中原有培养基,用排枪吸取100μL预先配好的聚肽各pH的培养基轻轻加入到高内涵96孔板中。
4)细胞成像:在材料处理两小时后、八小时后分别每孔中心3*3分别进行成像(EGFP、mCherry两个通道和明场)。
5)选取合适的图片(四种类型:明场、GFP、mCherry和merge图)保存。
结果如图34所示,随着pH降低和时间的延长,视野里出现大量绿色荧光(细胞膜),而红色的mCherry荧光淬灭,说明聚肽破坏了细胞膜结构,导致内容物mCherry泄露。
实施例6体内抗肿瘤效果
本实施例通过体内抑瘤实验评价抗肿瘤效果,具体步骤如下:
1)采用含10%胎牛血清的DMEM培养基(Gibco)扩增培养EMT6肿瘤细胞;
2)使用1×PBS清洗细胞,加入含有EDTA的0.25%胰酶(碧云天),于37℃消化数分钟;1000rpm离心5分钟后弃上清,用无血清的培养基重悬细胞沉淀;
3)模型构建:
小鼠原位EMT6乳腺癌肿瘤模型:无血清的培养基重悬和调整EMT6细胞浓度为6.0×10
6细胞/mL;于雌性BABL/C小鼠右侧第二乳房脂肪垫注射50μL细胞悬液;
4)EMT6肿瘤模型肿瘤体积计算方法见公式:V=长×宽
2/2。
5)待肿瘤体积大约50mm
3时,将荷瘤小鼠随机分为3组。按以下分组尾静脉注射:PBS,30mg/kg、60mg/kg所需评价的药物。
6)测量并记录肿瘤长径和短径,按照公式计算肿瘤体积。
结果如图35所示,mPEG
44-PLys-DB
86表现出明显的剂量依赖性,60mg/kg给药剂量可以很好的抑制肿瘤生长并不带来明显毒性,并且表现出和抗细胞程序性死亡配体1的抗体(αPD1)具有联合治疗效果。
实施例7三级胺修饰的聚乙二醇-聚肽的pH响应性抗菌活性
实施例1制备的聚肽库中很多聚肽具有较低的溶血活性,除了抗肿瘤活性以外,还具有抗菌活性。本实施例抗菌实验所用到的细菌菌株包括革兰氏阴性菌(大肠杆菌Escherichia coli,ATCC35218、铜绿假单胞菌P.aeruginosa ATCC27853)。
(一)三级胺修饰的聚乙二醇-聚肽对大肠杆菌的杀菌活性
抗菌实验所使用的试剂制备简述如下:
1)LB(Luria-Bertani)培养基的配制:称取10g蛋白胨,5g酵母粉和10g氯化钠溶解于1L超纯水中,高温高压灭菌(121℃灭菌20min),降至室温后4℃保存备用。
2)LB琼脂的配制:称取36g LB琼脂粉末,溶解于1L超纯水中,高温高压灭菌(121℃灭菌20min)。待LB琼脂降至合适温度(~50℃)时,倒入60mm无菌培养皿中,待LB琼脂凝固后4℃保存备用。
3)M9培养基的配制:称取17.1g Na
2HPO
4·12H
2O,3.0g KH
2PO
4,0.5gNaCl,1.0g NH
4Cl和4g D-(+)-葡萄糖,溶解于1L无菌超纯水中,依次加入0.1mL 1mol/L CaCl
2溶液以及2mL 1mol/L MgSO
4,溶解完全后,调节pH值为6.0、6.2、6.4、6.5、6.6、6.8、7.0、7.2、7.4,0.22μm无菌滤膜除菌,4℃保存备用。
抗菌实验所使用细菌的培养及处理方法简述如下:
1)ATCC35218(E.coli)均使用LB培养基于温度为37℃、转速为220rpm的台式恒温振荡器中培养。使用传代12-16h的平台期细菌,传代比例为LB培养基:菌液=200:1(v:v);
2)如无特殊说明,所有实验使用的细菌均需经过以下处理后进行使用:无菌1×PBS洗涤3次(离心条件:10,000rpm,1min),最后一次离心后使用无菌1×PBS重悬细菌,取100μL上述菌液加到900μL无菌PBS中(稀释10倍),取稀释10倍的菌液到石英比色皿中,并且以1×无菌PBS扣除背景,600nm下测试菌液的吸光度,根据细菌吸光度计算原始菌液的细菌浓度。
所有细菌相关实验均在生物安全柜中操作,所使用的所有试剂和耗材均进行高温高压灭菌(121℃灭菌20min)处理或使用0.22μm无菌滤膜处理。
细菌培养及预处理后,用pH 6.5的M9培养基将平台期菌液稀释至1×10
6CFU/mL;将聚肽用pH 6.5的M9培养基配制成32μg/mL,将系列聚肽与细菌等体积混匀,对照组为等体积的空白M9培养基与细菌混匀,将所有体系于37℃孵育2h;充分涡旋后涂板,琼脂板置于培养箱中培养过夜后,比较各材料组之间的菌落数目,并与空白对照组比较,菌落数目越少表明抗菌效果越好。
结果如图36所示,相比于对照组,本发明的聚肽具有一定的杀菌效果,其中mPEG
44-PLys-DB
33和mPEG
44-PLys-C5P
33两种聚肽的杀菌效果更好。
(二)mPEG
44-PLys-C5P
33对铜绿假单胞菌的杀菌活性。
细菌培养及预处理后(方法同(一)),分别用pH 7.4、7.2、7.0、6.8、6.6、6.4、6.2、6.0的M9培养基将平台期菌液稀释至1×10
6CFU/mL,用pH 7.4、7.2、7.0、6.8、6.6、6.4、6.2、6.0的M9培养基配制32μg/mL的聚肽溶液,将聚肽溶液与细菌等体积孵育,空白对照为等体积的不同pH的M9培养基,于37℃孵育4h,用冷LB稀释10倍、100倍,充分涡旋后取稀释液涂板,琼脂板置于培养箱中培养过夜后,计算菌落数。将空白M9培养基组表面细菌数量作为对应pH的空白对照组。计算细菌存活率,结果为2个平行琼脂板(n=2)的平均值±s.d.。结果如图37所示,说明聚肽在pKa附近具有较好的杀菌活性。
实施例8:疏水基团掺杂的聚肽
本实施例合成了一系列含有不同疏水基团的氨基酸与赖氨酸共聚的聚肽。
(一)亮氨酸共聚的聚肽
本实施例选择mPEG
44-NH
2引发Lys(Z)-NCA和Leu-NCA以不同比例共聚,得到总聚合度(n+m)接近的聚合物mPEG-P(Lys(Z)-co-Leu),并在HBr/CH
3COOH中脱保护得到mPEG-P(Lys-co-Leu),分别用N-羟基乙基哌啶和2-(六甲撑亚胺)乙醇修饰聚赖氨酸侧链,研究疏水性亮氨酸掺杂比例对聚肽pKa和螺旋结构的影响。反应方程式如:
合成mPEG-P(Lys(Z)-co-Leu)的投料比例如下表,为了方便,对其编号:
编号 | 0 | 1 | 2 | 3 | 4 | 5 |
Leu理论聚合度 | 0 | 10 | 20 | 30 | 40 | 50 |
Lys(Z)理论聚合度 | 100 | 90 | 80 | 70 | 60 | 50 |
mPEG 44-NH 2投料质量/g | 0.1 | 0.1 | 0.1 | 0.1 | 0.1 | 0.1 |
Leu-NCA投料质量/g | 0 | 0.0756 | 0.1512 | 0.2268 | 0.3023 | 0.3779 |
Lys(Z)-NCA投料质量/g | 1.5316 | 1.3784 | 1.2252 | 1.0721 | 0.9619 | 0.7658 |
具体步骤如下:
(1)将mPEG
44-NH
2用甲苯共沸除去少量水汽,油泵抽干,转入手套箱备用。
(2)按照上表称取Leu-NCA和Lys(Z)-NCA于各个样品瓶中,加入5mL的DMF溶解,分别称取0.1g的mPEG
44-NH
2溶解于二氯甲烷中,将溶液加到单体中,反应24h,红外示踪,反应结束后抽干溶剂,用2.0mL的二氯甲烷溶解,沉淀到乙醚和正己烷中,去掉上清,重复沉淀两次,抽干备用。通过凝胶色谱分析,确认聚合物都具有单分散性,如图38所示。
(3)分别将步骤(2)制备的聚合物溶解在2mL的CF
3COOH,加入2.0mLHBr/CH
3COOH,反应4h,用油泵抽干溶液,加入DMF溶解,沉淀到乙醚中,去掉上清,抽干后用去离子水溶解,用截留分子量3500的透析袋在去离子水中透析24h,每2h换一次水,冻干备用。通过核磁表征证明结构正确,完全脱保护,如图39所示。
(4)将CDI置于圆底烧瓶中,加入无水二氯甲烷搅拌分散(1g CDI加5mL二氯甲烷),胶塞封口,用注射器缓慢加入N-羟基乙基哌啶或者2-(六甲撑亚胺)乙醇(CDI过量2倍),溶液逐渐澄清,反应4h后添加与二氯甲烷等量的去离子水,反应约5min,分液漏斗取下层二氯甲烷相,加入无水硫酸镁干燥1h,过滤去除固体,得到溶液并抽干,即R-CDI。
(5)将系列聚合物分别溶解于DMF中,用注射器加入R-CDI(过量2倍),加入三乙胺(与赖氨酸侧链氨基等量),反应24h,滴加到无水乙醚中沉淀,去掉乙醚,抽干,用DMSO溶解,用3500的透析袋装载,在去离子水中透析24h,2h换一次水,冻干备用。通过核磁表征证明结构正确,完全修饰,如图40和图41所示。
滴定所得修饰后的聚合物,得到质子化曲线和螺旋度曲线(方法同实施例1)。其中,
修饰后的聚肽,如图42所示,随着亮氨酸掺杂比例增加,聚肽的pKa逐步降低, 在pH=2时,聚肽侧链的三级胺完全质子化,此时,随着亮氨酸比例增加,多肽从非螺旋到稳定的螺旋结构,可能是共聚物中亮氨酸分散了侧链的电荷相互作用。计算pH=6.8和pH=7.4时的质子化率和螺旋度,并将亮氨酸所占多肽嵌段的比例作为一个参考指标进行分析,PD表示质子化率,具体数据如下表所示:
(二)苯丙氨酸共聚的聚肽
本实施例选择mPEG
44-NH
2(mPEG
2k-NH
2)引发Lys(Z)-NCA和Phe-NCA以不同比例共聚,得到总聚合度(n+m)接近的聚合物,并在HBr/CH
3COOH中脱保护得到mPEG-P(Lys-co-Phe),分别用N-羟基乙基哌啶和2-(六甲撑亚胺)乙醇修饰聚赖氨酸侧链,研究疏水性苯丙氨酸掺杂比例对聚肽对其pKa和螺旋结构的影响。反应方程式如下:
具体步骤同本实施例2中的(一),具体投料如下表所示:
编号 | 2 | 3 | 4 | 5 |
Phe理论聚合度 | 20 | 30 | 40 | 50 |
Lys(Z)理论聚合度 | 80 | 70 | 60 | 50 |
mPEG 44-NH 2投料质量/g | 0.1 | 0.1 | 0.1 | 0.1 |
Phe-NCA投料质量/g | 0.19 | 0.29 | 0.38 | 0.48 |
Lys(Z)-NCA投料质量/g | 1.22 | 1.07 | 0.92 | 0.76 |
所得未修饰的聚合物mPEG-P(Lys(Z)-co-Phe)通过凝胶渗透色谱表征,如图44所示,为单峰分布;其核磁谱图如图45所示,计算聚合度。在酸性条件下脱保护,通过N-羟基乙基哌啶修饰后的聚肽核磁如图46所示,已经修饰完全。通过2-(六甲撑亚胺)乙醇修饰后的聚肽核磁如图47所示,已经修饰完全。通过滴定,如图48所示,随着苯丙氨酸的比例增加,聚肽的pKa逐渐降低。
N-羟基乙基哌啶修饰后滴定结果如下表所示:
序号 | n | m | pKa |
2 | 85 | 22 | 7.28 |
3 | 76 | 32 | 7.2 |
4 | 62 | 43 | 7.06 |
5 | 54 | 53 | 6.92 |
2-(六甲撑亚胺)乙醇修饰后滴定结果如下表所示:
序号 | n | m | pKa |
2 | 85 | 22 | 7.22 |
3 | 76 | 32 | 6.9 |
4 | 62 | 43 | 6.98 |
5 | 54 | 53 | 6.83 |
将本实施例(二)中的mPEG
44-NH
2替换成mPEG
112-NH
2,合成Lys(Z)-NCA和Phe-NCA以不同比例共聚的聚肽,合成步骤与本实施例的(一)相同。
具体投料比例如下表:
编号 | 0 | 1 | 2 | 3 | 4 | 5 |
Phe理论聚合度 | 0 | 10 | 20 | 30 | 40 | 50 |
Lys(Z)理论聚合度 | 100 | 90 | 80 | 70 | 60 | 50 |
mPEG 112-NH 2投料质量/g | 0.2 | 0.2 | 0.2 | 0.2 | 0.2 | 0.2 |
Phe-NCA投料质量/g | 0 | 0.076 | 0.152 | 0.229 | 0.306 | 0.382 |
Lys(Z)-NCA投料质量/g | 1.225 | 1.103 | 0.980 | 0.857 | 0.735 | 0.612 |
所得聚合物通过凝胶渗透色谱表征,如图49所示,为单峰分布。脱保护后的核磁氢谱表征如图50所示,完全脱保护,通过N-羟基乙基哌啶修饰,得到聚肽产物通过核磁氢谱表征如图51所示,完全修饰。经过滴定(方法同实施例1)得到质子化率曲线,如图52所示,可以看出,随着苯丙氨酸的比例增加,聚肽的pKa逐渐降低,且比mPEG
44-NH
2引发的聚合物的pKa偏大。
序号 | n | m | pKa |
0 | 90 | 0 | 7.33 |
1 | 80 | 10 | 7.29 |
2 | 70 | 20 | 7.25 |
3 | 65 | 35 | 7.16 |
4 | 55 | 40 | 7.05 |
5 | 50 | 50 | 6.95 |
(三)正亮氨酸(NorLeu)、L-氨基辛酸(S-Capryline)或者色氨酸共聚的聚肽
采用本实施例的(一)相同的方法,通过共聚不同比例的正亮氨酸得到一系列聚合物,其凝胶渗透色谱表征如图53所示,聚合物都是单峰分布;根据核磁计算聚合物的聚合度,如图54所示;脱保护后的核磁氢谱表征如图55所示,证明脱保护完全;最后用N-羟基乙基哌啶的三级胺修饰,得到具有pH响应的聚肽产物,其核磁氢谱如图56所示,证明完全修饰。
采用本实施例的(一)相同的方法,制备得到哌啶环三级胺修饰的L-氨基辛酸共聚的聚肽,核磁如图57所示,证明结构正确。
采用本实施例的(一)相同的方法,得到疏水氨基酸为色氨酸,且掺杂比例为50%情况下的聚肽mPEG
44-P(Lys-C6
50-co-Trp
50),核磁结果如图58所示,证明结构正确。
在含有150mM的氯化钠体系中滴定聚肽的pKa,结果如下表所示:随着疏水单体掺杂比例越高,聚肽的pKa越低。
(四)疏水基团掺杂聚肽的抗肿瘤活性及选择性。
测试本实施例制备的系列共聚的聚肽大分子材料在正常组织和肿瘤组织特征pH下的细胞毒性,具体实验方法同实施例3和实施例4。
聚肽的溶血毒性结果如图59所示,聚肽的溶血活性不仅仅和pKa有关,还和疏水单体的亲疏水性有关,结果显示含有苯丙氨酸共聚的聚肽具有较低的溶血活性,这可能和β-折叠结构有关。
不同pH下的肿瘤细胞杀伤结果如图60和图61所示,疏水基团掺杂的聚肽均具有较好的肿瘤杀伤选择性,其中,含有苯环结构的聚肽具有更好的肿瘤杀伤选择性和较低的溶血毒性,这可能是因为苯环结构更有利于纳米颗粒的稳定。
(五)疏水基团掺杂聚肽的杀伤机制
细胞凋亡或坏死而造成的细胞膜结构的破坏会导致细胞浆内的酶释放到培养液里,其中包括酶活性较为稳定的乳酸脱氢酶(lactate dehydrogenase,LDH)。本发明的聚肽具有两亲性结构,会通过与细胞质膜发生作用而杀死细胞。以mPEG
44-P(Lys-C6
50-co-Trp
50)为例,测定细胞死亡过程中LDH释放,具体方法如下:
1)配制5.0mg/mL的mPEG
44-P(Lys-C6
50-co-Trp
50)水溶液。
2)药物处理:梯度稀释配制mPEG
44-P(Lys-C6
50-co-Trp
50)聚肽溶液,注意:为避免血清中乳酸脱氢酶的影响,药物处理时不需要加入血清。每孔加入100μL对应浓度的mPEG
44-P(Lys-C6
50-co-Trp
50)聚肽溶液,37℃恒温培养箱孵育4小时。
3)在处理时间结束前一小时在最大酶活性对照孔加入LDH释放试剂,加入量为原有培养液体积的10%,反复吹打数次混匀,然后继续在细胞培养箱中孵育。
4)到达预定时间后,将细胞培养板用多孔板离心机400g离心5min。分别取各孔的上清液80μL,加入到一新的96孔板相应孔中,随即进行样品测定。
5)各孔分别加入40μL LDH检测工作液。
6)混匀,室温(约25℃)避光孵育30min(可用铝箔包裹后置于水平摇床或侧摆摇床上缓慢摇动)。然后在490nm处测定吸光度。使用600nm或大于600nm的任一波长作为参考波长进行双波长测定。
7)计算(测得的各组吸光度均应减去背景空白对照孔吸光度):细胞毒性或死亡率(%)=(处理样品吸光度-样品对照孔吸光度)/(细胞最大酶活性的吸光度-样品对照孔吸光度)×100。
如图62所示,mPEG
44-P(Lys-C6
50-co-Trp
50)在pH=7.4下不会导致LDH释放,在pH=6.8下细胞死亡同时释放LDH,说明mPEG
44-P(Lys-C6
50-co-Trp
50)有可能是通过破膜方式杀死细胞。
(六)疏水基团掺杂聚肽的体内治疗效果
方法同实施例6,以mPEG
44-P(Lys-C6
50-co-Trp
50)为例,如图63所示,mPEG
44-P(Lys-C6
50-co-Trp
50)可以很好的抑制肿瘤的生长。
以上所述实施例的各技术特征可以进行任意的组合,为使描述简洁,未对以下实施例中的各个技术特征所有可能的组合都进行描述,然而,只要这些技术特征的组合不存在矛盾,都应当认为是本说明书记载的范围。
以上所述实施例仅表达了本发明的几种实施方式,其描述较为具体和详细,但并不能因此而理解为对本发明专利范围的限制。应当指出的是,对于本领域的普通技术人员来说,在不脱离本发明构思的前提下,还可以做出若干变形和改进,这些都属于本发明的保护范围。因此,本发明专利的保护范围应以所附权利要求为准。
Claims (40)
- 具有式(I)所示结构的破膜聚肽或者其立体异构体或者其药学上可接受的盐:L选自:-NH-C(=O)O-、-NH-C(=O)-、-C(=O)-NH-、-C(=O)-O-;R 1选自:亚烷基;R 2选自:C 1-C 12烷基、C 6-C 14芳基、C 6-C 14芳基取代的C 1-C 12烷基、苄氧羰基取代的C 1-C 12烷基、5-10元杂芳基取代的C 1-C 12烷基;R 3选自:亚烷基、C 6-C 14芳基取代的亚烷基;R 4、R 5分别独立地选自:烷基、C 6-C 14芳基取代的烷基,或者R 3、R 4和与其相连的氮原子一起形成杂环烷基;y选自:2-150;R 6选自:C 1-C 15烷基、C 6-C 14芳基、C 6-C 14芳基取代的C 1-C 15烷基;n+m大于0,并且n不为0;q选自:0、1、2、3、4。
- 根据权利要求1所述的破膜聚肽或者其立体异构体或者其药学上可接受的盐,其特征在于,R 1选自:C 1-C 6亚烷基。
- 根据权利要求2所述的破膜聚肽或者其立体异构体或者其药学上可接受的盐,其特征在于,R 1选自:-(CH 2) x-,其中,x选自:1、2、3、4、5、6。
- 根据权利要求6所述的破膜聚肽或者其立体异构体或者其药学上可接受的盐,其特征在于,R 3选自:C 1-C 6亚烷基、苯基取代的C 1-C 6亚烷基。
- 根据权利要求7所述的破膜聚肽或者其立体异构体或者其药学上可接受的盐,其特征在于,R 3选自:-(CH 2) x-、苯基取代的-(CH 2) x-;其中,x选自:1、2、3、4、5、6。
- 根据权利要求1-5任一项所述的破膜聚肽或者其立体异构体或者其药学上可接受的盐,其特征在于,R 4、R 5分别独立地选自:C 1-C 6烷基、苯基取代的C 1-C 6烷基、萘基取代的C 1-C 6烷基,或者R 4、R 5和与其相连的氮原子一起形成5-10元杂环烷基。
- 根据权利要求9所述的破膜聚肽或者其立体异构体或者其药学上可接受的盐,其特征在于,R 4、R 5分别独立地选自:C 1-C 4烷基、苯基取代的C 1-C 3烷基、萘基取代的C 1-C 3烷 基,或者R 4、R 5和与其相连的氮原子一起形成5-8元杂环烷基。
- 根据权利要求1-5任一项所述的破膜聚肽或者其立体异构体或者其药学上可接受的盐,其特征在于,R 6选自:C 1-C 6烷基、苯基、萘基、苯基取代的C 1-C 6烷基。
- 根据权利要求1-5任一项所述的破膜聚肽或者其立体异构体或者其药学上可接受的盐,其特征在于,R 2选自:C 1-C 8烷基、苯基、萘基、苯基取代的C 1-C 6烷基、苄氧羰基取代的C 1-C 6烷基、5-10元杂芳基取代的C 1-C 6烷基。
- 根据权利要求1-5任一项所述的破膜聚肽或者其立体异构体或者其药学上可接受的盐,其特征在于,R 2选自:甲基、乙基、正丙基、异丙基、正丁基、异丁基、戊烷基、己基、庚基、辛基、壬烷基、癸烷基、十一烷基、十二烷基、苯基、萘基、苄基、苄氧羰基取代的 乙基、苯并吡咯取代的乙基。
- 根据权利要求1-5任一项所述的破膜聚肽或者其立体异构体或者其药学上可接受的盐,其特征在于,y选自:30-120,优选为40-48或者108-116。
- 根据权利要求1-5任一项所述的破膜聚肽或者其立体异构体或者其药学上可接受的盐,其特征在于,n+m不小于5,更优选为不小于10。
- 根据权利要求17所述的破膜聚肽或者其立体异构体或者其药学上可接受的盐,其特征在于,n+m为10-200,更优选为10-150,更优选为10-110。
- 根据权利要求1-5任一项所述的破膜聚肽或者其立体异构体或者其药学上可接受的盐,其特征在于,m为0;n为5-200,优选为10-150,优选为10-110,n进一步优选为10-15、30-35、60-65、80-90、或者120-130。
- 根据权利要求1-5任一项所述的破膜聚肽或者其立体异构体或者其药学上可接受的盐,其特征在于,m为n+m的0-60%,更优选为0-50%。
- 一种破膜聚肽纳米颗粒,其特征在于,由权利要求1-23任一项所述的破膜聚肽在水介质中自组装形成。
- 一种权利要求24所述的破膜聚肽纳米颗粒的制备方法,其特征在于,包括如下步骤:将所述破膜聚肽溶于有机溶剂或者pH为1.5-2.5的盐酸溶液中,然后将所得溶液在搅拌状态下逐滴加入水中,继续搅拌,低温透析除去溶剂,即得所述的破膜聚肽纳米颗粒;优选地,所述有机溶剂为N,N-二甲基甲酰胺;优选地,所述破膜聚肽、所述有机溶剂或盐酸溶液、与所述水的配比为10mg~30mg:1mL:4-6mL;优选地,所述破膜聚肽纳米颗粒的制备方法包括如下步骤:将所述破膜聚肽按配比10mg~30mg:1mL溶于N,N-二甲基甲酰胺中,然后将所得溶液在转速为400~800转/分钟的搅拌状态下逐滴加入水中,继续以200~600转/分钟的转速搅拌8~20分钟,使用截留分子量为10000~20000的透析袋在水中透析除去溶剂,即得所述破膜聚肽纳米颗粒。
- 权利要求1-23任一项所述的破膜聚肽或者其立体异构体或者其药学上可接受的盐在制备预防和/或治疗肿瘤的药物中的应用。
- 权利要求24所述的破膜聚肽纳米颗粒在制备预防和/或治疗肿瘤的药物中的应用。
- 权利要求1-23任一项所述的破膜聚肽或者其立体异构体或者其药学上可接受的盐联合免疫检查点抑制剂在制备预防和/或治疗肿瘤的药物中的应用。
- 权利要求24所述的破膜聚肽纳米颗粒联合免疫检查点抑制剂在制备预防和/或治疗肿瘤的药物中的应用。
- 根据权利要求28或29所述的应用,其特征在于,所述免疫检查点抑制剂为PD-1抑制剂。
- 根据权利要求26-29任一项所述的应用,其特征在于,所述肿瘤为胰腺癌、黑色素瘤、结直肠癌、结肠癌、肺癌、舌鳞癌、宫颈癌、卵巢癌、骨肉瘤、肝癌、乳腺癌、膀胱癌、卵巢上皮癌。
- 权利要求1-23任一项所述的破膜聚肽或者其立体异构体或者其药学上可接受的盐在 制备抗细菌感染的药物中的应用。
- 权利要求24所述的破膜聚肽纳米颗粒在制备抗细菌感染的药物中的应用。
- 根据权利要求32或者33所述的应用,其特征在于,所述细菌为革兰氏阴性杆菌、革兰氏阴性假单胞菌、革兰氏阳性葡萄球菌、革兰氏阳性球菌、革兰氏阳性球杆菌、链球菌。
- 根据权利要求34所述的应用,其特征在于,所述细菌为大肠杆菌、沙门氏菌、金黄色葡萄球菌、肺炎克雷伯菌、铜绿假单胞菌、粪肠球菌、化脓性链球菌、肺炎链球菌、鲍曼不动杆菌、肺炎双球菌、绿脓杆菌。
- 一种预防和/或治疗肿瘤的药物,其特征在于,由活性成分和药学上可接受的辅料和/或载体制备得到,所述活性成分包括权利要求1-23任一项所述的破膜聚肽或者其立体异构体或者其药学上可接受的盐,和/或权利要求24所述的破膜聚肽纳米颗粒。
- 一种预防和/或治疗肿瘤的联合用药物,其特征在于,其活性成分包括:组分1:权利要求1-23任一项所述的破膜聚肽或者其立体异构体或者其药学上可接受的盐,和/或权利要求24所述的破膜聚肽纳米颗粒;以及组分2:组分1之外的抗肿瘤药物;所述组分1和组分2分别成为独立的给药单元,或所述组分1和组分2共同形成组合的给药单元。
- 根据权利要求37所述的预防和/或治疗肿瘤的联合用药物,其特征在于,所述组分2为免疫检查点抑制剂。
- 根据权利要求38所述的预防和/或治疗肿瘤的联合用药物,其特征在于,所述免疫检查点抑制剂为PD-1抑制剂。
- 一种抗细菌感染的药物,其特征在于,由活性成分和药学上可接受的辅料和/或载体制备得到,所述活性成分包括权利要求1-23任一项所述的破膜聚肽或者其立体异构体或者其药学上可接受的盐,和/或权利要求24所述的破膜聚肽纳米颗粒。
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202280005645.7A CN116635080A (zh) | 2021-12-21 | 2022-12-20 | pH敏感的破膜聚肽及其应用 |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202111572620.9 | 2021-12-21 | ||
CN202111572620 | 2021-12-21 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2023116702A1 true WO2023116702A1 (zh) | 2023-06-29 |
Family
ID=86901246
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/CN2022/140396 WO2023116702A1 (zh) | 2021-12-21 | 2022-12-20 | pH敏感的破膜聚肽及其应用 |
Country Status (2)
Country | Link |
---|---|
CN (1) | CN116635080A (zh) |
WO (1) | WO2023116702A1 (zh) |
Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN103087311A (zh) * | 2012-12-25 | 2013-05-08 | 深圳先进技术研究院 | 两亲性三嵌段聚合物及其制备方法和应用 |
CN103374128A (zh) * | 2012-04-28 | 2013-10-30 | 中国科学院深圳先进技术研究院 | 两亲性三嵌段共聚物、聚合物纳米载体制剂及制备方法 |
CN105440229A (zh) * | 2015-12-17 | 2016-03-30 | 华南理工大学 | 一种pH/温度双重敏感的两亲性共聚物及其制备与应用 |
WO2020092633A1 (en) * | 2018-10-30 | 2020-05-07 | Vanderbilt University | Graft copolymers, methods of forming graft copolymers, and methods of use thereof |
CN113549184A (zh) * | 2021-07-23 | 2021-10-26 | 南充市中心医院 | 同时具有pH和氧化还原双响应的聚合物载体、载药胶束及制备方法和应用 |
-
2022
- 2022-12-20 WO PCT/CN2022/140396 patent/WO2023116702A1/zh active Application Filing
- 2022-12-20 CN CN202280005645.7A patent/CN116635080A/zh active Pending
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN103374128A (zh) * | 2012-04-28 | 2013-10-30 | 中国科学院深圳先进技术研究院 | 两亲性三嵌段共聚物、聚合物纳米载体制剂及制备方法 |
CN103087311A (zh) * | 2012-12-25 | 2013-05-08 | 深圳先进技术研究院 | 两亲性三嵌段聚合物及其制备方法和应用 |
CN105440229A (zh) * | 2015-12-17 | 2016-03-30 | 华南理工大学 | 一种pH/温度双重敏感的两亲性共聚物及其制备与应用 |
WO2020092633A1 (en) * | 2018-10-30 | 2020-05-07 | Vanderbilt University | Graft copolymers, methods of forming graft copolymers, and methods of use thereof |
CN113549184A (zh) * | 2021-07-23 | 2021-10-26 | 南充市中心医院 | 同时具有pH和氧化还原双响应的聚合物载体、载药胶束及制备方法和应用 |
Non-Patent Citations (2)
Title |
---|
GAO ZHILIANG, ZHANG ZHONGHE, GUO JIANMAN, HAO JINGCHENG, ZHANG PEIYU, CUI JIWEI: "Polypeptide Nanoparticles with pH-Sheddable PEGylation for Improved Drug Delivery", LANGMUIR, AMERICAN CHEMICAL SOCIETY, US, vol. 36, no. 45, 17 November 2020 (2020-11-17), US , pages 13656 - 13662, XP093073666, ISSN: 0743-7463, DOI: 10.1021/acs.langmuir.0c02532 * |
SHENG LI, HONG CHEN; WEN-XIN FU; ZHI-BO LI: "Synthesis and Solution Self-assembly of pH-responsive ABC Triblock Copolymers", ACTA POLYMERICA SINICA, KEXUE CHUBANSHE, BEIJING, CN, vol. 8, 31 August 2015 (2015-08-31), CN , pages 982 - 988, XP093073664, ISSN: 1000-3304, DOI: 10.11777/j.issn1000-3304.2015.15075 * |
Also Published As
Publication number | Publication date |
---|---|
CN116635080A (zh) | 2023-08-22 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US9649309B2 (en) | Therapeutic uses of selected pyrimidine compounds with anti-Mer tyrosine kinase activity | |
US20200170960A1 (en) | Prostate specific membrane antigen (psma) targeted nanoparticles for therapy of prostate cancer | |
JP6759326B2 (ja) | 細胞結合分子の共役のための架橋連結体 | |
JP5826961B2 (ja) | 置換2,3−ジヒドロイミダゾ[1,2−c]キナゾリン塩類 | |
EP2477985B1 (en) | Crlx101 for use in the treatment of cancer | |
CN101754966B (zh) | 丙型肝炎病毒抑制剂 | |
JP4820758B2 (ja) | 新規ブロック共重合体、ミセル調製物及びそれを有効成分とする抗癌剤 | |
CN108289964A (zh) | 新型连接体及其用于药物和生物分子的特异性偶联 | |
KR101941929B1 (ko) | 2-아미노피리미딘계 화합물 및 이의 약물 조성물과 응용 | |
CN108811499A (zh) | 细胞结合分子的特异性偶联 | |
CN112125929A (zh) | 用于偶联的亲水链接体 | |
CA2813056C (en) | N-carboxyalkyl auristatins and the use thereof | |
WO2016207104A1 (de) | Antikörper-wirkstoff-konjugate (adcs) von ksp-inhibitoren mit anti-b7h3-antikörpern | |
CN111757757A (zh) | 吡咯并苯并二氮呯抗体共轭物 | |
JP2021507928A (ja) | 分岐連結体を備えたチューブリシン類縁体の共役体 | |
JP6532515B2 (ja) | 新規な含窒素化合物もしくはその塩またはそれらと金属との錯体 | |
EP2579887A1 (de) | Neue auristatin-derivate und ihre verwendung | |
CA2830174C (en) | A cyclodextrin-containing polymer-camptothecin conjugate, particle or composition in combination with one or more additional agent(s) | |
CN111704614A (zh) | 一种新型系列免疫激动剂 | |
CA3039811A1 (en) | Treatment of cancer | |
CN112334127A (zh) | 生物响应水凝胶基质及使用方法 | |
WO2023116702A1 (zh) | pH敏感的破膜聚肽及其应用 | |
CN117545479A (zh) | Pi3k抑制剂、纳米制剂及其用途 | |
CN116375994A (zh) | pH敏感的破膜聚酯及其应用 | |
EP1286673A2 (de) | Liganden von integrinrezeptoren |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
WWE | Wipo information: entry into national phase |
Ref document number: 202280005645.7 Country of ref document: CN |
|
121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 22910014 Country of ref document: EP Kind code of ref document: A1 |