CN109438707A - A kind of poly- dithiothreitol (DTT) nanometer system and its preparation method and application for anti-tumor drug delivering - Google Patents
A kind of poly- dithiothreitol (DTT) nanometer system and its preparation method and application for anti-tumor drug delivering Download PDFInfo
- Publication number
- CN109438707A CN109438707A CN201810997265.1A CN201810997265A CN109438707A CN 109438707 A CN109438707 A CN 109438707A CN 201810997265 A CN201810997265 A CN 201810997265A CN 109438707 A CN109438707 A CN 109438707A
- Authority
- CN
- China
- Prior art keywords
- dtt
- dithiothreitol
- drug
- poly
- polymer
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- VHJLVAABSRFDPM-QWWZWVQMSA-N dithiothreitol Chemical compound SC[C@@H](O)[C@H](O)CS VHJLVAABSRFDPM-QWWZWVQMSA-N 0.000 title claims abstract description 248
- 239000002246 antineoplastic agent Substances 0.000 title claims abstract description 28
- 229940041181 antineoplastic drug Drugs 0.000 title claims abstract description 28
- 238000002360 preparation method Methods 0.000 title claims abstract description 21
- 239000003814 drug Substances 0.000 claims abstract description 120
- 229940079593 drug Drugs 0.000 claims abstract description 77
- 229920000642 polymer Polymers 0.000 claims abstract description 55
- 239000002105 nanoparticle Substances 0.000 claims abstract description 38
- 238000000034 method Methods 0.000 claims abstract description 30
- 230000004043 responsiveness Effects 0.000 claims abstract description 25
- 239000002539 nanocarrier Substances 0.000 claims abstract description 7
- 239000002245 particle Substances 0.000 claims abstract description 7
- 239000000203 mixture Substances 0.000 claims abstract description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 29
- 239000003960 organic solvent Substances 0.000 claims description 24
- 230000009467 reduction Effects 0.000 claims description 15
- 238000006116 polymerization reaction Methods 0.000 claims description 14
- 238000006243 chemical reaction Methods 0.000 claims description 13
- 238000012377 drug delivery Methods 0.000 claims description 13
- 239000007787 solid Substances 0.000 claims description 12
- 238000003756 stirring Methods 0.000 claims description 11
- 239000003381 stabilizer Substances 0.000 claims description 10
- 238000005917 acylation reaction Methods 0.000 claims description 8
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 7
- 238000004090 dissolution Methods 0.000 claims description 7
- 239000003937 drug carrier Substances 0.000 claims description 7
- 239000000839 emulsion Substances 0.000 claims description 7
- 238000009835 boiling Methods 0.000 claims description 6
- 239000002904 solvent Substances 0.000 claims description 6
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 5
- 239000005864 Sulphur Substances 0.000 claims description 5
- 239000003054 catalyst Substances 0.000 claims description 5
- 150000007523 nucleic acids Chemical class 0.000 claims description 5
- 102000039446 nucleic acids Human genes 0.000 claims description 5
- 108020004707 nucleic acids Proteins 0.000 claims description 5
- 108090000623 proteins and genes Proteins 0.000 claims description 5
- 102000004169 proteins and genes Human genes 0.000 claims description 5
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 claims description 4
- 238000004945 emulsification Methods 0.000 claims description 4
- 230000008901 benefit Effects 0.000 claims description 3
- 125000001475 halogen functional group Chemical group 0.000 claims description 3
- UNXHWFMMPAWVPI-QWWZWVQMSA-N D-threitol Chemical compound OC[C@@H](O)[C@H](O)CO UNXHWFMMPAWVPI-QWWZWVQMSA-N 0.000 claims description 2
- UNXHWFMMPAWVPI-UHFFFAOYSA-N Erythritol Natural products OCC(O)C(O)CO UNXHWFMMPAWVPI-UHFFFAOYSA-N 0.000 claims description 2
- 230000010933 acylation Effects 0.000 claims 1
- 210000004881 tumor cell Anatomy 0.000 abstract description 10
- 238000013270 controlled release Methods 0.000 abstract description 5
- 125000002887 hydroxy group Chemical group [H]O* 0.000 abstract description 5
- 238000011161 development Methods 0.000 abstract description 2
- RWSXRVCMGQZWBV-WDSKDSINSA-N glutathione Chemical compound OC(=O)[C@@H](N)CCC(=O)N[C@@H](CS)C(=O)NCC(O)=O RWSXRVCMGQZWBV-WDSKDSINSA-N 0.000 description 54
- VSJKWCGYPAHWDS-FQEVSTJZSA-N camptothecin Chemical compound C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-FQEVSTJZSA-N 0.000 description 53
- 229960003180 glutathione Drugs 0.000 description 27
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 15
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 15
- 230000000694 effects Effects 0.000 description 15
- 239000012071 phase Substances 0.000 description 13
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical group CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 12
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 12
- 206010028980 Neoplasm Diseases 0.000 description 12
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 12
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 10
- 230000015572 biosynthetic process Effects 0.000 description 9
- 238000002296 dynamic light scattering Methods 0.000 description 9
- 108010024636 Glutathione Proteins 0.000 description 7
- 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 7
- 235000003969 glutathione Nutrition 0.000 description 7
- 229960000485 methotrexate Drugs 0.000 description 7
- 239000000178 monomer Substances 0.000 description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- 210000004027 cell Anatomy 0.000 description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 5
- 229910052786 argon Inorganic materials 0.000 description 5
- 238000002474 experimental method Methods 0.000 description 5
- 239000007789 gas Substances 0.000 description 5
- 239000001257 hydrogen Substances 0.000 description 5
- 229910052739 hydrogen Inorganic materials 0.000 description 5
- 230000035484 reaction time Effects 0.000 description 5
- 238000001228 spectrum Methods 0.000 description 5
- 230000008685 targeting Effects 0.000 description 5
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 4
- 239000002202 Polyethylene glycol Substances 0.000 description 4
- 238000010521 absorption reaction Methods 0.000 description 4
- 239000003513 alkali Substances 0.000 description 4
- 201000011510 cancer Diseases 0.000 description 4
- 230000008859 change Effects 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- 230000003013 cytotoxicity Effects 0.000 description 4
- 231100000135 cytotoxicity Toxicity 0.000 description 4
- 201000010099 disease Diseases 0.000 description 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 4
- 229940022353 herceptin Drugs 0.000 description 4
- 230000002209 hydrophobic effect Effects 0.000 description 4
- 229910052757 nitrogen Inorganic materials 0.000 description 4
- 229920001223 polyethylene glycol Polymers 0.000 description 4
- WCGUUGGRBIKTOS-GPOJBZKASA-N (3beta)-3-hydroxyurs-12-en-28-oic acid Chemical compound C1C[C@H](O)C(C)(C)[C@@H]2CC[C@@]3(C)[C@]4(C)CC[C@@]5(C(O)=O)CC[C@@H](C)[C@H](C)[C@H]5C4=CC[C@@H]3[C@]21C WCGUUGGRBIKTOS-GPOJBZKASA-N 0.000 description 3
- KLWPJMFMVPTNCC-UHFFFAOYSA-N Camptothecin Natural products CCC1(O)C(=O)OCC2=C1C=C3C4Nc5ccccc5C=C4CN3C2=O KLWPJMFMVPTNCC-UHFFFAOYSA-N 0.000 description 3
- CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical compound ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 description 3
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- 230000001093 anti-cancer Effects 0.000 description 3
- 230000005540 biological transmission Effects 0.000 description 3
- 229940127093 camptothecin Drugs 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 229960004397 cyclophosphamide Drugs 0.000 description 3
- 238000001514 detection method Methods 0.000 description 3
- VSJKWCGYPAHWDS-UHFFFAOYSA-N dl-camptothecin Natural products C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)C5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-UHFFFAOYSA-N 0.000 description 3
- YJGVMLPVUAXIQN-UHFFFAOYSA-N epipodophyllotoxin Natural products COC1=C(OC)C(OC)=CC(C2C3=CC=4OCOC=4C=C3C(O)C3C2C(OC3)=O)=C1 YJGVMLPVUAXIQN-UHFFFAOYSA-N 0.000 description 3
- 150000002148 esters Chemical class 0.000 description 3
- 229960002949 fluorouracil Drugs 0.000 description 3
- 229910052736 halogen Inorganic materials 0.000 description 3
- 150000002367 halogens Chemical class 0.000 description 3
- 229960001627 lamivudine Drugs 0.000 description 3
- JTEGQNOMFQHVDC-NKWVEPMBSA-N lamivudine Chemical compound O=C1N=C(N)C=CN1[C@H]1O[C@@H](CO)SC1 JTEGQNOMFQHVDC-NKWVEPMBSA-N 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Substances [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 3
- 229910052697 platinum Inorganic materials 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 210000001519 tissue Anatomy 0.000 description 3
- 229940096998 ursolic acid Drugs 0.000 description 3
- PLSAJKYPRJGMHO-UHFFFAOYSA-N ursolic acid Natural products CC1CCC2(CCC3(C)C(C=CC4C5(C)CCC(O)C(C)(C)C5CCC34C)C2C1C)C(=O)O PLSAJKYPRJGMHO-UHFFFAOYSA-N 0.000 description 3
- FUXVKZWTXQUGMW-FQEVSTJZSA-N 9-Aminocamptothecin Chemical compound C1=CC(N)=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 FUXVKZWTXQUGMW-FQEVSTJZSA-N 0.000 description 2
- 206010006187 Breast cancer Diseases 0.000 description 2
- 208000026310 Breast neoplasm Diseases 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- LEVWYRKDKASIDU-QWWZWVQMSA-N D-cystine Chemical compound OC(=O)[C@H](N)CSSC[C@@H](N)C(O)=O LEVWYRKDKASIDU-QWWZWVQMSA-N 0.000 description 2
- YTBSYETUWUMLBZ-QWWZWVQMSA-N D-threose Chemical compound OC[C@@H](O)[C@H](O)C=O YTBSYETUWUMLBZ-QWWZWVQMSA-N 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- XLYOFNOQVPJJNP-ZSJDYOACSA-N Heavy water Chemical compound [2H]O[2H] XLYOFNOQVPJJNP-ZSJDYOACSA-N 0.000 description 2
- -1 Herceptin Chemical compound 0.000 description 2
- UGQMRVRMYYASKQ-KQYNXXCUSA-N Inosine Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C2=NC=NC(O)=C2N=C1 UGQMRVRMYYASKQ-KQYNXXCUSA-N 0.000 description 2
- 229930010555 Inosine Natural products 0.000 description 2
- 102000014150 Interferons Human genes 0.000 description 2
- 108010050904 Interferons Proteins 0.000 description 2
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 2
- 108010040201 Polymyxins Proteins 0.000 description 2
- 239000004372 Polyvinyl alcohol Substances 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 108010023197 Streptokinase Proteins 0.000 description 2
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Natural products CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 2
- 229960000583 acetic acid Drugs 0.000 description 2
- 239000003242 anti bacterial agent Substances 0.000 description 2
- 230000000259 anti-tumor effect Effects 0.000 description 2
- 230000000840 anti-viral effect Effects 0.000 description 2
- 229940088710 antibiotic agent Drugs 0.000 description 2
- 238000013459 approach Methods 0.000 description 2
- 230000015556 catabolic process Effects 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 229960003067 cystine Drugs 0.000 description 2
- 238000006731 degradation reaction Methods 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 229940088598 enzyme Drugs 0.000 description 2
- 239000012362 glacial acetic acid Substances 0.000 description 2
- 230000036541 health Effects 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- 229960003786 inosine Drugs 0.000 description 2
- 229940079322 interferon Drugs 0.000 description 2
- 230000003834 intracellular effect Effects 0.000 description 2
- 229940076783 lucentis Drugs 0.000 description 2
- 238000003760 magnetic stirring Methods 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- HAWPXGHAZFHHAD-UHFFFAOYSA-N mechlorethamine Chemical compound ClCCN(C)CCCl HAWPXGHAZFHHAD-UHFFFAOYSA-N 0.000 description 2
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 2
- 229940087004 mustargen Drugs 0.000 description 2
- 210000000056 organ Anatomy 0.000 description 2
- 229960001237 podophyllotoxin Drugs 0.000 description 2
- YJGVMLPVUAXIQN-XVVDYKMHSA-N podophyllotoxin Chemical compound COC1=C(OC)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@H](O)[C@@H]3[C@@H]2C(OC3)=O)=C1 YJGVMLPVUAXIQN-XVVDYKMHSA-N 0.000 description 2
- YVCVYCSAAZQOJI-UHFFFAOYSA-N podophyllotoxin Natural products COC1=C(O)C(OC)=CC(C2C3=CC=4OCOC=4C=C3C(O)C3C2C(OC3)=O)=C1 YVCVYCSAAZQOJI-UHFFFAOYSA-N 0.000 description 2
- 229940041153 polymyxins Drugs 0.000 description 2
- 229920002451 polyvinyl alcohol Polymers 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 238000005086 pumping Methods 0.000 description 2
- 238000002390 rotary evaporation Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 231100000331 toxic Toxicity 0.000 description 2
- 230000002588 toxic effect Effects 0.000 description 2
- 238000011282 treatment Methods 0.000 description 2
- 238000010792 warming Methods 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- DZNNFZGDBUXWMV-ZUWDIFAMSA-N 581079-18-7 Chemical compound C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(OC(=O)[C@H](C)NC(=O)COCCOCC(=O)N[C@@H](C)C(=O)O[C@@]3(CC)C5=C(C(N6CC7=CC8=CC=CC=C8N=C7C6=C5)=O)COC3=O)CC)C4=NC2=C1 DZNNFZGDBUXWMV-ZUWDIFAMSA-N 0.000 description 1
- 241000219198 Brassica Species 0.000 description 1
- 235000003351 Brassica cretica Nutrition 0.000 description 1
- 235000003343 Brassica rupestris Nutrition 0.000 description 1
- 206010059866 Drug resistance Diseases 0.000 description 1
- 102000010834 Extracellular Matrix Proteins Human genes 0.000 description 1
- 108010037362 Extracellular Matrix Proteins Proteins 0.000 description 1
- 229940123457 Free radical scavenger Drugs 0.000 description 1
- SUAKHGWARZSWIH-UHFFFAOYSA-N N,N‐diethylformamide Chemical compound CCN(CC)C=O SUAKHGWARZSWIH-UHFFFAOYSA-N 0.000 description 1
- NQTADLQHYWFPDB-UHFFFAOYSA-N N-Hydroxysuccinimide Chemical compound ON1C(=O)CCC1=O NQTADLQHYWFPDB-UHFFFAOYSA-N 0.000 description 1
- LOUPRKONTZGTKE-WZBLMQSHSA-N Quinine Chemical compound C([C@H]([C@H](C1)C=C)C2)C[N@@]1[C@@H]2[C@H](O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-WZBLMQSHSA-N 0.000 description 1
- UCKMPCXJQFINFW-UHFFFAOYSA-N Sulphide Chemical compound [S-2] UCKMPCXJQFINFW-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 238000013019 agitation Methods 0.000 description 1
- 229960004821 amikacin Drugs 0.000 description 1
- LKCWBDHBTVXHDL-RMDFUYIESA-N amikacin Chemical compound O([C@@H]1[C@@H](N)C[C@H]([C@@H]([C@H]1O)O[C@@H]1[C@@H]([C@@H](N)[C@H](O)[C@@H](CO)O1)O)NC(=O)[C@@H](O)CCN)[C@H]1O[C@H](CN)[C@@H](O)[C@H](O)[C@H]1O LKCWBDHBTVXHDL-RMDFUYIESA-N 0.000 description 1
- 229940024606 amino acid Drugs 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 229960000723 ampicillin Drugs 0.000 description 1
- AVKUERGKIZMTKX-NJBDSQKTSA-N ampicillin Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C(O)=O)(C)C)=CC=CC=C1 AVKUERGKIZMTKX-NJBDSQKTSA-N 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- QKSKPIVNLNLAAV-UHFFFAOYSA-N bis(2-chloroethyl) sulfide Chemical compound ClCCSCCCl QKSKPIVNLNLAAV-UHFFFAOYSA-N 0.000 description 1
- 210000001124 body fluid Anatomy 0.000 description 1
- 239000010839 body fluid Substances 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- 230000007541 cellular toxicity Effects 0.000 description 1
- 229940106164 cephalexin Drugs 0.000 description 1
- ZAIPMKNFIOOWCQ-UEKVPHQBSA-N cephalexin Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@@H]3N(C2=O)C(=C(CS3)C)C(O)=O)=CC=CC=C1 ZAIPMKNFIOOWCQ-UEKVPHQBSA-N 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 239000000599 controlled substance Substances 0.000 description 1
- 230000000254 damaging effect Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 239000003405 delayed action preparation Substances 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 238000009513 drug distribution Methods 0.000 description 1
- 238000003255 drug test Methods 0.000 description 1
- 229960000980 entecavir Drugs 0.000 description 1
- YXPVEXCTPGULBZ-WQYNNSOESA-N entecavir hydrate Chemical compound O.C1=NC=2C(=O)NC(N)=NC=2N1[C@H]1C[C@H](O)[C@@H](CO)C1=C YXPVEXCTPGULBZ-WQYNNSOESA-N 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 210000002744 extracellular matrix Anatomy 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 229920001002 functional polymer Polymers 0.000 description 1
- 229960002963 ganciclovir Drugs 0.000 description 1
- IRSCQMHQWWYFCW-UHFFFAOYSA-N ganciclovir Chemical compound O=C1NC(N)=NC2=C1N=CN2COC(CO)CO IRSCQMHQWWYFCW-UHFFFAOYSA-N 0.000 description 1
- 229960002989 glutamic acid Drugs 0.000 description 1
- 150000004676 glycans Chemical class 0.000 description 1
- 239000000017 hydrogel Substances 0.000 description 1
- 238000005286 illumination Methods 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 230000002147 killing effect Effects 0.000 description 1
- 239000002502 liposome Substances 0.000 description 1
- 229920002521 macromolecule Polymers 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 238000005374 membrane filtration Methods 0.000 description 1
- 125000001434 methanylylidene group Chemical group [H]C#[*] 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 235000010460 mustard Nutrition 0.000 description 1
- AJFDBNQQDYLMJN-UHFFFAOYSA-N n,n-diethylacetamide Chemical compound CCN(CC)C(C)=O AJFDBNQQDYLMJN-UHFFFAOYSA-N 0.000 description 1
- OAOSXODRWGDDCV-UHFFFAOYSA-N n,n-dimethylpyridin-4-amine;4-methylbenzenesulfonic acid Chemical compound CN(C)C1=CC=NC=C1.CC1=CC=C(S(O)(=O)=O)C=C1 OAOSXODRWGDDCV-UHFFFAOYSA-N 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 238000011275 oncology therapy Methods 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 150000003904 phospholipids Chemical class 0.000 description 1
- 230000004962 physiological condition Effects 0.000 description 1
- 239000002861 polymer material Substances 0.000 description 1
- 229920001282 polysaccharide Polymers 0.000 description 1
- 239000005017 polysaccharide Substances 0.000 description 1
- 230000001376 precipitating effect Effects 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 229930002341 quinoline alkaloid Natural products 0.000 description 1
- 239000002516 radical scavenger Substances 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 239000013049 sediment Substances 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 229960005202 streptokinase Drugs 0.000 description 1
- 150000005846 sugar alcohols Chemical class 0.000 description 1
- 150000003462 sulfoxides Chemical class 0.000 description 1
- 238000002626 targeted therapy Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000005909 tumor killing Effects 0.000 description 1
- 238000000108 ultra-filtration Methods 0.000 description 1
- 238000002604 ultrasonography Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G75/00—Macromolecular compounds obtained by reactions forming a linkage containing sulfur with or without nitrogen, oxygen, or carbon in the main chain of the macromolecule
- C08G75/02—Polythioethers
- C08G75/0204—Polyarylenethioethers
- C08G75/025—Preparatory processes
- C08G75/0268—Preparatory processes using disulfides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
- A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
-
- 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
- A61K47/69—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 conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
- A61K47/6921—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 conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere
- A61K47/6927—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 conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere the form being a solid microparticle having no hollow or gas-filled cores
- A61K47/6929—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 conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere the form being a solid microparticle having no hollow or gas-filled cores the form being a nanoparticle, e.g. an immuno-nanoparticle
- A61K47/6931—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 conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere the form being a solid microparticle having no hollow or gas-filled cores the form being a nanoparticle, e.g. an immuno-nanoparticle the material constituting the nanoparticle being a polymer
- A61K47/6935—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 conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere the form being a solid microparticle having no hollow or gas-filled cores the form being a nanoparticle, e.g. an immuno-nanoparticle the material constituting the nanoparticle being a polymer the polymer being obtained otherwise than by reactions involving carbon to carbon unsaturated bonds, e.g. polyesters, polyamides or polyglycerol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Nanotechnology (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Polymers & Plastics (AREA)
- Immunology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The medicament-carried nano system and its preparation method and application based on poly- dithiothreitol (DTT) that the invention discloses a kind of.The present invention prepares the controllable poly- dithiothreitol (DTT) of the novel polymer containing disulfide bond of the Nomenclature Composition and Structure of Complexes, successfully constructs the nano-carrier of anti-tumor drug targeted delivery;And different anti-tumor drugs is grafted on the hydroxyl on poly- dithiothreitol (DTT), then by nanoparticles preparation processes such as mon-galacta method, nanoprecipitation methods, form uniform particle diameter and stable nanoparticle solution.Property is stablized after the poly- dithiothreitol (DTT) grafting drug of novel polymer of the invention, there are good biocompatibility and degradability, and there is GSH quickly to restore responsiveness, improve the targeted delivery efficiency of nano-carrier, realize positioning controlled release of the drug in tumour cell, the bioavilability for improving dewatering medicament has a good application prospect and wide development space in field of medicaments.
Description
Technical field
The invention belongs to functional polymer materials and biomedicine technical field.More particularly, to one kind for anti-swollen
The poly- dithiothreitol (DTT) nanometer system and its preparation method and application of tumor medicine delivering.
Background technique
Malignant tumour has become one of the principal disease for threatening human life health.Although clinically having more than more than 90 kinds to resist
Tumour medicine, but most anti-tumor drugs are there are poorly water-soluble, controlled-release effect is poor, targeting is poor and it is strong to promote tumour to generate
The disadvantages of strong drug resistance.Meanwhile these drug normal tissues and organ can also bring serious toxic side effect, reduce human body and exempt from
Epidemic disease power.
Stimulating responsive polymer system because can be responded to external environments such as temperature, illumination, enzyme, pH, by
It is widely used in Nano medication field.Wherein reduction response controlled release method is reported by many researchers, is mainly used for target
Preparation to the controlled drug delivery systems of tumour cell.Reduction responsiveness generally refers to that will there is the group of reduction-sensitive to be introduced into
In high molecular polymer, using the reduction of high concentration glutathione in tumour cell, by drug system these are specific
Group such as disulfide bonds, to release medicine intracellular.Glutathione is free radical scavenger important in vivo and resists
Oxidant, studies have shown that concentration of the glutathione in body fluid and extracellular matrix is 2~20 μM, intracytoplasmic concentration is 2
~10mM, and the glutathione concentrations in tumour cell are at least 4 times of normal cell.The change of this special concentration gradient
Change, the delivery system containing disulfide bond is allowed to show broad application prospect in field of biomedicine in recent years.
Traditional chemotherapy and targeted therapy is the important and strong means of current clinical cancer therapy, but in therapeutic process
In, since the specificity of drug is lower, water-soluble low, toxicity is high, and causing also can be inevitable while killing cancer cell
Damaging action is generated to organism normal cell, to influence the function of body health organ.For example, camptothecine be 1966 by
The anticancer drug that M.E.Wall and M.C.Wani are screened is a kind of quinoline alkaloid.Since camptothecine water solubility is lower,
It is difficult to prepare comparatively ideal preparation.Currently, camptothecine for nanometer medicine-carried system method there are mainly two types of: physics carries medicine and change
It learns and carries medicine.The former is by liposome, and micella etc. contains camptothecine using physical absorption, and the latter is then by chemical bond by camplotheca acuminata
Alkali grafts on carrier.Many studies have shown that the stability of its lactonic ring can be increased by the grafting of position 20 of camptothecins hydroxyl, change
Become hydrophilicity and hydrophobicity.Most commonly camptothecine is grafted on the polyethylene glycol of 3kDa to 40kDa and forms polyethyleneglycol prodrug.
Camptothecine is connected to the both ends for the polyethylene glycol that molecular weight is 4000, at present by the Prothecan that Enzon company is developed
Through entering III clinical investigation phase.In addition to this, the macromolecular carrier for camptothecine grafting is there are also L-glutamic acid (PGA),
Polysaccharide and some synthesis macromolecules.
Summary of the invention
The technical problem to be solved by the present invention is to overcome the defect of the above-mentioned prior art and deficiencies, provide a kind of for anti-swollen
The poly- dithiothreitol (DTT) nanometer system of tumor medicine delivering.The present invention quickly and is easily prepared into using dithiothreitol (DTT) as monomer
To the poly- dithiothreitol (DTT) with good biocompatibility;With poly- dithiothreitol (DTT) grafted hydrophobic anti-tumor drug to shape
At anti-tumor drug delivery system, realize the controllable load medicine of dewatering medicament, improve the dissolubility of drug, greatly improve
The utilizability of dewatering medicament, and there is GSH quickly to restore responsiveness, improve the targeting of anti-tumor drug.
The first purpose of the invention is to provide a kind of polymer P DTT.
A second object of the present invention is to provide the preparation methods of above-mentioned polymer P DTT.
Third object of the present invention is to provide above-mentioned polymer P DTT as or in terms of preparing drug carrier system
Using.
Fourth object of the present invention is to provide a kind of poly- two sulphur threose for drug delivery with reduction responsiveness
Alcohol nanometer system.
Fifth object of the present invention is to provide the preparation methods of above-mentioned poly- dithiothreitol (DTT) nanometer system.
Sixth object of the present invention is to provide the poly- dithiothreitol (DTT) nanometer systems of above-mentioned polymer P DTT or above-mentioned to make
Application in standby anticancer drug.
Above-mentioned purpose of the present invention is achieved through the following technical solutions:
A kind of polymer P DTT, the polymer P DTT for drug delivery is by multiple duplicate dithiothreitol (DTT) structures
Unit composition, shown in structural formula such as following formula (I):
Wherein, n=5~10000.
Preferably, the molecular weight of the polymer P DTT is 1500~45000.
The present invention prepares the controllable poly- dithiothreitol (DTT) of the novel polymer containing disulfide bond (PDT T) of the Nomenclature Composition and Structure of Complexes, at
Function constructs the nano-carrier of anti-tumor drug targeted delivery;And different anti-tumor drugs is grafted to poly- dithiothreitol (DTT)
(PDTT) on the hydroxyl on (PDTT-CPT), then by nanoparticles preparation processes such as mon-galacta method, nanoprecipitation methods, partial size is formed
Uniform and stable nanoparticle solution, or orally available sustained-release preparation or injectable can also be prepared by other formulation methods
The pharmaceutical carriers such as type hydrogel.
Property is stablized after novel polymer of the invention poly- dithiothreitol (DTT) grafting drug, has good biocompatibility and can
Degradability, and there is GSH quickly to restore responsiveness, the targeted delivery efficiency of nano-carrier is improved, realizes drug in tumour
Intracellular positioning controlled release, improves the bioavilability of dewatering medicament, for disease it is effective treatment opened up it is a kind of newly
Approach.
The present invention also provides the preparation methods of polymer P DTT: after dithiothreitol (DTT) is dissolved with organic solvent A, true
Polymerization reaction is carried out under empty condition, the sulfydryl of dithiothreitol (DTT) end is made to be oxidized to disulfide bond, to obtain polymer P DTT.
Reaction equation is as follows:
Preferably, the temperature of the polymerization reaction is 40~180 DEG C, and the time of the polymerization reaction is 10min~48h.
It is highly preferred that the temperature of the polymerization reaction is 90~100 DEG C, the time of the polymerization reaction is 10~20h.
Preferably, the dithiothreitol (DTT) and the mass volume ratio of organic solvent A are 1~5g:2~20mL.Such as 1:2,1:
5,1:10,1:15,1:20,3:10,4:10,5:2,5:5,5:10,5:15,5:20g/mL etc..
It is highly preferred that the dithiothreitol (DTT) and the mass volume ratio of organic solvent A are 2~4g:5~11mL.As 2:5,
2:8,2:11,3:5,3:7,3:11,4:5,4:8,4:11g/mL etc..
Preferably, the organic solvent A be selected from dimethyl sulfoxide, n,N-Dimethylformamide, N, N- diethylformamide,
One of N, N- diethyl acetamide, acetone, tetrahydrofuran are a variety of.
The present invention also provides polymer P DTT as or application in terms of preparing drug carrier system.
Preferably, the transmitting carrier is the transmitting carrier with reduction responsiveness.
The present invention also provides it is a kind of with reduction responsiveness the poly- dithiothreitol (DTT) nanometer system for drug delivery,
It is using the polymer P DTT as nano-carrier carrying medicament.
The present invention also provides the preparation methods of the poly- dithiothreitol (DTT) nanometer system, comprising the following steps:
S1. drug and organic basic catalyst are added solid phosgene and be acylated instead after organic solvent B dissolution stirring
It answers, then the polymer P DTT of dissolution in a solvent is added dropwise and carries out graft reaction, be grafted the polymer of drug
PDTT;
S2. partial size is prepared by single emulsion method or nanoprecipitation method in the above-mentioned polymer P DTT for being grafted drug
Uniform, stable nanoparticle solution, the as described poly- dithiothreitol (DTT) nanometer system for being used for drug delivery.
Preferably, in step S1, the mass ratio of the drug and organic basic catalyst is 1~5:1~10.Such as 1:1,1:
2.5,1:5,1:8,1:10,1:1,1:2.5,1:5,1:8,1:10,3:5:3:9,4:1,4:9,5:1,5:8 etc..
It is highly preferred that the mass ratio of the drug and organic basic catalyst is 1~2:1~5 in step S1.As 1:1,
1:5,1.5:1,1.5:4,2:1:2:3,2:5 etc..
Preferably, in step S1, the concentration of the polymer P DTT is 0.01~2.5g/mL.Such as 0.01,0.03,
0.045,0.1,0.15,0.2,0.25g/mL etc..
It is highly preferred that the concentration of the polymer P DTT is 0.01~1g/mL in step S1.
Preferably, in step S1, the time of the acylation reaction is 10~60min;The time of the graft reaction be 3~
48h。
Preferably, in step S1, the temperature of the graft reaction is room temperature.The room temperature refers to 15~25 DEG C.
Preferably, in step S1, the acylation reaction and graft reaction are to carry out under protection of argon gas.
Preferably, in step S1, the mixing time is 1min~1h.
Preferably, in step S1, the organic solvent B is selected from methylene chloride and/or tetrahydrofuran.
There is no particular/special requirement to the solvent for dissolving polymer P DTT, polymer P DTT can be dissolved.
Preferably, in step S1, the organic basic catalyst is selected from 4-dimethylaminopyridine (DMAP), 4- dimethylamino
Any one in pyridine-p- toluene fulfonate (DPTS) or n-hydroxysuccinimide (NHS).
Preferably, in step S2, method that nanoparticle solution is prepared by single emulsion method, comprising the following steps:
S21. it will be grafted the polymer P DTT of drug, ultrasonic dissolution is in organic solvent C immiscible and low boiling point with water
In, obtain emulsion oil phase;
S22. stabilizer is added into pure water and is used as water phase, by oil it is mutually mixed with water after, ultrasonic removing organic solvent C,
Uniform particle diameter, stable nanoparticle solution can be obtained.
It is described to refer to that solubility in water is less than the organic solvent of 0.01g with the immiscible organic solvent of water.
The organic solvent of the low boiling point refers to that boiling point is lower than 60 DEG C of organic solvent.
Preferably, in step S21, the organic solvent C immiscible with water and low boiling point, including but not limited to chloroform,
Methylene chloride, acetone or ethyl acetate etc..
Preferably, in step S2, method that nanoparticle solution is prepared by nanoprecipitation method, comprising the following steps:
S221. it will be grafted the polymer P DTT and stabilizer of drug, be dissolved in organic solvent D miscible with water, shape
At oily phase;
S222. under stirring condition, oil is mutually added drop-wise in water phase, uniform particle diameter, stable nanoparticle solution can be obtained.
Preferably, in step S221, oil is mutually slowly dropped in water phase, rate of addition is 0.01~1mL/ seconds.
Preferably, in step S221, by the polymer P DTT and the stabilizer that have been grafted drug with the mass ratio of 1~20:1,
It is completely dissolved in organic solvent D miscible with water.Such as 1:1,2:1,5:1,10:1,20:1.
It is highly preferred that in step S221, it is complete by the polymer P DTT and stabilizer that have been grafted drug with the mass ratio of 5:1
In fully dissolved organic solvent D miscible with water.
The organic solvent D miscible with water refers to that solubility in water is greater than the organic solvent of 100g.
Preferably, the organic solvent D miscible with water includes but is not limited to dimethyl sulfoxide, N, N- dimethyl formyl
Amine, tetrahydrofuran, dioxane, pyridine etc..
Preferably, in step S22 neutralization procedure S221, the stabilizer includes that distearoylphosphatidylethanolamine-is poly-
Ethylene glycol (DSPE-PEG) class stabilizer, polyvinyl alcohol (PVA), phospholipid molecule etc..
The drug includes hydrophobicity or hydrophilic drug.Polymer P DTT of the invention can load hydrophobicity medicine
Object improves the dissolubility of hydrophobic drug, improves its bioavilability, can also load hydrophilic medicament, has good biology
Compatibility.
Preferably, the drug includes containing-OH ,-NH2,-COOH or halogen functional group drug, protein medicaments or core
Acids drug.Experiment discovery, polymer P DTT of the present invention can be realized containing-OH ,-NH2,-COOH or halogen functional group
The high-efficient carrier of the drugs such as drug, protein medicaments, nucleic acid drug.
The protein medicaments include but is not limited to Herceptin, Lucentis, interferon, hematopoietin,
The protein medicaments such as streptokinase.
The nucleic acid drug includes but is not limited to the nucleic acid drugs such as Lamivudine, Aldoforwe ester, inosine, coacetylase.
The drug includes anti-tumor drug, antibiotics, antiviral class drug.
The anti-tumor drug is selected from camptothecine, ursolic acid, methotrexate (MTX), 9-aminocamptothecin, Herceptin, nitrogen
One of mustard, cis-platinum, cyclophosphamide, fluorouracil, podophyllotoxin etc. are a variety of.
The antibiotics includes polymyxins, ampicillin, cefalexin, amikacin etc..
The antiviral class drug includes Lamivudine, Ganciclovir, Entecavir, Aldoforwe ester etc..
Shown in the structural formula such as following formula (II) of the poly- dithiothreitol (DTT) grafting camptothecine:
Shown in the structural formula such as following formula (III) of the poly- dithiothreitol (DTT) grafting ursolic acid:
Shown in the poly- dithiothreitol (DTT) grafting structure of methotrexate formula such as following formula (IV):
Shown in the structural formula such as following formula (V) of the poly- dithiothreitol (DTT) grafting 9-aminocamptothecin:
The drug of the functional group Han-COOH includes that methotrexate (MTX), amino acids (polymyxins) drug, protide are (dry
Disturb element) drug etc..
The poly- dithiothreitol (DTT) and drug (R-COOH) with carboxyl react, and generate the drug with ester bond.
Shown in the structural formula such as following formula (VI) of poly- dithiothreitol (DTT) grafting drug containing carboxyl:
The halogen-containing drug R-X (X=F, Cl, Br, I) includes mustargen, cis-platinum, cyclophosphamide, fluorouracil etc..
The poly- dithiothreitol (DTT) and the drug with halogen react, and generate the drug with ehter bond.
Shown in the structural formula such as following formula (VII) of poly- dithiothreitol (DTT) grafting drug containing halogen:
The nanoparticle solution prepared by above method by DLS measurement, the size controlling of the nanoparticle 10~
500nm。
It is highly preferred that the partial size of the nanoparticle is 10~150nm.
Nanoparticle after the polymer poly dithiothreitol (DTT) grafting drug has quick GSH responsiveness.When according to 37 DEG C
In the PBS solution of different GSH concentration, nanometer system release free drug testing result show: be not present GSH phase
Than in the presence of GSH, free drug release increased significantly the nanoparticle, and with the raising of GSH concentration, nanometer
The speed that system discharges free drug is faster.This is because the cystine linkage in the sulfydryl attack system of GSH, so that cystine linkage restores
At sulfydryl, sulfydryl increases the degradation for accelerating degradable chemical key (such as ester bond) in environment.It is above to act on while carrying out, add
The speed degradation of nanometer system, drug are able to quick release.
Shown in the structure such as following formula (VIII) of reduced glutathione (GSH):
Poly- dithiothreitol (DTT) of the invention has good pharmaceutical carrier application prospect, is also embodied in: by poly- two sulphur
Threitol new material and monomer dithiothreitol (DTT) carry out the detection of MCF-7/A549/HpeG-2/CT-26/4T1 cytotoxicity and send out
Existing, in sufficiently large concentration range, poly- dithiothreitol (DTT) does not obviously inhibit cell growth, and with two sulphur threose of monomer
Alcohol is compared, and shows better biocompatibility.After being grafted drug formation nanometer system, compared with single medicine drug, poly- two sulphur Soviet Union
The antitumous effect of sugar alcohol is suitable, still shows excellent anti-tumor activity.
Therefore, the poly- dithiothreitol (DTT) nanometer system for drug delivery with reduction responsiveness is in preparation anticancer
Application in drug, also within protection scope of the present invention.
Compared with prior art, the invention has the following advantages:
(1) present invention is by sulfydryl by polymerization reaction, and what is be simple and efficient has synthesized polymer poly dithiothreitol (DTT), the polymerization
Object stable structure, its biocompatibility are good, can contain hydrophobic anti-tumor drug, and a large amount of existing two in polymer
Sulfide linkage makes system that there is GSH quickly to restore responsiveness.
(2) drug is grafted on poly- dithiothreitol (DTT) side group by the present invention, is realized such as camptothecine and is contained-OH or-NH2Equal officials
The controllable load medicine for the dewatering medicament that can be rolled into a ball, improves the dissolubility of drug, greatly improves the utilizability of dewatering medicament.
(3) present invention can obtain the nanoparticle of controllable grain size, partial size using poly- dithiothreitol (DTT) as carrier loaded drug
Distribution is small, is accumulated in tumor tissues by the high-permeability and high retention (EPR effect) of tumor tissues, from
And realize the effect of passive target, poly- dithiothreitol (DTT) nanometer system can reduce release of the drug under normal physiological conditions with
Reduce burst drug release bring toxic side effect;And after being absorbed by tumour cell, under the effect of tumour cell glutathion inside, nanometer
Disulfide bonds in system, are reduced into sulfydryl, and the monomer energy promotion system with sulfydryl is disintegrated, and promote drug release;Meanwhile
The small molecule of separate out acts on carbonic acid ester bond, accelerates the release of drug, enhances the therapeutic effect of cancer, has high face
Bed application value.
(4) present invention has reaction process simple, and reaction step is few, and reaction time is short, the advantages such as reproducible, in medicine
Field has a good application prospect and wide development space.
Detailed description of the invention
Fig. 1 is the nanoparticle and its releasing in tumour cell that the present invention has been grafted that the poly- dithiothreitol (DTT) of camptothecine is formed
Put schematic diagram.
Fig. 2 is the nucleus magnetic hydrogen spectrum figure of poly- dithiothreitol (DTT) in the present invention.
Fig. 3 is the nucleus magnetic hydrogen spectrum figure that the poly- dithiothreitol (DTT) of camptothecine has been grafted in the present invention.
Fig. 4 is transmission electron microscope (TEM) result figure for being grafted the nanoparticle of poly- dithiothreitol (DTT) formation of camptothecine.
Fig. 5 is dynamic light scattering (DLS) result figure for being grafted the nanoparticle of poly- dithiothreitol (DTT) formation of camptothecine.
Fig. 6 is drug of the nanoparticle for the poly- dithiothreitol (DTT) formation for being grafted camptothecine at 37 DEG C of various concentration GSH
Release figure.
Fig. 7 is poly- dithiothreitol (DTT) (PDTT), dithiothreitol (DTT) monomer (DTT) to the cell of MCF-7 breast tumor cell
Toxicity figure.
Fig. 8 is to be grafted nanoparticle (PDTT-CPT), the camptothecine list medicine (CPT) that the poly- dithiothreitol (DTT) of camptothecine is formed
To the cytotoxicity figure of MCF-7 breast tumor cell.
Specific embodiment
The present invention is further illustrated below in conjunction with Figure of description and specific embodiment, but embodiment is not to the present invention
It limits in any form.Unless stated otherwise, the present invention uses reagent, method and apparatus routinely try for the art
Agent, method and apparatus.
Unless stated otherwise, following embodiment agents useful for same and material are commercially available.
The synthesis of the poly- dithiothreitol (DTT) of embodiment 1
1, the polymer poly dithiothreitol (DTT) (PDTT) as pharmaceutical carrier, including following step are prepared by the following method
It is rapid:
(1) 4.62g dithiothreitol (DTT) is weighed, with dmso solution of the 11mL after dry, is frozen by liquid nitrogen is cooling
Pumping method makes reaction vessel interior keep high vacuum;
(2) after room temperature to be restored, 90 DEG C is warming up to, is kept stirring simultaneously, after reacting 10h, pump remaining dimethyl sulfoxide
With product water;
(3) ethyl acetate is added, it is cooling at room temperature that solid is precipitated after heating dissolves solid crude product, it is repeated several times
Afterwards, white solid is obtained, as poly- dithiothreitol (DTT).
2, result
The nucleus magnetic hydrogen spectrum figure of polymer P DTT is as shown in Fig. 2, the signal at as shown in Figure 2~5.17ppm is solvent heavy water
Absorption peak, the signal at~3.34ppm corresponds to the proton uptake peak on the connected-CH- of two hydroxyls of dithiothreitol (DTT) ,~
Signal at 3.02ppm ,~2.72ppm corresponds to two connected methylene-CH of two sulfydryls of dithiothreitol (DTT)2On proton
Absorption peak successfully synthesizes polymer P DTT as the result is shown, shown in specific general structure such as formula (I):
Wherein, n=5~10000.
The synthesis of the poly- dithiothreitol (DTT) of embodiment 2
1, the polymer poly dithiothreitol (DTT) (PDTT) as pharmaceutical carrier, including following step are prepared by the following method
It is rapid:
(1) 2.31g dithiothreitol (DTT) is weighed, with dmso solution of the 5.5mL after dry, is frozen by liquid nitrogen is cooling
Pumping method makes reaction vessel interior keep high vacuum;
(2) after room temperature to be restored, 100 DEG C is warming up to, is kept stirring simultaneously, after reacting 20h, pump remaining dimethyl sulfoxide
With product water;
(3) ethyl acetate is added, it is cooling at room temperature that solid is precipitated after heating dissolves solid crude product, it is repeated several times
Afterwards, white solid is obtained, as poly- dithiothreitol (DTT).
2, result
The poly- dithiothreitol (DTT) stable structure that is prepared, its biocompatibility are good, can contain hydrophobic antitumor
Drug, and a large amount of existing disulfide bond make system that there is GSH quickly to restore responsiveness in polymer, as drug delivery
There is applications well prospect in terms of carrier.
Embodiment 3 is grafted the preparation of drug (poly- dithiothreitol (DTT) grafting camptothecine)
1, it is prepared by the following method grafting drug, comprising the following steps:
(1) it is molten to weigh camptothecine 2g, 4-dimethylaminopyridine (DMAP) 2.11g for the 250mL round-bottomed flask for taking clean dried
Solution under argon gas protection, is placed on magnetic stirring apparatus in the methylene chloride of 100mL and stirs 10min;
(2) phosgene 0.57g is weighed, is quickly adding into round-bottomed flask, system continues to stir 30min, carries out acylation reaction;
(3) poly- dithiothreitol (DTT) 0.9g is dissolved in 30mL tetrahydrofuran, is placed in constant pressure funnel, under protection of argon gas
It instills in round-bottomed flask, carries out graft reaction for 24 hours at room temperature;
(4) it with concentrated by rotary evaporation solvent to 30mL, then instills in ethyl acetate, is statically placed in 20 DEG C of refrigerator overnights, filter,
It is rinsed solid 3 times with glacial acetic acid ethyl ester, drying has been grafted the poly- dithiothreitol (DTT) of camptothecine.
Be grafted the nucleus magnetic hydrogen spectrum figure of the poly- dithiothreitol (DTT) of camptothecine as shown in figure 3, from the figure 3, it may be seen that~8.69ppm,
~8.17ppm ,~8.11ppm ,~7.86ppm ,~7.72ppm ,~7.45ppm ,~5.51ppm, the signal at~5.43ppm
Proton uptake peak on corresponding camptothecine aromatic rings ,~1.74ppm ,~0.89ppm are represented on camptothecine on methylene and ethyl
Absorption peak ,~3.34ppm ,~3.05ppm ,~5.27ppm respectively represent methine on poly- dithiothreitol (DTT), methylene and hydroxyl
On proton uptake peak.These results suggest that camptothecin drug is successfully grafted on poly- dithiothreitol (DTT).
Embodiment 4 is grafted the preparation of drug (poly- dithiothreitol (DTT) grafting camptothecine)
1, it is prepared by the following method grafting drug, comprising the following steps:
(1) it is molten to weigh camptothecine 1g, 4-dimethylaminopyridine (DMAP) 1.05g for the 100mL round-bottomed flask for taking clean dried
Solution under argon gas protection, is placed on magnetic stirring apparatus in the tetrahydrofuran of 50mL and stirs 10min;
(2) phosgene 0.57g is weighed, is quickly adding into round-bottomed flask, system continues to stir 30min, carries out acylation reaction;
(3) poly- dithiothreitol (DTT) 0.45g is dissolved in 10mL tetrahydrofuran, is placed in constant pressure funnel, protected in argon gas
In lower instillation round-bottomed flask, graft reaction is carried out for 24 hours at room temperature;
(4) it with concentrated by rotary evaporation solvent to 30mL, then instills in ethyl acetate, is statically placed in 20 DEG C of refrigerator overnights, filter,
It is rinsed solid 3 times with glacial acetic acid ethyl ester, drying has been grafted the poly- dithiothreitol (DTT) of camptothecine.Through nucleus magnetic hydrogen spectrum analytical table
Bright, camptothecin drug is successfully grafted on poly- dithiothreitol (DTT).
A kind of poly- dithiothreitol (DTT) nanometer system for anti-tumor drug delivering with reduction responsiveness of embodiment 5
1, poly- dithiothreitol (DTT) nanometer system is prepared by single emulsion method, comprising the following steps:
(1) the poly- dithiothreitol (DTT) ultrasonic dissolution that embodiment 3 has been grafted camptothecine obtains emulsion in methylene chloride
Oily phase, the concentration of oily phase are 30mg/mL;
(2) 3000 2mg of stabilizer DSPE-PEG is added in 10mL pure water as water phase;Oily phase 0.2mL is taken to instill water
Xiang Zhong, the ultrasound 5min under ice bath obtain white mixed emulsion;
(3) white mixed emulsion is transferred to room temperature, after stirring one day night, vapors away low-boiling methylene chloride, obtain
There must be the nanoparticle solution of Tyndall effect, remove large granular impurity through 0.8 μm of membrane filtration, the nanoparticle for obtaining carrying medicine is molten
Liquid, the as described poly- dithiothreitol (DTT) nanometer system for anti-tumor drug delivering with reduction responsiveness.
2, result
(1) DLS detection is carried out, the partial size of the present embodiment nanoparticle is statically placed in 4 DEG C of refrigerators and produces without precipitating in 150nm
It is raw.Its transmission electron microscope (TEM) result figure and dynamic light scattering (DLS) result figure difference are as shown in Figure 4 and Figure 5.The result shows that carrying
The PDTT nanoparticle of camptothecine is spherical in shape, and size is more uniform, and particle diameter distribution is relatively narrow.
(2) nanoparticle made from the present embodiment is under the conditions of 37 DEG C, in various concentration glutathione (0mM, 2mM, 10mM,
Drug release experiment is carried out in PBS solution 20mM), detects the free camplotheca acuminata that nanometer system discharges in 72 hours in PBS solution
Alkali concentration.Experimental result as shown in fig. 6, thus prove heretofore described nanometer medicine-carried system have GSH restore responsiveness,
And as GSH concentration increases, reduction responsiveness is reinforced.
(3) poly- dithiothreitol (DTT) (PDTT), dithiothreitol (DTT) monomer (DTT), the present embodiment the poly- of camptothecine has been grafted
Nanoparticle (PDTT-CPT), the camptothecine list medicine (CPT) of dithiothreitol (DTT) formation carry out external anti-MCF-7 tumor cytotoxicity respectively
Property experiment, effect is as shown in Figure 7 and Figure 8.As can be seen that poly- dithiothreitol (DTT) biocompatibility is fine, the life to MCF-7 cell
It grows and inhibits without obvious in the range of a larger activity.The PDTT nanoparticle for carrying camptothecine, with simple camptothecine
It compares, maintains the excellent anticancer activity of camptothecine.
A kind of poly- dithiothreitol (DTT) nanometer system for anti-tumor drug delivering with reduction responsiveness of embodiment 6
1, poly- dithiothreitol (DTT) nanometer system is prepared by nanoprecipitation method, comprising the following steps:
(1) the poly- dithiothreitol (DTT) and stabilizer DSPE-PEG 3000 for embodiment 4 being grafted camptothecine are with the matter of 2:1
Ratio is measured, is dissolved completely in dimethyl sulfoxide, the oily phase that polymer concentration is 20mg/mL is obtained;
(2) pure water of 10mL is taken to be placed on magnetic agitation platform, speed of agitator 1500r/min mutually slowly drips 0.2mL oil
Enter in water phase, rate of addition is 0.05mL/ seconds, obtains the milky emulsion with Tyndall effect, removes diformazan after ultrafiltration 3 times
Base sulfoxide filters out big molecular impurity with 0.8 μm of organic phase filter membrane, obtains the nanoparticle solution for carrying medicine, as described to have also
The poly- dithiothreitol (DTT) nanometer system for anti-tumor drug delivering of former responsiveness.
2, result
(1) DLS detection is carried out, the partial size of the present embodiment nanoparticle is statically placed in 4 DEG C of refrigerators in 100nm or so without heavy
It forms sediment and generates.Its transmission electron microscope (TEM) result figure and dynamic light scattering (DLS) result figure difference are as shown in Figure 4 and Figure 5.As a result table
Bright, the PDTT nanoparticle for carrying camptothecine is spherical in shape, and size is more uniform, and particle diameter distribution is relatively narrow.
(2) nanoparticle made from the present embodiment is under the conditions of 37 DEG C, in various concentration glutathione (0mM, 2mM, 10mM,
Drug release experiment is carried out in PBS solution 20mM), detects the free camplotheca acuminata that nanometer system discharges in 72 hours in PBS solution
Alkali concentration.Experimental result as shown in fig. 6, thus prove heretofore described nanometer medicine-carried system have GSH restore responsiveness,
And as GSH concentration increases, reduction responsiveness is reinforced.
(3) poly- dithiothreitol (DTT) (PDTT), dithiothreitol (DTT) monomer (DTT), the present embodiment the poly- of camptothecine has been grafted
Nanoparticle (PDTT-CPT), the camptothecine list medicine (CPT) of dithiothreitol (DTT) formation carry out external anti-MCF-7 tumor cytotoxicity respectively
Property experiment, effect is as shown in Figure 7 and Figure 8.As can be seen that poly- dithiothreitol (DTT) biocompatibility is fine, the life to MCF-7 cell
It grows and inhibits without obvious in the range of a larger activity.The PDTT nanoparticle for carrying camptothecine, with simple camptothecine
It compares, maintains the excellent anticancer activity of camptothecine, there is significant tumor killing effect, there is certain application in field of cancer treatment
Potentiality.
The preparation of 7 polymer P DTT of embodiment
Other conditions are same as Example 1, only difference is that, the temperature of polymerization reaction is 40 DEG C, polymerization reaction
Time be 48h, solid white polymer PDTT is prepared.
The preparation of 8 polymer P DTT of embodiment
Other conditions are same as Example 2, only difference is that, the temperature of polymerization reaction is 180 DEG C, polymerization reaction
Time be 10min, solid white polymer PDTT is prepared.
Embodiment 9 is grafted the preparation of drug (poly- dithiothreitol (DTT) grafting camptothecine)
Other conditions are same as Example 3, only difference is that, the time of acylation reaction is 10min, graft reaction
Time be 48h, be prepared the poly- dithiothreitol (DTT) for being grafted camptothecine, finally obtained anti-tumor drug delivery system,
The controllable load medicine for realizing dewatering medicament, improves the dissolubility of drug, greatly improves the utilizability of dewatering medicament, and
And there is GSH quickly to restore responsiveness, improve the targeting of anti-tumor drug.
Embodiment 10 is grafted the preparation of drug (poly- dithiothreitol (DTT) grafting camptothecine)
Other conditions are same as Example 4, only difference is that, the time of acylation reaction is 60min, graft reaction
Time be 3h, be prepared the poly- dithiothreitol (DTT) for being grafted camptothecine, finally obtained anti-tumor drug delivery system is real
The controllable load medicine for having showed dewatering medicament, improves the dissolubility of drug, greatly improves the utilizability of dewatering medicament, and
Responsiveness is quickly restored with GSH, improves the targeting of anti-tumor drug.
A kind of poly- dithiothreitol (DTT) nanometer system for anti-tumor drug delivering with reduction responsiveness of embodiment 11
Other conditions are same as Example 6, only difference is that, it has been grafted the poly- dithiothreitol (DTT) of camptothecine and steady
The mass ratio for determining agent DSPE-PEG 3000 is 5:1.Finally obtained anti-tumor drug delivery system, realize camptothecine can
Control carries medicine, improves the dissolubility of camptothecine, greatly improves the utilizability of camptothecine, and there is GSH quickly to restore
Responsiveness improves the targeting of camptothecin drug.
In addition, poly- dithiothreitol (DTT) nanometer system of the invention is applied also for such as ursolic acid, methotrexate (MTX), 9- amino camplotheca acuminata
The anti-tumor drugs such as alkali, Herceptin, mustargen, cis-platinum, cyclophosphamide, fluorouracil, podophyllotoxin, as Herceptin,
Lucentis, interferon, hematopoietin, streptokinase protein medicaments, such as Lamivudine, Aldoforwe ester, inosine, auxiliary
The delivering of the nucleic acid drugs such as enzyme A, property is stablized after the poly- dithiothreitol (DTT) of novel polymer of the invention is grafted said medicine, has good
Good biocompatibility and degradability, and there is GSH quickly to restore responsiveness, improve the targeted delivery effect of nano-carrier
Rate realizes positioning controlled release of the drug in tumour cell, improves the bioavilability of dewatering medicament, is the effective of disease
It treats and has opened up a kind of new approach.
The preferred embodiment that the above specific embodiment is of the invention for ease of understanding and illustrates, but the invention is not limited to
Above-described embodiment does not mean that the present invention must rely on above-described embodiment and could implement.Person of ordinary skill in the field
It is the addition of equivalence replacement and auxiliary element to raw material selected by the present invention, specific it will be clearly understood that any improvement in the present invention
The selection etc. of mode, all of which fall within the scope of protection and disclosure of the present invention.
Claims (10)
1. a kind of polymer P DTT for drug delivery, which is characterized in that the polymer P DTT is by multiple duplicate two sulphur
Threitol structural unit composition, shown in the following formula (I) of structural formula:
,
Wherein, n=5~10000.
2. the preparation method of polymer P DTT described in claim 1, which is characterized in that dithiothreitol (DTT) organic solvent A is molten
Xie Hou carries out polymerization reaction under vacuum conditions, and the sulfydryl of dithiothreitol (DTT) end is made to be oxidized to disulfide bond, to be gathered
Close object PDTT.
3. preparation method according to claim 2, which is characterized in that the temperature of the polymerization reaction is 40~180 DEG C, institute
The time for stating polymerization reaction is the h of 10 min~48.
4. polymer P DTT described in claim 1 as or application in terms of preparing drug carrier system.
5. a kind of poly- dithiothreitol (DTT) nanometer system for drug delivery with reduction responsiveness, which is characterized in that with power
Benefit requires the 1 polymer P DTT as nano-carrier carrying medicament.
6. poly- dithiothreitol (DTT) nanometer system according to claim 5, which is characterized in that by method comprising the following steps
It is prepared:
S1. drug and organic basic catalyst are added solid phosgene and carry out acylation reaction after organic solvent B dissolution stirring,
The polymer P DTT of dissolution in a solvent is added dropwise again and carries out graft reaction, has been grafted the polymer of drug
PDTT;
S2. it is equal that partial size is prepared by single emulsion method or nanoprecipitation method in the above-mentioned polymer P DTT for being grafted drug
One, stable nanoparticle solution, the as described poly- dithiothreitol (DTT) nanometer system.
7. poly- dithiothreitol (DTT) nanometer system according to claim 6, which is characterized in that in step S1, the acylation is anti-
The time answered is 10~60 min;The time of the graft reaction is 3~48 h.
8. poly- dithiothreitol (DTT) nanometer system according to claim 6, which is characterized in that in step S2, pass through single emulsion
The method that method prepares nanoparticle solution, comprising the following steps:
S21. the polymer P DTT of drug will be grafted, ultrasonic dissolution in organic solvent C immiscible and low boiling point with water,
Obtain emulsion oil phase;
S22. stabilizer is added into pure water and is used as water phase, by oil it is mutually mixed with water after, ultrasonic removing organic solvent C
Obtain uniform particle diameter, stable nanoparticle solution;
In step S2, method that nanoparticle solution is prepared by nanoprecipitation method, comprising the following steps:
S221. it will be grafted the polymer P DTT and stabilizer of drug, be dissolved in organic solvent D miscible with water, oil is formed
Phase;
S222. under stirring condition, oil is mutually added drop-wise in water phase, uniform particle diameter, stable nanoparticle solution can be obtained.
9. poly- dithiothreitol (DTT) nanometer system according to claim 5, which is characterized in that the drug include containing-OH ,-
NH2,-COOH or halogen functional group drug, protein drug or nucleic acid drug.
10. polymer P DTT described in claim 1 or any poly- dithiothreitol (DTT) nanometer system of claim 5~9
Preparing the application in anticancer drug.
Priority Applications (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201810997265.1A CN109438707B (en) | 2018-08-29 | 2018-08-29 | Poly dithiothreitol nano system for delivering antitumor drugs and preparation method and application thereof |
PCT/CN2018/122760 WO2020042470A1 (en) | 2018-08-29 | 2018-12-21 | Polydithiothreitol nano system for antitumor drug delivery and preparation method therefor and use thereof |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201810997265.1A CN109438707B (en) | 2018-08-29 | 2018-08-29 | Poly dithiothreitol nano system for delivering antitumor drugs and preparation method and application thereof |
Publications (2)
Publication Number | Publication Date |
---|---|
CN109438707A true CN109438707A (en) | 2019-03-08 |
CN109438707B CN109438707B (en) | 2021-04-06 |
Family
ID=65530174
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201810997265.1A Active CN109438707B (en) | 2018-08-29 | 2018-08-29 | Poly dithiothreitol nano system for delivering antitumor drugs and preparation method and application thereof |
Country Status (2)
Country | Link |
---|---|
CN (1) | CN109438707B (en) |
WO (1) | WO2020042470A1 (en) |
Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN109908084A (en) * | 2019-04-11 | 2019-06-21 | 临沂大学 | A kind of platinum crosslinking camptothecine prodrug micelle Nano medication and its preparation method and application |
CN110804178A (en) * | 2019-10-17 | 2020-02-18 | 中山大学 | Nano drug-loaded system with glutathione responsiveness and preparation method and application thereof |
CN113265050A (en) * | 2021-04-30 | 2021-08-17 | 浙江大学 | Degradable high polymer material, self-assembled nano composite and application |
CN114177302A (en) * | 2021-11-12 | 2022-03-15 | 中山大学 | Glycosaminoglycan modifier for delivering antitumor drugs and preparation method and application thereof |
CN114767875A (en) * | 2022-03-28 | 2022-07-22 | 上海长征医院 | Nanoparticle for treating gastric cancer and preparation method and application thereof |
Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2008150996A1 (en) * | 2007-05-30 | 2008-12-11 | University Of Wyoming | Degradable thermoresponsive poly(ethylene glycol) analogue materials |
CN102268436A (en) * | 2011-07-18 | 2011-12-07 | 中国人民解放军第二军医大学 | Oligonucleotide aptamer of prostatic cancer target gene, delivery carrier, delivery system and preparation methods thereof |
CN102731786A (en) * | 2012-06-19 | 2012-10-17 | 浙江大学 | Method for controllably preparing polymer gel particles through non-aqueous emulsion polymerization system |
CN105561324A (en) * | 2007-07-19 | 2016-05-11 | 阿列克斯塞尔公司 | Self-assembly amphiphilic polymer used as anticancer agent |
CN108425104A (en) * | 2018-03-12 | 2018-08-21 | 江苏菲沃泰纳米科技有限公司 | A kind of coating production using sulfhydryl compound as transition zone |
-
2018
- 2018-08-29 CN CN201810997265.1A patent/CN109438707B/en active Active
- 2018-12-21 WO PCT/CN2018/122760 patent/WO2020042470A1/en active Application Filing
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2008150996A1 (en) * | 2007-05-30 | 2008-12-11 | University Of Wyoming | Degradable thermoresponsive poly(ethylene glycol) analogue materials |
CN105561324A (en) * | 2007-07-19 | 2016-05-11 | 阿列克斯塞尔公司 | Self-assembly amphiphilic polymer used as anticancer agent |
CN102268436A (en) * | 2011-07-18 | 2011-12-07 | 中国人民解放军第二军医大学 | Oligonucleotide aptamer of prostatic cancer target gene, delivery carrier, delivery system and preparation methods thereof |
CN102731786A (en) * | 2012-06-19 | 2012-10-17 | 浙江大学 | Method for controllably preparing polymer gel particles through non-aqueous emulsion polymerization system |
CN108425104A (en) * | 2018-03-12 | 2018-08-21 | 江苏菲沃泰纳米科技有限公司 | A kind of coating production using sulfhydryl compound as transition zone |
Non-Patent Citations (1)
Title |
---|
王蔼廉等: ""超支化双亲性聚合物作为药物载体研究新进展"", 《高分子通报》 * |
Cited By (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN109908084A (en) * | 2019-04-11 | 2019-06-21 | 临沂大学 | A kind of platinum crosslinking camptothecine prodrug micelle Nano medication and its preparation method and application |
CN110804178A (en) * | 2019-10-17 | 2020-02-18 | 中山大学 | Nano drug-loaded system with glutathione responsiveness and preparation method and application thereof |
CN113265050A (en) * | 2021-04-30 | 2021-08-17 | 浙江大学 | Degradable high polymer material, self-assembled nano composite and application |
CN113265050B (en) * | 2021-04-30 | 2022-08-23 | 浙江大学 | Degradable high polymer material, self-assembled nano composite and application |
CN114177302A (en) * | 2021-11-12 | 2022-03-15 | 中山大学 | Glycosaminoglycan modifier for delivering antitumor drugs and preparation method and application thereof |
CN114767875A (en) * | 2022-03-28 | 2022-07-22 | 上海长征医院 | Nanoparticle for treating gastric cancer and preparation method and application thereof |
Also Published As
Publication number | Publication date |
---|---|
WO2020042470A1 (en) | 2020-03-05 |
CN109438707B (en) | 2021-04-06 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN109438707A (en) | A kind of poly- dithiothreitol (DTT) nanometer system and its preparation method and application for anti-tumor drug delivering | |
Xu et al. | pH-Responsive nanoparticles based on cholesterol/imidazole modified oxidized-starch for targeted anticancer drug delivery | |
Yang et al. | Redox-sensitive self-assembled nanoparticles based on alpha-tocopherol succinate-modified heparin for intracellular delivery of paclitaxel | |
Zhou et al. | Redox-and MMP-2-sensitive drug delivery nanoparticles based on gelatin and albumin for tumor targeted delivery of paclitaxel | |
CN110801431B (en) | Construction and application of core-shell type intelligent nano delivery system | |
Sang et al. | Preparation of pH/redox dual responsive polymeric micelles with enhanced stability and drug controlled release | |
CN103435718B (en) | The hyaluronic acid cholesteryl ester that PEG modifies | |
Li et al. | Antitumor drug Paclitaxel-loaded pH-sensitive nanoparticles targeting tumor extracellular pH | |
CN107556438B (en) | Multi-responsive cross-linked polymer, drug-loaded nano micelle and preparation method thereof | |
KR20140041522A (en) | Polymeric nanoparticles for drug delivery | |
Yu et al. | Synthesis, characterization and in vitro evaluation of dual pH/redox sensitive marine laminarin-based nanomedicine carrier biomaterial for cancer therapy | |
CN115433291B (en) | Synthesis of alginic acid-g-coumarin derivative and method for preparing Pickering emulsion loaded with doxorubicin | |
CN112876578B (en) | Amphiphilic glucan derivative carrier targeting tumor-associated fibroblasts, and preparation and application of pharmaceutical composition of amphiphilic glucan derivative carrier | |
CN111870579B (en) | Tumor-targeted nano micelle, preparation method and application of nano micelle as drug carrier | |
Zhang et al. | Preparations of hyperbranched polymer nano micelles and the pH/redox controlled drug release behaviors | |
Khan et al. | Chondroitin sulfate-based redox-responsive nanoparticles for melanoma-targeted drug delivery | |
Michailova et al. | Nanoparticles formed from PNIPAM-g-PEO copolymers in the presence of indomethacin | |
Huo et al. | Integrated metalloproteinase, pH and glutathione responsive prodrug-based nanomedicine for efficient target chemotherapy | |
CN105859990B (en) | The polymer of side chain sulfur-bearing caprylyl, its preparation method and polymer vesicle prepared therefrom and its application | |
CN108310395A (en) | A kind of convertible polymer nanocomposite pharmaceutical carrier of surface charge and preparation method and application | |
Yang et al. | Stepwise pH/reduction-responsive polymeric conjugates for enhanced drug delivery to tumor | |
CN111407740A (en) | Albumin nanoparticles capable of activating and releasing drugs by ultrasound, and preparation method and application thereof | |
CN113651959A (en) | Nano drug loading system based on amino acid-hydroxy acid copolymer and preparation method and application thereof | |
CN109232875A (en) | The pH/ reduction sensitive carrier material and its preparation method and application that Cys and its derivative and polyester polymers are formed | |
Lin et al. | Synthesis and characterization of triple-responsive PNiPAAm-SSP (αN3CL-g-alkyne) copolymers bearing cholesterol and fluorescence monitor |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
GR01 | Patent grant | ||
GR01 | Patent grant |