CN116987208A - Amphiphilic glucan block polymer with pH response decomposition function, cationic antibacterial peptide nano-drug and application - Google Patents
Amphiphilic glucan block polymer with pH response decomposition function, cationic antibacterial peptide nano-drug and application Download PDFInfo
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- CN116987208A CN116987208A CN202310962001.3A CN202310962001A CN116987208A CN 116987208 A CN116987208 A CN 116987208A CN 202310962001 A CN202310962001 A CN 202310962001A CN 116987208 A CN116987208 A CN 116987208A
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- 239000003814 drug Substances 0.000 title claims abstract description 84
- 229940079593 drug Drugs 0.000 title claims abstract description 75
- 125000002091 cationic group Chemical group 0.000 title claims abstract description 47
- 229920000642 polymer Polymers 0.000 title claims abstract description 46
- 239000003910 polypeptide antibiotic agent Substances 0.000 title claims abstract description 45
- 230000004044 response Effects 0.000 title claims abstract description 21
- 229920001503 Glucan Polymers 0.000 title claims abstract description 20
- 238000000354 decomposition reaction Methods 0.000 title claims abstract description 15
- 238000011068 loading method Methods 0.000 claims abstract description 14
- 241000894006 Bacteria Species 0.000 claims abstract description 9
- 239000002253 acid Substances 0.000 claims abstract description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 60
- 229920002307 Dextran Polymers 0.000 claims description 47
- -1 orthoester amine Chemical class 0.000 claims description 31
- 238000002360 preparation method Methods 0.000 claims description 13
- 238000004108 freeze drying Methods 0.000 claims description 12
- ILOJFJBXXANEQW-UHFFFAOYSA-N aminooxy(phenyl)borinic acid Chemical compound NOB(O)C1=CC=CC=C1 ILOJFJBXXANEQW-UHFFFAOYSA-N 0.000 claims description 9
- 238000000502 dialysis Methods 0.000 claims description 7
- 230000000694 effects Effects 0.000 claims description 6
- 125000002092 orthoester group Chemical group 0.000 claims description 6
- 238000003756 stirring Methods 0.000 claims description 6
- XIPRTRJDLZVSHO-UHFFFAOYSA-N aminooxy(phenoxy)borinic acid Chemical compound NOB(O)OC1=CC=CC=C1 XIPRTRJDLZVSHO-UHFFFAOYSA-N 0.000 claims description 5
- 125000000524 functional group Chemical group 0.000 claims description 5
- 238000000034 method Methods 0.000 claims description 5
- 208000035473 Communicable disease Diseases 0.000 claims description 4
- DIRRKLFMHQUJCM-UHFFFAOYSA-N (2-aminophenyl)boronic acid Chemical compound NC1=CC=CC=C1B(O)O DIRRKLFMHQUJCM-UHFFFAOYSA-N 0.000 claims description 3
- 230000000975 bioactive effect Effects 0.000 claims description 3
- JMZFEHDNIAQMNB-UHFFFAOYSA-N m-aminophenylboronic acid Chemical compound NC1=CC=CC(B(O)O)=C1 JMZFEHDNIAQMNB-UHFFFAOYSA-N 0.000 claims description 3
- HXITXNWTGFUOAU-UHFFFAOYSA-N phenylboronic acid Chemical group OB(O)C1=CC=CC=C1 HXITXNWTGFUOAU-UHFFFAOYSA-N 0.000 claims description 3
- 238000009833 condensation Methods 0.000 claims description 2
- 230000005494 condensation Effects 0.000 claims description 2
- 238000005859 coupling reaction Methods 0.000 claims description 2
- 239000002861 polymer material Substances 0.000 claims description 2
- 230000035440 response to pH Effects 0.000 claims description 2
- 150000001412 amines Chemical class 0.000 claims 1
- FZWBNHMXJMCXLU-BLAUPYHCSA-N isomaltotriose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1OC[C@@H]1[C@@H](O)[C@H](O)[C@@H](O)[C@@H](OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C=O)O1 FZWBNHMXJMCXLU-BLAUPYHCSA-N 0.000 claims 1
- 125000003345 AMP group Chemical group 0.000 abstract description 32
- 229920006227 ethylene-grafted-maleic anhydride Polymers 0.000 abstract description 32
- 208000015181 infectious disease Diseases 0.000 abstract description 8
- 108091005804 Peptidases Proteins 0.000 abstract description 4
- 239000004365 Protease Substances 0.000 abstract description 4
- 102100037486 Reverse transcriptase/ribonuclease H Human genes 0.000 abstract description 4
- 206010018910 Haemolysis Diseases 0.000 abstract description 3
- 230000008588 hemolysis Effects 0.000 abstract description 3
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 abstract description 2
- 230000001988 toxicity Effects 0.000 abstract description 2
- 231100000419 toxicity Toxicity 0.000 abstract description 2
- 108010032153 thanatin Proteins 0.000 description 12
- 238000006243 chemical reaction Methods 0.000 description 11
- 238000005538 encapsulation Methods 0.000 description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 8
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 8
- 239000002245 particle Substances 0.000 description 8
- 239000000243 solution Substances 0.000 description 8
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- 230000002378 acidificating effect Effects 0.000 description 6
- 230000003115 biocidal effect Effects 0.000 description 6
- 239000008367 deionised water Substances 0.000 description 6
- 229910021641 deionized water Inorganic materials 0.000 description 6
- 108090000765 processed proteins & peptides Proteins 0.000 description 6
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 4
- 238000004458 analytical method Methods 0.000 description 4
- 229910052786 argon Inorganic materials 0.000 description 4
- 238000002296 dynamic light scattering Methods 0.000 description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 4
- 239000000693 micelle Substances 0.000 description 4
- 239000011259 mixed solution Substances 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- 241001465754 Metazoa Species 0.000 description 3
- BAPJBEWLBFYGME-UHFFFAOYSA-N acrylic acid methyl ester Natural products COC(=O)C=C BAPJBEWLBFYGME-UHFFFAOYSA-N 0.000 description 3
- 230000000845 anti-microbial effect Effects 0.000 description 3
- 238000012377 drug delivery Methods 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 230000002209 hydrophobic effect Effects 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 239000002105 nanoparticle Substances 0.000 description 3
- 230000007935 neutral effect Effects 0.000 description 3
- 230000001105 regulatory effect Effects 0.000 description 3
- UTHULKKJYXJZLV-UHFFFAOYSA-N (3-aminophenoxy)boronic acid Chemical compound NC1=CC=CC(OB(O)O)=C1 UTHULKKJYXJZLV-UHFFFAOYSA-N 0.000 description 2
- 239000004475 Arginine Substances 0.000 description 2
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 2
- 239000004472 Lysine Substances 0.000 description 2
- 108091027981 Response element Proteins 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 125000003277 amino group Chemical group 0.000 description 2
- 239000003242 anti bacterial agent Substances 0.000 description 2
- 230000000844 anti-bacterial effect Effects 0.000 description 2
- 239000004599 antimicrobial Substances 0.000 description 2
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 238000012412 chemical coupling Methods 0.000 description 2
- 238000007385 chemical modification Methods 0.000 description 2
- 230000001186 cumulative effect Effects 0.000 description 2
- 239000000017 hydrogel Substances 0.000 description 2
- 238000010253 intravenous injection Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 229940065472 octyl acrylate Drugs 0.000 description 2
- 125000003386 piperidinyl group Chemical group 0.000 description 2
- CZLJVZVIMFMGCH-UHFFFAOYSA-N (2-aminophenoxy)boronic acid Chemical compound NC1=CC=CC=C1OB(O)O CZLJVZVIMFMGCH-UHFFFAOYSA-N 0.000 description 1
- 108700042778 Antimicrobial Peptides Proteins 0.000 description 1
- 102000044503 Antimicrobial Peptides Human genes 0.000 description 1
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical group [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 230000004543 DNA replication Effects 0.000 description 1
- 241000588724 Escherichia coli Species 0.000 description 1
- 241000206602 Eukaryota Species 0.000 description 1
- 208000001860 Eye Infections Diseases 0.000 description 1
- 108010026389 Gramicidin Proteins 0.000 description 1
- 241000258937 Hemiptera Species 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- 241000588747 Klebsiella pneumoniae Species 0.000 description 1
- 206010057249 Phagocytosis Diseases 0.000 description 1
- 241000589517 Pseudomonas aeruginosa Species 0.000 description 1
- 108010070741 Tachypleus tridentatus tachyplesin peptide Proteins 0.000 description 1
- TZHYBRCGYCPGBQ-UHFFFAOYSA-N [B].[N] Chemical compound [B].[N] TZHYBRCGYCPGBQ-UHFFFAOYSA-N 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 208000026935 allergic disease Diseases 0.000 description 1
- 125000000539 amino acid group Chemical group 0.000 description 1
- 238000002266 amputation Methods 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 230000000840 anti-viral effect Effects 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- PKQRELHNODUEDZ-UHFFFAOYSA-N butan-1-amine;prop-2-enoic acid Chemical compound CCCC[NH3+].[O-]C(=O)C=C PKQRELHNODUEDZ-UHFFFAOYSA-N 0.000 description 1
- 229940041011 carbapenems Drugs 0.000 description 1
- 239000002041 carbon nanotube Substances 0.000 description 1
- 229910021393 carbon nanotube Inorganic materials 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 125000003636 chemical group Chemical group 0.000 description 1
- 230000003013 cytotoxicity Effects 0.000 description 1
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- 230000003247 decreasing effect Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 210000000613 ear canal Anatomy 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 208000011323 eye infectious disease Diseases 0.000 description 1
- IUAYMJGZBVDSGL-XNNAEKOYSA-N gramicidin S Chemical compound C([C@@H]1C(=O)N2CCC[C@H]2C(=O)N[C@H](C(=O)N[C@@H](CCCN)C(=O)N[C@H](C(N[C@H](CC=2C=CC=CC=2)C(=O)N2CCC[C@H]2C(=O)N[C@H](C(=O)N[C@@H](CCCN)C(=O)N[C@@H](CC(C)C)C(=O)N1)C(C)C)=O)CC(C)C)C(C)C)C1=CC=CC=C1 IUAYMJGZBVDSGL-XNNAEKOYSA-N 0.000 description 1
- 229950009774 gramicidin s Drugs 0.000 description 1
- 230000009610 hypersensitivity Effects 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 229920002521 macromolecule Polymers 0.000 description 1
- 210000002540 macrophage Anatomy 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 150000002739 metals Chemical class 0.000 description 1
- 231100000956 nontoxicity Toxicity 0.000 description 1
- KQGNTYNLWGIMEJ-UHFFFAOYSA-N octan-1-amine;prop-2-enoic acid Chemical compound OC(=O)C=C.CCCCCCCCN KQGNTYNLWGIMEJ-UHFFFAOYSA-N 0.000 description 1
- 244000052769 pathogen Species 0.000 description 1
- 230000008782 phagocytosis Effects 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 239000011148 porous material Substances 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 238000001243 protein synthesis Methods 0.000 description 1
- 108010036892 spinigerin Proteins 0.000 description 1
- MXSUQOOOYVELFP-LFMHPJLRSA-N spinigerin Chemical compound NC(=N)NCCC[C@@H](C(=O)N[C@@H](CC(C)C)C(O)=O)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCSC)NC(=O)[C@H]([C@@H](C)CC)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](C(C)C)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](C)NC(=O)[C@H](C(C)C)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@@H](N)CC1=CN=CN1 MXSUQOOOYVELFP-LFMHPJLRSA-N 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- ZJQFYZCNRTZAIM-PMXBASNASA-N tachyplesin Chemical compound C([C@H]1C(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(=O)N[C@H](C(N[C@H]2CSSC[C@H](NC(=O)[C@H](C(C)C)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC=3C=CC=CC=3)NC(=O)[C@@H](NC(=O)[C@H](CC=3C4=CC=CC=C4NC=3)NC(=O)[C@@H](N)CCCCN)CSSC[C@H](NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC=3C=CC(O)=CC=3)NC2=O)C(=O)N[C@@H](CCCNC(N)=N)C(N)=O)C(=O)N1)=O)[C@@H](C)CC)C1=CC=C(O)C=C1 ZJQFYZCNRTZAIM-PMXBASNASA-N 0.000 description 1
- 108010003434 termicin Proteins 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- 230000014616 translation Effects 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
- C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
- C08B37/0006—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid
- C08B37/0009—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid alpha-D-Glucans, e.g. polydextrose, alternan, glycogen; (alpha-1,4)(alpha-1,6)-D-Glucans; (alpha-1,3)(alpha-1,4)-D-Glucans, e.g. isolichenan or nigeran; (alpha-1,4)-D-Glucans; (alpha-1,3)-D-Glucans, e.g. pseudonigeran; Derivatives thereof
- C08B37/0021—Dextran, i.e. (alpha-1,4)-D-glucan; Derivatives thereof, e.g. Sephadex, i.e. crosslinked dextran
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/02—Peptides of undefined number of amino acids; Derivatives thereof
-
- 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
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
-
- 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
- A61K47/61—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 the organic macromolecular compound being a polysaccharide or a derivative thereof
-
- 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
- A61P31/04—Antibacterial agents
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Engineering & Computer Science (AREA)
- Epidemiology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Chemistry (AREA)
- Biochemistry (AREA)
- Inorganic Chemistry (AREA)
- Polymers & Plastics (AREA)
- Materials Engineering (AREA)
- Molecular Biology (AREA)
- Immunology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Medicinal Preparation (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
The invention provides an amphiphilic glucan block polymer with pH response decomposition, a cationic antibacterial peptide nano-drug and application, wherein the amphiphilic glucan block polymer with pH response decomposition and nano AMPs are self-assembled into the cationic antibacterial peptide nano-drug by utilizing electrostatic acting force, N-B coordination bond acting force and piperidinyl-pi electron acting force, so that the nano AMPs can be effectively grabbed, the drug loading rate of the amphiphilic glucan block polymer is improved, free amino in nano AMPs residues can be protected, the stability of the nano AMPs to protease is improved, the toxicity to normal cells is reduced, and the risk of hemolysis is reduced; and the cationic antibacterial peptide nano-drug is gradually hydrolyzed in the weak acid environment of the infection part, so that the enrichment of the drug at the infection part is realized, the bioavailability is improved, and a new solution is provided for overcoming the problem of clinical severe drug-resistant bacteria infection.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to an amphiphilic dextran block polymer capable of decomposing in a pH response mode, a cationic antibacterial peptide nano-drug and application thereof.
Background
Antibacterial peptides (Antimicrobial peptides, AMPs) are important immune molecules in eukaryotes that protect the host from invasive pathogens. Unlike traditional antibiotics which act by disrupting cell membranes, interrupting DNA replication, or protein synthesis, AMPs can act on non-specific targets in a variety of ways, thus being less prone to developing resistance. These properties make AMPs a sharp tool to kill most resistant bacteria, and are considered to be the most potential new generation of antimicrobial drugs for later antibiotic era. However, although over 5000 AMPs have been isolated and identified, only a few AMPs have entered clinical use. The large amount of cationic amino acids (lysine and arginine) contained in AMPs are very easy to be acting sites of protease, so that AMPs have poor circulatory stability in animals and even cause hemolysis risks. Because of these limitations, most AMPs are limited to topical administration, such as ear canal infections (Gramicidin S), eye infections, and the like. Therefore, improving the circulatory stability of AMPs in animals is a bottleneck in the overall approach of AMPs-type antimicrobial agents to clinical use.
Therefore, scientists have invented very inspired strategies including chemical modification, nano-polymer drug delivery systems, hydrogel embedding, and the like, successfully improving the protease stability of AMPs and reducing cytotoxicity. However, chemical modifications typically involve structural changes in the chemical structure (primary and secondary) of AMPs, which are difficult to guarantee with respect to their original antimicrobial activity and mechanism of action. Some nanoparticles (metals, carbon nanotubes, etc.) are difficult to degrade by organisms after entering the animal body, most hydrogels cannot be administered systemically by intravenous injection for stability reasons, and these limitations greatly limit the clinical application of AMPs drug delivery systems.
Disclosure of Invention
In order to solve the problems in the prior art, the invention provides an amphiphilic dextran block polymer with pH response decomposition, a cationic antibacterial peptide nano-drug and application thereof, and the prepared antibacterial peptide nano-drug has pH hypersensitivity and solves the key problems of poor circulation stability, low bioavailability and the like of AMPs bioactive molecules.
In order to achieve the above purpose, the present invention provides the following technical solutions: an amphiphilic dextran block polymer that disintegrates in response to pH comprising a carrier chain host: dextran; drug-loading functional groups: phenylboronic acid groups; pH responsive element: orthoester group, the dextran, the aminophenylboric acid and the orthoester amine are dissolved in DMSO together, and the amphiphilic dextran block polymer with pH response decomposition is obtained by a method of condensation coupling reaction of dicarbonyl carbonate.
Further, the molar ratio of the glucan, the aminophenylboronic acid and the orthoester amine is 1:1.3:0.1.
further, the orthoester amine comprises methyl acrylate amine, butyl acrylate amine or octyl acrylate amine, and the aminophenylboronic acid comprises 3-aminophenylboronic acid or 2-aminophenylboronic acid and the like.
The invention also provides application of the amphiphilic dextran block polymer as a cationic antibacterial peptide carrier.
The invention also provides application of the amphiphilic dextran block polymer in preparing cationic antibacterial peptide nano-drugs.
The invention also provides a cationic antibacterial peptide nano-drug, which comprises cationic antibacterial peptide and the amphiphilic glucan block polymer as claimed in any one of claims 1-3, wherein the amphiphilic glucan block polymer is self-assembled with the cationic antibacterial peptide through N-B coordination bond acting force and the piperidinyl-pi electron effect to obtain the cationic antibacterial peptide nano-drug.
Further, the usage ratio of the amphiphilic dextran block polymer to the cationic antibacterial peptide is 1: (0.1-0.4), the cationic antibacterial peptide and the functionalized glucan block polymer material are dissolved in DMSO together, and the cationic antibacterial peptide nano-drug is obtained through stirring, dialysis and freeze drying.
Furthermore, the cationic antibacterial peptide nano-drug disintegrates under the condition of pH value of 5.5-6.5 to release the bioactive component of the antibacterial peptide.
The invention also provides application of the cationic antibacterial peptide nano-drug as a drug for treating infectious diseases caused by gram-negative drug-resistant bacteria.
The invention also provides a medicine for treating infectious diseases caused by gram-negative drug-resistant bacteria, which is characterized by comprising the cationic antibacterial peptide nano-medicine.
Compared with the prior art, the invention has at least the following beneficial effects:
the invention provides a cationic antibacterial peptide nano-drug, which is characterized in that orthoester group and aminophenylboric acid are modified on glucan through CDI chemical coupling reaction to obtain an amphiphilic glucan block polymer with pH response decomposition, the amphiphilic glucan block polymer with pH response decomposition and nano AMPs are self-assembled into the cationic antibacterial peptide nano-drug by utilizing electrostatic acting force, N-B coordination bond acting force and glycosyl-pi electron acting force, wherein the amphiphilic glucan block polymer takes electronegative macromolecule Dextran as a basic skeleton, has the advantages of safety, no toxicity and difficult phagocytosis by mononuclear macrophage system (MPS), and can also load electropositive nano AMPs through electrostatic action; the amino phenylboronic acid is taken as a drug-carrying functional group, boron atoms and benzene rings in the phenylboronic acid group can generate nitrogen-boron coordination effect and a piperidinyl-pi electron effect with amino groups and piperidinyl groups in the antibacterial peptide residue, so that the effective grabbing of the nanometer AMPs is realized, the drug-carrying capacity of the amphiphilic glucan block polymer is improved, free amino groups in the nanometer AMPs residue can be protected, the stability of the nanometer AMPs to protease is improved, the toxicity to normal cells is reduced, and the risk of hemolysis is reduced; the orthoester group is used as a hydrophobic source and a pH response element of a drug delivery system, the chemical structure is kept stable under the neutral pH condition, and the chemical structure is gradually hydrolyzed under the weak acidic environment of an infection site, so that enrichment of the drug at the infection site is realized and the bioavailability is improved.
Furthermore, the amphiphilic property of the functionalized amphiphilic dextran block polymer can be regulated by regulating the length of the orthoester group fatty chain, so that the morphology of the amphiphilic dextran block polymer can be regulated.
Drawings
FIG. 1 is a preparation flow of a cationic antibacterial peptide nano drug-loaded micelle;
FIG. 2 is a Dex-PBA-OM fabrication roadmap;
FIG. 3 is a DLS analysis of THANPs with different Thanatin content;
FIG. 4 is a graph showing the encapsulation efficiency and drug loading rate of THANPs
Fig. 5 shows the particle size change (n=3) of the thamps-3 at pH 7.4,6.5 and 5.5;
FIG. 6 is a graph showing the drug release profile of THANPs-3 at pH 7.4,6.5 and 5.5.
Detailed Description
The invention is further described below with reference to the drawings and the detailed description.
As shown in fig. 1, the present invention provides an amphiphilic dextran block polymer having a pH response decomposition, comprising a carrier chain body: dextran (Dextran), drug-carrying functional groups: aminophenylboronic acid (PBA) to provide a reliable binding site for AMPs, and a hydrophobic acid-responsive chemical group; orthoester amine (OM) is used as a hydrophobic source and a pH response element, can promote the formation of nano drug-loaded micelles, and utilizes aminophenylboric acid and orthoester amine to carry out functional modification on glucan through dicarbonyl carbonate CDI chemical coupling reaction to obtain the amphiphilic glucan block polymer.
The invention also provides a cationic antibacterial peptide nano-drug, wherein nano AMPs and the amphiphilic dextran block polymer are dissolved in DMSO, a nano-drug solution is prepared by a dialysis method, and then the nano-drug solution is freeze-dried to obtain the cationic antibacterial peptide nano-drug, the amino phenylboronic acid in the amphiphilic dextran block polymer realizes the entrapment of the nano AMPs through the acting force of N-B coordination bonds and the effect of the piperidinyl-pi electrons, and the orthoester structure is used as an acidic pH response functional group to promote the response drug release of the nano micelle in an acidic microenvironment.
Further, the particle size of the prepared cationic antibacterial peptide nano-drug is about 200nm, the PDI is less than 0.2, the encapsulation efficiency is not less than 65%, the drug loading rate is not less than 15%, the AMPs active ingredients are released in response to disintegration in an acidic environment with the pH value of 5.5-6.5, the drug sustained release time is 1 hour when the pH value is 5.5, the drug release time is 4 hours when the pH value is 6.5, the drug cumulative release rate is higher than 90%, and the drug is not released under neutral conditions.
Cationic amino acids (lysine, arginine) are commonly present in AMPs (e.g., thanatin, spinigerin, proteorin-1,Termicin,Tachyplesin I, etc.), and are important building blocks for AMPs to exert cationic-related properties (antibacterial, antitumor, antiviral).
As shown in fig. 2, the invention provides a preparation method of an amphiphilic dextran block polymer with pH response decomposition, which comprises the following specific steps:
under the protection of argon, dextran with the molecular weight of 20kDa is dissolved in anhydrous DMSO (the concentration is 20-30 mg/mL), dicarbonyl imidazole (CDI) is then added, and stirring is carried out for 2 hours at room temperature, so that the hydroxyl groups in the dextran are fully activated.
Then, orthoester amine was added, and after 2 hours of reaction, aminophenylboronic acid (PBA) was added, and the reaction was continued for 24 hours. Wherein the dosage ratio of glucan, aminophenylboric acid and orthoester amine is 1:1.3:0.1 (molar ratio).
After the reaction is finished, dialyzing the mixed solution for 48 hours by using a dialysis bag with the molecular weight cutoff of 3500Da, and freeze-drying to obtain a series of amputation Dex-PBA-OM containing different orthoester amines, thus obtaining the cationic antibacterial peptide nano drug-loaded micelle.
Preferably, the orthoester amine comprises methyl acrylate amine, butyl acrylate amine or octyl acrylate amine.
Preferably, the aminophenylboronic acid comprises 3-aminophenylboronic acid, 2-aminophenylboronic acid, and other amino-substituted phenylboronic acid compounds.
As shown in fig. 2, the invention also provides a preparation method of the cationic antibacterial peptide nano-drug, which comprises the following specific steps:
the nano AMPs of the invention adopts the Thanatin (expressed by THA), which is an AMPs derived from hemiptera insects, has high-efficiency inhibitory activity on bacteria including various gram-negative drug-resistant bacteria, and the amino acid residue of the nano AMPs contains 4 primary amino groups and three piperidine groups;
quality-improving Dex-PBA-OM and THAThe weight ratio is 1: (0.1-0.4) is dissolved in DMSO and stirred for 1 hour (8000 rmp/min) at 25 ℃. With deionized water (containing 0.1% net) 3 ) Dialyzing for 48h, and freeze-drying to obtain the Thanatin nano-drug (THANPs).
The THANPs prepared by the invention are administrated by intravenous injection, the EPR effect of the nano particles can lead the THANPs to be directionally enriched at an infection part, and the acidic microenvironment of the infection part promotes the disintegration of the nano particles so as to release AMPs active ingredients.
Specifically, gram-negative drug-resistant bacteria are Klebsiella pneumoniae, escherichia coli, pseudomonas aeruginosa and the like which are resistant to carbapenems.
Example 1
The preparation method of the amphiphilic dextran block polymer with pH response decomposition comprises the following specific steps:
under the protection of argon, dextran with the molecular weight of 20kDa is dissolved in anhydrous DMSO (the concentration is 20 mg/mL), dicarbonyl imidazole (CDI) is added, and stirring is carried out for 2 hours at room temperature, so that hydroxyl groups in the dextran are fully activated;
then adding methyl acrylate amine, reacting for 2h, adding 3-aminophenylboric acid, and continuing the reaction for 24h.
After the reaction is finished, the mixed solution is dialyzed for 48 hours by a dialysis bag with the molecular weight cutoff of 3500Da, and the functionalized dextran block polymer Dex-PBA-OM-Methyl is obtained after freeze drying.
Example 2
The preparation method of the amphiphilic dextran block polymer with pH response decomposition comprises the following specific steps:
under the protection of argon, dextran with the molecular weight of 20kDa is dissolved in anhydrous DMSO (the concentration is 20 mg/mL), dicarbonyl imidazole (CDI) is added, and stirring is carried out for 2 hours at room temperature, so that hydroxyl groups in the dextran are fully activated;
then adding butyl ammonium acrylate, reacting for 2 hours, adding 2-aminophenylboric acid, and continuing the reaction for 24 hours.
After the reaction is finished, the mixed solution is dialyzed for 48 hours by a dialysis bag with the molecular weight cutoff of 3500Da, and the functionalized dextran block polymer Dex-PBA-OM-Butyl is obtained after freeze drying.
Example 3
The preparation method of the amphiphilic dextran block polymer with pH response decomposition comprises the following specific steps:
under the protection of argon, dextran with the molecular weight of 20kDa is dissolved in anhydrous DMSO (the concentration is 20 mg/mL), dicarbonyl imidazole (CDI) is added, and stirring is carried out for 2 hours at room temperature, so that hydroxyl groups in the dextran are fully activated;
then adding octyl ammonium acrylate, reacting for 2 hours, adding 3-aminophenylboric acid, and continuing the reaction for 24 hours.
After the reaction is finished, the mixed solution is dialyzed for 48 hours by a dialysis bag with the molecular weight cutoff of 3500Da, and the functionalized dextran block polymer Dex-PBA-OM-Octyl is obtained after freeze drying.
Example 4
The preparation process of nanometer cationic antibiotic peptide medicine includes the following steps:
dextran block polymer Dex-PBA-OM-Butyl prepared in example 2;
20mg of Dex-PBA-OM-Butyl was dissolved in 5mL of DMSO, and mixed with 1mL of DMSO containing 2mg of THA, respectively, and stirred vigorously for 1.0h. With deionized water (containing 0.1% net) 3 ) Dialyzing for 48h, and freeze-drying to obtain the Thanatin nano-drug THANPs-1 with the encapsulation rate of 93% and the drug loading rate of 8%.
Example 5
The preparation process of nanometer cationic antibiotic peptide medicine includes the following steps:
dextran block polymer Dex-PBA-OM-Butyl prepared in example 2;
20mg of Dex-PBA-OM-Butyl was dissolved in 5mL of DMSO, and mixed with 1mL of DMSO containing 4mg of THA, respectively, and stirred vigorously for 1.0h. With deionized water (containing 0.1% net) 3 ) Dialyzing for 48h, and freeze-drying to obtain the Thanatin nano-drug THANPs-2 with the encapsulation rate of 87% and the drug loading rate of 14%.
Example 6
The preparation process of nanometer cationic antibiotic peptide medicine includes the following steps:
dextran block polymer Dex-PBA-OM-Butyl prepared in example 2;
20mg of Dex-PBA-OM-Butyl was dissolved in 5mL of DMSO, and mixed with 1mL of DMSO containing 6mg of THA, respectively, and stirred vigorously for 1.0h. With deionized water (containing 0.1% net) 3 ) Dialyzing for 48h, and freeze-drying to obtain the Thanatin nano-drug THANPs-3 with the encapsulation rate of 73% and the drug loading rate of 16.8%.
Example 7
The preparation process of nanometer cationic antibiotic peptide medicine includes the following steps:
dextran block polymer Dex-PBA-OM-Butyl prepared in example 2;
20mg of Dex-PBA-OM-Butyl was dissolved in 5mL of DMSO, and mixed with 1mL of DMSO containing 8mg of THA, respectively, and stirred vigorously for 1.0h. With deionized water (containing 0.1% net) 3 ) Dialyzing for 48h, and freeze-drying to obtain the Thanatin nano-drug THANPs-4 with the encapsulation rate of 60% and the drug loading rate of 17%.
Example 8
The preparation process of nanometer cationic antibiotic peptide medicine includes the following steps:
dextran block polymer Dex-PBA-OM-Butyl prepared in example 2;
20mg of Dex-PBA-OM-Butyl was dissolved in 5mL of DMSO, and mixed with 1mL of DMSO containing 10mg of THA, respectively, and stirred vigorously for 1.0h. With deionized water (containing 0.1% net) 3 ) Dialyzing for 48h, and freeze-drying to obtain the Thanatin nano-drug THANPs-5 with the encapsulation rate of 52% and the drug loading rate of 15%.
The antimicrobial of the THANPs prepared in the above examples was subjected to a characteristic test, specifically as follows:
(1) Nano-drugs were subjected to dynamic light scattering experiments (DLS).
Instrument apparatus: the Malvern particle size analyzer was tested at 25 ℃.
Analysis of results: as shown in FIG. 3, as the THA content increases, the particle size of THANPs decreases and then increases, and when the mass ratio of Thanatin to Dex-PBA-OM-Butyl is 3:10, the particle size of the obtained nano-antimicrobial agent is 185.1nm, PDI:0.185, zeta potential-30.2 mV; when the ratio of THA to drug-carrying material is 4:10, the particle size of the obtained nano antibacterial agent is 255 nm, PDI:0.2, zeta potential-27.2 mV.
(2) High Performance Liquid Chromatography (HPLC) standard curve method for measuring drug loading and encapsulation efficiency.
Sample preparation: 1mg of THANPs with different drug loading amounts was dissolved in 1mL of an aqueous solution containing 0.1% TFA (trifluoroacetic acid), and after shaking for 2 hours, the solution was filtered by a filter head having a pore size of 0.4. Mu.m, and the resulting solution was subjected to HPLC test. Liquid phase test conditions: c18 chromatographic column, 25 ℃; detection wavelength 214nm; gradient elution: 0.01min 5% acetonitrile/95% water (0.1% tfa), 25min 50% acetonitrile/50% water (0.1% tfa); retention time t=13.98 min. The concentration of Thanatin in each sample was converted against the Thanatin concentration-absorbance peak standard curve.
Analysis of results: the test results are shown in fig. 4, wherein the encapsulation efficiency is reduced from 93% to 52% with increasing amount of THA, and the drug loading is reduced from increasing to decreasing, wherein the ratio of THA to drug loading material is 16.8% at 3:10 and 17.1% at 4:10.
(3) PH response behavior of THANPs-3
The method for studying the pH response and drug release behavior of THANPs-3 was as follows: THANPs were dissolved in 1 XPBS buffer at pH 7.4,6.5 and 5.5 at a concentration of 1.0mg mL -1 . Then, 100. Mu.L of the nano-solution was added to 2mL of distilled water every 10min, and the change in particle size was detected by a dynamic light scattering instrument. At room temperature, 400. Mu.L of the nano-solution was ultrafiltered at 0.5,1.0,2.0,3.0,4.0,6.0,8.0 and 10 hours, and HPLC was performed to analyze the release characteristics of the lantin.
Analysis of results: as shown in FIG. 5, the THANPs-3 had a particle size of about 190nm and remained almost unchanged at pH 7.4, but increased significantly at pH 6.5, and increased more significantly at pH 5.5 below, and eventually increased to 1400nm or more within 60 minutes. As shown in FIG. 6, the drug release curves under different pH conditions show that THANPs-3 does not detect the release of the drug at pH 7.4, which indicates that the material has good stability under neutral conditions and does not cause drug leakage, and releases obviously under acidic conditions, wherein the drug release is basically completed within 4 hours at pH 6.5, the drug release is basically completed within 1 hour at pH 5.5, and the cumulative release rate is 92%.
The above description is only of the preferred embodiments of the present invention, and is not intended to limit the present invention. Any simple modification, variation and equivalent variation of the above embodiments according to the technical substance of the invention still fall within the scope of the technical solution of the invention.
Claims (10)
1. An amphiphilic dextran block polymer that disintegrates in response to pH, comprising a carrier chain body: dextran; drug-loading functional groups: phenylboronic acid groups; pH responsive element: orthoester group, the dextran, the aminophenylboric acid and the orthoester amine are dissolved in DMSO together, and the amphiphilic dextran block polymer with pH response decomposition is obtained by a method of condensation coupling reaction of dicarbonyl carbonate.
2. The amphiphilic dextran block polymer of pH response decomposition according to claim 1, wherein the molar ratio of the amount of dextran, aminophenylboronic acid and orthoester amine used is 1:1.3:0.1.
3. the pH-responsive decomposed amphiphilic dextran block polymer of claim 1, wherein said orthoester amine comprises methyl-, butyl-or octyl-circular acid amine and said aminophenylboronic acid comprises 3-aminophenylboronic acid or 2-aminophenylboronic acid.
4. Use of the amphiphilic dextran block polymer of any one of claims 1 to 3 as a cationic antibacterial peptide carrier.
5. Use of the amphiphilic dextran block polymer of any one of claims 1 to 3 for the preparation of cationic antibacterial peptide nano-drugs.
6. The cationic antibacterial peptide nano-drug is characterized by comprising cationic antibacterial peptide and the amphiphilic glucan block polymer according to any one of claims 1-3, wherein the amphiphilic glucan block polymer is self-assembled with the cationic antibacterial peptide through N-B coordination bond acting force and the piperidinyl-pi electron effect to obtain the cationic antibacterial peptide nano-drug.
7. The cationic antibacterial peptide nano-drug according to claim 6, wherein the ratio of the amphiphilic dextran block polymer to the cationic antibacterial peptide is 1: (0.1-0.4), the cationic antibacterial peptide and the functionalized glucan block polymer material are dissolved in DMSO together, and the cationic antibacterial peptide nano-drug is obtained through stirring, dialysis and freeze drying.
8. The cationic antibacterial peptide nano-drug according to claim 6, wherein the cationic antibacterial peptide nano-drug disintegrates to release the bioactive component of the antibacterial peptide under the condition of pH value of 5.5-6.5.
9. Use of a cationic antibacterial peptide nano-drug according to any one of claims 6 to 8 as a medicament for the treatment of infectious diseases caused by gram-negative resistant bacteria.
10. A medicament for treating infectious diseases caused by gram-negative resistant bacteria, comprising a cationic antibacterial peptide nano-drug according to claim 7 or 8.
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