CN109078017A - Polymer vesicle and the preparation method and application thereof is buried in a kind of targeting double-contracting - Google Patents

Polymer vesicle and the preparation method and application thereof is buried in a kind of targeting double-contracting Download PDF

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Publication number
CN109078017A
CN109078017A CN201811219002.4A CN201811219002A CN109078017A CN 109078017 A CN109078017 A CN 109078017A CN 201811219002 A CN201811219002 A CN 201811219002A CN 109078017 A CN109078017 A CN 109078017A
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polymer
solution
dissolved
5min
pdllaga
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熊向源
曹文杰
龚妍春
李资玲
李玉萍
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Jiangxi Science and Technology Normal University
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Jiangxi Science and Technology Normal University
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    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
    • A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
    • 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
    • A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/127—Liposomes
    • A61K9/1271—Non-conventional liposomes, e.g. PEGylated liposomes, liposomes coated with polymers
    • A61K9/1273—Polymersomes; Liposomes with polymerisable or polymerised bilayer-forming substances
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • 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
    • C08G63/00—Macromolecular compounds obtained by reactions forming a carboxylic ester link in the main chain of the macromolecule
    • C08G63/02—Polyesters derived from hydroxycarboxylic acids or from polycarboxylic acids and polyhydroxy compounds
    • C08G63/06—Polyesters derived from hydroxycarboxylic acids or from polycarboxylic acids and polyhydroxy compounds derived from hydroxycarboxylic acids
    • C08G63/08—Lactones or lactides
    • 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
    • C08G63/00—Macromolecular compounds obtained by reactions forming a carboxylic ester link in the main chain of the macromolecule
    • C08G63/78—Preparation processes
    • C08G63/82—Preparation processes characterised by the catalyst used
    • C08G63/826—Metals not provided for in groups C08G63/83 - C08G63/86
    • 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
    • C08G65/00—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule
    • C08G65/02—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from cyclic ethers by opening of the heterocyclic ring
    • C08G65/32—Polymers modified by chemical after-treatment
    • C08G65/329—Polymers modified by chemical after-treatment with organic compounds
    • C08G65/333—Polymers modified by chemical after-treatment with organic compounds containing nitrogen
    • C08G65/33396—Polymers modified by chemical after-treatment with organic compounds containing nitrogen having oxygen in addition to nitrogen
    • 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
    • C08G2650/00—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule
    • C08G2650/02—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule characterized by the type of post-polymerisation functionalisation
    • C08G2650/04—End-capping
    • 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
    • C08G2650/00—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule
    • C08G2650/28—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule characterised by the polymer type
    • C08G2650/50—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule characterised by the polymer type containing nitrogen, e.g. polyetheramines or Jeffamines(r)

Abstract

Polymer vesicle and the preparation method and application thereof is buried in a kind of targeting double-contracting.The invention belongs to biomedicine fields, are related to a kind of novel targeted pharmaceutical carrier.The invention discloses a kind of polymer, which has both pharmaceutical carrier and target function, can embed simultaneously hydrophobicity and hydrophilic medicament acts synergistically on tumour cell, have a good application prospect.In addition, pharmaceutical carrier of the present invention, has good biocompatibility and biodegradability.

Description

Polymer vesicle and the preparation method and application thereof is buried in a kind of targeting double-contracting
Technical field
The invention belongs to biomedicine field, it is related to a kind of targeting double-contracting and buries polymer vesicle and preparation method thereof and answer With.
Background technique
It is well known that the multidrug resistance of tumour is the main reason for causing chemotherapy of tumors to fail.Single anti-tumor drug The purpose effectively treated is extremely difficult to cytotoxicity, the synergistic effect of a variety of anti-tumor drugs is just as oncotherapy A kind of new means.Fortunately, the vesica that the amphipathy macromolecule material of some biocompatibilities is formed can be used as one kind Pharmaceutical carrier, by the way that hydrophobic drug is embedded in double-deck shell, hydrophilic medicament is wrapped in kernel, is further being repaired It, can be with targeting in tumour cell, to improve the therapeutic effect of cancer after adoring vesicle surface.So-called amphipathy macromolecule, The namely high molecular material containing hydrophilic segment and hydrophobic segment.Wherein racemic polylactide [poly (d, l-lactic Acid), PDLLA] and polyglycolide [poly (glycolide), PGA] be exactly a kind of hydrophobic segment being usually selected because It had not only had biocompatibility but also had had biodegradability, had also been approved by the FDA in the United States use.It can degrade in human body As small molecule, to be easy to be excreted, so it is widely used in biomedicine field.It is carried as a kind of drug Body, Pluronic inherently have good biocompatibility, and commercially use.Secondly, in Pluronic structure PEO block hydroxyl have good modifiability, can further be transformed, therefore studied extensively by scientists.
In drug delivery system, a kind of new structure is obtained, and the pharmaceutical carrier for capableing of efficient treating cancer is urgently It solves the problems, such as.
Summary of the invention
It is an object of that present invention to provide a kind of polymer vesicles of novel folate-targeted formed by five block polymers i.e. Folic acid-Pluronic- poly- (D, L- lactide-b- glycolide) (FA-F127-PDLLAGA) can embed hydrophily simultaneously and dredge Aqueous pharmaceutical molecule, and targeting is in tumour cell.The preparation method and embedding method of the polymer are additionally provided simultaneously.
Inventive polymers concrete structure formula is as follows:
Its synthetic route such as Fig. 2, specific preparation method is:
(1) according to weight ratio, first by dried folic acid (folic acid, FA) (0.77-0.91g, 1.75- 2.07mmol) it is added in the anhydrous DMSO solution of 50ml with 1,3- dicyclohexylcarbodiimide (DCC) (0.36g, 1.75mmol), and It is stirred at room temperature for 24 hours.Then by the F127 (20g, 1.59mmol) and 4-dimethylaminopyridine (DMAP) after drying (0.02mg, 0.17mmol) is added in the mixed solution of FA and DCC, is placed in and is stirred 48h at room temperature.Then by above-mentioned mixed liquor Be centrifuged (5000rpm, 5min), dialysed in bag filter (MWCO=3.5KDa) with the DMSO of 8-10 times of volume, respectively 3h, 5h, 8h are respectively changed the liquid once.If there is precipitating, low-speed centrifugal is removed.Then after dialysing 3 days in deionized water, rotary evaporation is used The precipitating that instrument is slowly spin-dried for the solution low temperature in bag filter is FA-F127-OH.
(2) macromole evocating agent and stannous octoate ([Sn (Oct) are done with FA-F127-OH2]) it is catalyst, in anhydrous, nothing Under conditions of oxygen, cause cyclic monomer D, L- lactide (d, l-lactide, D, L-LA) and glycolide (GA) carry out ring-opening polymerisation Reaction, finally obtains required copolymer.Specific synthetic method are as follows: reaction flask is by repeatedly vacuumizing-leading to argon gas deoxygenation dehumidifying Afterwards, FA-F127-OH, D, L-LA, GA and Sn (Oct) is added under the conditions of logical argon gas2, the amount of D, L-LA are FA-F127-OH weight The amount of 70%, GA of amount is the 80% of FA-F127-OH weight, and the amount of stannous octoate is D, the total charged material weight of L-LA and GA monomer 0.1-0.15%, reactant is heated to 140-160 DEG C, under stiring reaction continue 7-9 hours；By reactant dichloromethane Alkane dissolution, then sinks in methanol, has whiteness to settle out, and filters；Then polymer is dissolved with methylene chloride again, and sinks to first In alcohol, filter, it is dry, obtain FA-F127-PDLLAGA copolymer；Pass through the hand of nuclear magnetic resonance (NMR) and the ultraviolet full scan of FA Segment table levies copolymer FA-F127-PDLLAGA, determines its structure feature and content.
(3) FA-F127-PDLLAGA and taxol (PTX) is weighed to be dissolved in 1-2mLDMF by weight 5:1, hydrochloric acid Ah Mycin (DOXHCL) is dissolved in suitable PBS, is vortexed and is shaken 3-5min or ultrasound 1-2min to help it to be completely dissolved, wherein The amount of DOX is that the amount of 50%, PBS of polymer is identical as the amount of polymer；Then by DMF solution under mild stirring condition It is slowly added drop-wise in PBS solution dropwise, is stirred for 1-2h after dripping off；Mixed solution is transferred in bag filter again (MWCO=3500), dialyse 5.5h, change a deionized water in 0.5h, 1h, 2h, 2h respectively, so as to remove the DOX not embedded and PTX.After the completion of dialysing, low-speed centrifugal (3000rpm, 5min), as required nano-particle solution.PTX content passes through height Effect liquid phase chromatogram (HPLC) detects at 227nm to be obtained；DOX content is detected at 480nm by ultraviolet specrophotometer and is obtained.
Polymer provided by the invention is the pharmaceutical carrier with novel chemical structure and target function, and can be same When embed hydrophobic and hydrophilic medicament to act synergistically, thus targeting therapy on tumor cell.With existing FA-F127-PLA phase Than racemic PDLLA is amorphous structure, and PLA is semicrystalline structure.Compared with PLA, the crystallinity of PDLLAGA is lower Hydrophily is higher.Therefore, compared with FA-F127-PLA, FA-F127-PDLLAGA should would be even more beneficial to carry out amphipathic drug Embedding.
Detailed description of the invention
Fig. 1 is the chemical structural formula of FA-F127-PDLLA of the present invention；
Fig. 2 is Inventive polymers synthetic route；
Fig. 3 is the nuclear magnetic spectrum of Inventive polymers；
Fig. 4 is the ultraviolet full scan map of FA；
Fig. 5 is formed the characterization result of nanoparticle by Inventive polymers.
Specific embodiment
Embodiment 1
1, according to weight ratio, first by dried folic acid (folic acid, FA) (0.77g, 1.75) and 1,3-, bis- hexamethylene Base carbodiimide (DCC) (0.36g, 1.75mmol) is added in the anhydrous DMSO solution of 50ml, and is stirred at room temperature for 24 hours.Then By after drying F127 (20g, 1.59mmol) and 4-dimethylaminopyridine (DMAP) (0.02mg, 0.17mmol) be added to FA with In the mixed solution of DCC, it is placed in and stirs 48h at room temperature.Then above-mentioned mixed liquor is centrifuged (5000rpm, 5min), in dialysis It is dialysed in bag (MWCO=3.5KDa) with the DMSO of 8 times of volumes, is respectively changed the liquid once in 3h, 5h, 8h respectively.If there is precipitating, low speed It is centrifuged off.Then in deionized water dialyse 3 days after, after having dialysed with 8% NaHCO3Solution extracts reaction solution to remove Remove the impurity such as unreacted FA.Then extract liquor is slowly spin-dried for using Rotary Evaporators low temperature.CH is used after being spin-dried for again2Cl2It is molten Solution is added in ice ether and purifies, and is FA-F127-OH after taking precipitating to dry repeatedly twice.Gained copolymer is weighed as 10.60g, yield 51.19%.
2, reaction flask by vacuumize-lead to argon gas deoxygenation dehumidifying after, under the conditions of argon gas addition FA-F127-OH 4.07g, Reactant is heated to 120 DEG C, under stirring by D, L- lactide 2.82g, glycolide 3.22g and stannous octoate 6mg, and reaction continues 6 Hour；Reactant methylene chloride is dissolved, is then sunk in methanol, has whiteness to settle out, is filtered；Then methylene chloride is used again Polymer is dissolved, and is sunk in methanol, is filtered, it is dry, FA-F127-PDLLAGA copolymer 1 .78g is finally obtained, yield is 17.62%.
Structural characterization1H NMR(400MHz,CDCl3,ppm):1.1-1.2(m,CH3ofPPO block in F127), 1.5-1.7(m,CH3ofPDLLA block),3.3-3.7(m,OCH2CH2ofPEO block and OCH2CH ofPPO block in F127),4.7-5.0(m,CH2ofPGA block),5.1-5.3(m,CH ofPDLLA block),
The molecular weight for the FA-F127-PDLLAGA copolymer being prepared and the segment content of PDLLA and PGA are by FA- The nuclear magnetic spectrogram of F127-PDLLAGA is calculated (nuclear magnetic spectrum such as Fig. 3), and result is the molecular weight of FA-F127-PDLLAGA It (Mn) be the content of 38568, PDLLA segment is 31.2wt%, the content of PGA segment is 36wt%, the i.e. knot of phase emergencing copolymer Structure formula is FA-PEO100-PPO65-PEO100-P(DLLA168-b-GA240).Wherein shown in the ultraviolet full scan Fig. 4 of FA, illustrate FA success It is connect with F127.It is 12.75% that molar content of the FA in polymer FA-F127-PDLLAGA, which is obtained by calculation,.
3, it the preparation of nanoparticle: weighs FA-F127-PDLLAGA 10mg and taxol (PTX) 2mg and is dissolved in 2mLDMF In, doxorubicin hydrochloride (DOXHCL) 5mg is dissolved in 10gPBS, is vortexed concussion 5min or ultrasound 2min to help it completely molten Solution；Then DMF solution is slowly added drop-wise in PBS solution dropwise under mild stirring condition, is stirred for 1-2h after dripping off； Mixed solution is transferred in bag filter (MWCO=3500) again, dialyse 5.5h, changes once in 0.5h, 1h, 2h, 2h respectively Deionized water, to remove the DOX and PTX that do not embed.After the completion of dialysing, low-speed centrifugal (3000rpm, 5min), as institute The nano-particle solution needed.
Nanoparticle characterization: partial size, form and the size of nanoparticle can be shown by Zeta Plus particle instrument and transmitted electron The detection of the methods of micro mirror (TEM) obtains.As a result such as Fig. 5, particle size is 106.71 ± 6.0, dispersion 0.298 ± 0.005.
The embedding rate and drugloading rate of drug: PTX content is obtained by high performance liquid chromatography (HPLC) detection, ultraviolet detection wavelength 227nm, mobile phase are acetonitrile: water=6:4, sample volume 100 μ L, flow velocity 1mL/min, 35 DEG C of column temperature.DOX content has ultraviolet spectrometry Photometer detects to obtain, and ultraviolet detection wavelength is 480nm.The PTX embedding rate being calculated is 3.31 ± 0.6%, DOX embedding rate It is 13.88 ± 1.59%.

Claims (4)

1. polymer vesicle polymer is buried in a kind of targeting double-contracting, molecular structural formula is as follows:
2. polymer as described in claim 1, preparation method includes the following steps:
(1) according to weight ratio, first by dried folic acid 0.77g, 1.75mmol and 1,3- dicyclohexylcarbodiimide 0.36g, 1.75mmol is added in the anhydrous DMSO solution of 50ml, and is stirred at room temperature for 24 hours, then by the F12720g after drying, 1.59mmol and 4-dimethylaminopyridine 0.02mg, 0.17mmol are added in the mixed solution of FA and DCC, are placed in and stir at room temperature Then above-mentioned mixed liquor centrifugal condition is 5000rpm, 5min by 48h；With 8-10 times in the bag filter of MWCO=3.5KDa The DMSO of volume dialyses, and respectively changes the liquid once in 3h, 5h, 8h respectively, if there is precipitating, low-speed centrifugal is removed, then in deionized water It the use of the precipitating that Rotary Evaporators are slowly spin-dried for the solution low temperature in bag filter is FA-F127- after middle dialysis 3 days OH；
(2) macromole evocating agent and stannous octoate-[Sn (Oct) are done with FA-F127-OH2]) it is catalyst, anhydrous, anaerobic Under the conditions of, cause cyclic monomer D, L- lactide-d, l-lactide, D, L-LA) and glycolide-GA progress ring-opening polymerization, Finally obtain required copolymer, specific synthetic method are as follows: after reaction flask is by repeatedly vacuumizing-leading to argon gas deoxygenation dehumidifying, FA-F127-OH, D, L-LA, GA and Sn (Oct) is added under the conditions of logical argon gas2, the amount of D, L-LA are FA-F127-OH weight The amount of 70%, GA are the 80% of FA-F127-OH weight, and the amount of stannous octoate is D, the total charged material weight of L-LA and GA monomer Reactant is heated to 140-160 DEG C by 0.1-0.15%, and reaction continues 7-9 hours under stiring；By reactant methylene chloride Dissolution, then sinks in methanol, has whiteness to settle out, and filters；Then polymer is dissolved with methylene chloride again, and sinks to methanol In, it filters, it is dry, obtain FA-F127-PDLLAGA copolymer；
(3) it weighs FA-F127-PDLLAGA 10mg and taxol-PTX 2mg to be dissolved in 2mLDMF, doxorubicin hydrochloride- DOXHCL5mg is dissolved in 10gPBS, and the concussion 5min or ultrasound 2min that is vortexed is to help it to be completely dissolved；Then by DMF solution It is slowly added drop-wise in PBS solution dropwise under mild stirring condition, is stirred for 1-2h after dripping off；Again by mixed solution Wherein MWCO=3500 is transferred in bag filter, dialyse 5.5h, a deionized water is changed in 0.5h, 1h, 2h, 2h respectively, so as to The DOX and PTX that do not embed are removed, after the completion of dialysing, low-speed centrifugal 3000rpm, 5min, as required nanoparticle is molten Liquid.
3. polymer described in claim 1 is in the application for preparing target medicinal carrier.
4. application according to claim 3, it is characterised in that hydrophobicity and hydrophilic medicament can be embedded simultaneously, and target work For tumour cell, therapeutic effect can be improved.
CN201811219002.4A 2018-10-19 2018-10-19 Polymer vesicle and the preparation method and application thereof is buried in a kind of targeting double-contracting Pending CN109078017A (en)

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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103893769A (en) * 2014-04-16 2014-07-02 江西科技师范大学 Poly(lactic-glycolic acid)-targeted polymer drug carrier and preparation method thereof

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103893769A (en) * 2014-04-16 2014-07-02 江西科技师范大学 Poly(lactic-glycolic acid)-targeted polymer drug carrier and preparation method thereof

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