Ovarian cancer specifically targeted biodegradable amphiphilic polymer, polymer vesicle prepared from same and application of amphiphilic polymer

A technology for polymers and ovarian cancer, which is applied in the direction of drug combinations, medical preparations of non-active ingredients, non-effective ingredients of polymer compounds, etc., and can solve problems such as easy to occur toxic side effects, narrow therapeutic window, and small maximum tolerated dose , to achieve the effect of overcoming the need for complex operations and purification processes, simple preparation methods, and overcoming cycle instability

Active Publication Date: 2016-06-15
BRIGHTGENE BIO MEDICAL TECH (SUZHOU) CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, there is also a problem with DOXIL
One is that its maximum tolerated dose (MTD) is small, so the treatment window is relatively narrow, and it is prone to side effects; second, DOXIL is a passive targeting effect based on the EPR effect. Due to individual differences, it is difficult to use a general unified mechanism to transport nano-drugs to all tumor tissues and cells (see: S. Eetezadi, SN. Ekdawi, C. Allen, Adv. Drug Deliv Rev, 2015, 91, 7 -22); for different tumors, due to the great difference in the surface properties of different tumors, the same tumor also has great differences among different patients; even the different tumor cells in the same tumor are not the same, so personalized treatment appears especially important

Method used

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  • Ovarian cancer specifically targeted biodegradable amphiphilic polymer, polymer vesicle prepared from same and application of amphiphilic polymer
  • Ovarian cancer specifically targeted biodegradable amphiphilic polymer, polymer vesicle prepared from same and application of amphiphilic polymer
  • Ovarian cancer specifically targeted biodegradable amphiphilic polymer, polymer vesicle prepared from same and application of amphiphilic polymer

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0049] Example 1 Synthesis of a cyclic carbonate monomer (CDC) containing a disulfide five-membered ring functional group

[0050] Sodium hydrosulfide monohydrate (28.25g, 381.7mmol) was dissolved in 400mL N,N-dimethylformamide (DMF), heated at 50°C until completely dissolved, and dibromoneopentyl glycol (20g, 76.4mmol) was added dropwise , reacted for 48 hours. The reactant was evaporated under reduced pressure to remove the solvent DMF, then diluted with 200mL distilled water, extracted four times with 250mL ethyl acetate, and finally the organic phase was rotary evaporated to obtain yellow viscous compound A, yield: 70%; dissolved in 400mL tetrahydrofuran (THF ) in the air for 24 hours, the intermolecular sulfhydryl groups were oxidized into sulfur-sulfur bonds to obtain compound B, yield; >98%; under nitrogen protection, compound B (11.7g, 70.5mmol) was dissolved in a dry THF (150 mL), stirred until completely dissolved. Following cooling to 0 °C, ethyl chloroformate (15...

Embodiment 2

[0051] Example 2 Synthesis of two-block polymer PEG5k-P (CDC5.8k-co-TMC23k)

[0052] Under nitrogen atmosphere, 0.1g (0.52mmol) of CDC monomer and 0.4g (4.90mmol) of trimethylene carbonate (TMC) were dissolved in 5mL of dichloromethane, added to the sealed reactor, and then 0.12g (0.02 mmol) CH 3 O-PEG5000 and 0.5mL dichloromethane solution (0.1mol / L) of the catalyst bis(bistrimethylsilyl)amine zinc, then seal the reactor well, transfer it out of the glove box, and react in an oil bath at 40°C for 2 Two days later, the reaction was terminated with glacial acetic acid, precipitated in glacial ether, and finally filtered and vacuum-dried to obtain PEG5k-P (CDC5.8k-co-TMC23k). 1 HNMR (400MHz, CDCl 3 ):2.08(t,-COCH 2 CH 2 CH 2 O-),3.08(s,-CCH 2 ),3.30(m,-OCH 3 ), 3.65 (-OCH 2 CH 2 O-), 4.28(t,-COCH 2 CH 2 CH 2 O-),4.31(m,-CCH 2 ). According to the NMR calculation, k=114, x=30.2, y=225.5 in the following formula. GPC molecular weight: 45.6kDa, molecular weight distri...

Embodiment 3

[0054] Example 3 Synthesis of two-block polymer Mal-PEG6k-P (CDC4.8k-co-TMC19.2k)

[0055] Under nitrogen atmosphere, 0.1g (0.52mmol) of CDC monomer and 0.4g (3.85mmol) of TMC were dissolved in 3mL of dichloromethane and added to the sealed reactor, then 0.12g (0.02mmol) of Mal-PEG6000 and 0.1 mol / L catalyst dichloromethane solution (0.1mol / L) of bis(bistrimethylsilyl)amine zinc, then seal the reactor well, transfer it out of the glove box, and react in an oil bath at 40°C for 2 days, then add glacial acetic acid The reaction was terminated, precipitated in glacial ether, and finally filtered and vacuum-dried to obtain Mal-PEG6k-P (CDC4.8k-co-TMC19.2k). 1 HNMR (400MHz, CDCl 3 ):2.08(t,-COCH 2 CH 2 CH 2 O-),3.08(s,-CCH 2 ),3.30(m,-OCH 3 ), 3.65 (t, -OCH 2 CH 2 O-), 4.28(t,-COCH 2 CH 2 CH 2 O-),4.31(m,-CCH 2 ), and 6.70 (s, Mal). In the following formula calculated by NMR, k=136, x=25, y=188. Molecular weight measured by GPC: 38.6 kDa, molecular weight distribution...

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Abstract

The invention discloses an ovarian cancer specifically targeted biodegradable amphiphilic polymer, a polymer vesicle prepared from the amphiphilic polymer and application of the amphiphilic polymer in ovarian cancer targeted therapy. The polymer vesicle obtained by utilizing the biodegradable amphiphilic polymer has biodegradability and can be used for controlling a drug release system; under the condition of no addition of a crosslinking agent, self crosslinking can be carried out, and a stable chemical crosslinked structure is formed, so that stable long circulation in a carrier supporting body can be realized, side effects of the crosslinking agent are avoided, and the crosslinking agent also has reduction sensitivity, is rapidly decrosslinked in cells and releases maximum drugs, so as to efficiently and specifically kill cancer cells to effectively inhibit the growth of ovarian tumors while no toxic or side effect is caused; more importantly, an extra crosslinking agent does not need to be added, so that clinical application production of a nano drug can be facilitated, the production cost is reduced, the final purity of the nano drug is also improved, and the biocompatibility of the nano drug is improved; and meanwhile, interference of the crosslinking agent on some drugs is avoided.

Description

technical field [0001] The invention relates to a biodegradable polymer material and its application, in particular to a biodegradable amphiphilic polymer specifically targeting ovarian cancer, polymer vesicles prepared therefrom, and its use in ovarian cancer targeted therapy. The application belongs to the field of medical materials. Background technique [0002] Biodegradable polymers have very unique properties and are widely used in various fields of biomedicine, such as surgical sutures, bone fixation devices, biotissue engineering scaffold materials, and drug controlled release carriers. Synthetic biodegradable polymers mainly include aliphatic polyester (polyglycolide PGA, polylactide PLA, lactide-glycolide copolymer PLGA, polycaprolactone PCL), polycarbonate (polytrimethylene Cyclocarbonate PTMC) etc. are the most commonly used biodegradable polymers, which have been approved by the US Food and Drug Administration (FDA). However, existing biodegradable polymers su...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C08G64/18C08G64/30A61K9/127A61K47/34A61K47/42A61P35/00
CPCA61K9/1273A61K47/34A61K47/42C08G64/18C08G64/30A61K9/5146A61K47/551A61K47/62A61K47/6855A61K47/6935A61P35/00B82Y5/00C08G63/64C08G63/688A61K31/337C08G64/025C08G64/42A61K9/5169
Inventor 孟凤华邹艳钟志远
Owner BRIGHTGENE BIO MEDICAL TECH (SUZHOU) CO LTD
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