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Anti-tumor nano-adjuvant based on cross-linked biodegradable polymer vesicles and preparation method and application thereof

A degradable polymer and anti-tumor technology, which is applied in the field of preparation of anti-tumor nano-drugs, can solve the problems of toxic side effects, low efficacy of nano-drugs, and low loading efficiency, and achieve the effects of low toxicity, avoiding losses and side effects

Active Publication Date: 2020-07-24
SUZHOU UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

In recent years, tumor immunotherapy has attracted extensive attention; however, due to the existence of the blood-brain barrier (BBB), the immune adjuvant CpG cannot directly enter the GBM.
At the same time, the rapid degradation of CpG in the body and the immunotoxicity caused by high doses also limit its immunotherapy mainly through intratumoral / intracranial administration.
However, intracranial administration is often accompanied by cerebral edema, inflammation, and associated toxicities due to rapid diffusion of immune stimulants into the bloodstream
Moreover, the loading efficiency of CpG in the existing vesicle technology is low; at the same time, there are problems such as unstable circulation of vesicles, low tumor cell uptake, and low intracellular drug concentration, resulting in low efficacy of nano-medicines and toxic side effects , which greatly limit the application of vesicles as carriers of such drugs

Method used

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  • Anti-tumor nano-adjuvant based on cross-linked biodegradable polymer vesicles and preparation method and application thereof
  • Anti-tumor nano-adjuvant based on cross-linked biodegradable polymer vesicles and preparation method and application thereof
  • Anti-tumor nano-adjuvant based on cross-linked biodegradable polymer vesicles and preparation method and application thereof

Examples

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preparation example Construction

[0069] Above-mentioned preparation method specifically comprises the following steps:

[0070] Reaction of MeO-PEG-P(TMC-DTC)-OH and hydroxyl activator in a dry solvent, then precipitation, suction filtration, and vacuum drying to obtain MeO-PEG-P(TMC-DTC)-CDI activated by terminal hydroxyl groups; Add its solution dropwise to spermine or PEI solution to react, then precipitate, filter with suction, and dry in vacuum to obtain MeO-PEG-P(TMC-DTC)-Sp or MeO-PEG-P(TMC-DTC)-PEI;

[0071] Reaction of Mal-PEG-P (TMC-DTC) and ApoE polypeptide dissolved in an organic solvent to obtain targeted ApoE-PEG-P (TMC-DTC);

[0072] The raw material solution is added into a non-ionic buffer solution, placed at room temperature, dialyzed, and cross-linked to obtain an anti-tumor nano drug based on a cross-linked biodegradable polymer vesicle.

[0073] The raw materials involved in the embodiments of the present invention are all existing products, such as PEG, Mal-PEG, TMC, DTC, DPP, oligonucl...

Embodiment 1

[0074] Embodiment 1 Synthesis of MeO-PEG5k-P (TMC14.9k-DTC2.0k) block copolymer

[0075] MeO-PEG5k-P (TMC14.9k-DTC2.0k) is prepared by ring-opening polymerization. The specific operation is as follows. In a nitrogen glove box, weigh MeO-PEG-OH ( M n = 5.0 kg / mol, 0.50 g, 100 μmol), TMC (1.5 g, 14.7mmol) , DTC (0.2 g, 1.0 mmol) and diphenyl phosphate (DPP, 0.25 g, 1000 μmol) and dissolved in dichloromethane ( DCM, 7.9 mL). The airtight reactor was sealed and placed under magnetic stirring in an oil bath at 40 °C for 3 days. After that, it was precipitated twice in glacial ether, filtered with suction, and dried under vacuum at room temperature to obtain the product. The yield is about 90%. 1 H NMR (400 MHz, CDCl 3 ): PEG: d 3.38, 3.65; TMC: d 4.24, 2.05; DTC: d 4.32, 3.02. attached figure 1 It is the nuclear magnetic spectrum of MeO-PEG5k-P (TMC14.9k-DTC2.0k), and it can be known by integration that the molecular weight of the final polymer obtained is PEG5k-P (TMC14.9k-...

Embodiment 2

[0084] Example 2 Synthesis of Mal-PEG7.5k-P (TMC15.2k-DTC2.0k) block copolymer

[0085] Mal-PEG7.5k-P (TMC15.2k-DTC2.0k) block copolymer is prepared by ring-opening polymerization, the specific operation is as follows, in the nitrogen glove box, weigh Mal-PEG-OH ( M n = 7.5 kg / mol, 0.75 g, 100 μmol), TMC (1.5 g, 14.7 mmol) , DTC (0.2 g, 1.0 mmol) and diphenyl phosphate (DPP, 0.25 g, 1000 μmol) and dissolved in dichloromethane ( DCM, 7.9 mL). The airtight reactor was sealed and placed under magnetic stirring in an oil bath at 40 °C for 3 days. After that, it was precipitated twice in glacial ether, filtered with suction, and dried under vacuum at room temperature to obtain the product. The yield is about 90%. 1 H NMR (400 MHz, CDCl 3 ): PEG: d 3.38, 3.65; TMC: d 4.24, 2.05; DTC: d 4.32, 3.02; Mal: ​​d 6.8. The NMR spectrum of Mal-PEG7.5k-P (TMC15.2k-DTC2.0k) is attached figure 2 , it can be known by integration that the molecular weight of the polymer finally obtained ...

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Abstract

The invention discloses an anti-tumor nano-adjuvant based on cross-linked biodegradable polymer vesicles and a preparation method and application thereof. The nano-adjuvant is obtained by loading drugs with reversibly cross-linked biodegradable polymer vesicles with asymmetric membrane structure. The drug is an oligonucleotide capable of activating the immune response. Degradable polymer vesiclesare obtained by cross-linking after self-assembly of polymers. The molecular chain of the polymer includes successively connected hydrophilic segments, hydrophobic segments and positively charged molecules. The hydrophobic segments are polycarbonate segments and / or polyester segments that are compounded and loaded with drugs through electrostatic interaction. The film is a polycarbonate and / or polyester segment that is reversibly cross-linked, biodegradable and biocompatible. The side chain of dithiolane is similar to natural antioxidant lipoic acid of the human body. The outer shell is basedon PEG, and can target cancer cells. The adjuvant is expected to become a nano-vaccine or nano-immune adjuvant that integrates the advantages of simplicity, stability, and multi-function, and can be used for efficient tumor immunotherapy.

Description

technical field [0001] The invention belongs to drug carrier technology, in particular to a preparation method and application of anti-tumor nano-medicine based on cross-linked biodegradable polymer vesicles. Background technique [0002] Glioblastoma (GBM) is a malignant brain cancer with high recurrence, high metastasis rate and poor prognosis. Currently, the standard clinical treatment usually includes surgical resection combined with chemotherapy and / or radiotherapy, but the treatment effect is not always satisfactory. In recent years, tumor immunotherapy has attracted widespread attention; however, due to the existence of the blood-brain barrier (BBB), the immune adjuvant CpG cannot directly enter GBM. At the same time, the rapid degradation of CpG in the body and the immunotoxicity caused by high doses also limit its immunotherapy mainly through intratumoral / intracranial administration. However, intracranial administration is often accompanied by cerebral edema, infl...

Claims

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Application Information

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IPC IPC(8): A61K9/127A61K47/34A61K47/42A61K39/39A61P35/00A61P37/04C08G64/30C08G64/18C08G63/688C08G63/64C08G63/78
CPCA61K9/1273A61K47/34A61K47/42A61K39/39A61P35/00A61P37/04C08G64/305C08G64/183C08G63/6882C08G63/64C08G63/78A61K2039/55561C08G2230/00C08G64/025C08G65/3344A61K2039/80A61K2039/55555C07K16/2818A61K2039/6093
Inventor 孟凤华魏晶晶钟志远
Owner SUZHOU UNIV
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