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Application of vesicle nano-drugs in the preparation of brain tumor therapeutic drugs

A nano-drug and therapeutic drug technology, applied in anti-tumor drugs, drug combinations, pharmaceutical formulations, etc., can solve problems such as limiting the therapeutic effect of brain tumors and limited penetration depth of brain tissue, so as to reduce protein adsorption, enrichment and Improved drug release rate, good effect on brain tumor cells and biosafety

Active Publication Date: 2020-07-21
SUZHOU UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In addition, the penetration of the blood-brain barrier can be achieved by modifying the targeting molecule on the surface of the drug carrier, but the actual amount of nano-drugs penetrating the blood-brain barrier and the penetration depth in brain tissue are limited, which still limits the therapeutic effect of brain tumors.

Method used

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  • Application of vesicle nano-drugs in the preparation of brain tumor therapeutic drugs
  • Application of vesicle nano-drugs in the preparation of brain tumor therapeutic drugs
  • Application of vesicle nano-drugs in the preparation of brain tumor therapeutic drugs

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0047] Embodiment 1 Synthetic block copolymer PEG5k-P (DTC2k-TMC15k) and PEG5k-P (DTC2k-TMC15k)-bPEI1.8k

[0048] In a nitrogen glove box, weigh MeO-PEG-OH ( M n = 5.0 kg / mol, 0.50 g, 100 μmol), TMC (1.52 g, 14.55 mmol) and DTC (0.23 g, 1.18 mmol) were dissolved in dichloromethane (DCM, 7.0 mL), and the catalyst diphenyl phosphate was added rapidly with stirring Ester (DPP, DPP / OH molar ratio is 10 / 1). The airtight reactor was sealed and placed in a 40°C oil bath for 2 days under magnetic stirring. Terminate with triethylamine, precipitate twice in glacial ether, filter with suction, and dry in vacuum to obtain PEG5k-P (DTC2k-TMC15k).

[0049] PEG5k-P (DTC2k-TMC15k) is prepared by NPC activation of the terminal hydroxyl chloroformate p-nitrophenyl, and then reacting with the primary amine of branched PEI (bPEI). Specifically, PEG5k-P(DTC2k-TMC15k) (0.4 g, hydroxyl 0.017 mmol) and NPC (50 mg, 0.09 mmol) were dissolved in dry DCM and reacted at 0°C for 24 hours, then precip...

Embodiment 2

[0051] Example 2 Synthesis of targeting polymer

[0052] Targeting polymers can be synthesized in various ways, depending on the terminal functionalization groups of PEG. The synthesis of targeted diblock polymer ApoE-PEG7.5k-P (DTC4.4k-LA19.8k) is divided into two steps, the first step is similar to the synthesis of PEG5k-P (DTC4.4k-LA19.8k), first Replace MeO-PEG-OH with Mal-PEG-OH (Mn = 7.5 kg / mol) ( M n = 5.0 kg / mol) initiated the ring-opening polymerization of DTC and LA to obtain Mal-PEG7.5k-P (DTC4.4k-LA19.8k). In the second step, the ratio of peptide ApoE (sequence Leu Arg Lys Leu Arg Lys Arg Leu Leu Arg Lys Leu Arg Lys Arg Leu Leu Cys) to Mal-PEG7.5k-P (DTC2k-LA15k) is 1.2:1 , ApoE dissolved in DMSO was added dropwise to Mal-PEG7.5k-P (DTC2k-LA15k) dissolved in DMSO under nitrogen, and stirred at 37 degrees for 8 hours. After dialysis with DMSO for 24 hours and then with secondary water for 12 hours, ApoE-PEG7.5k-P (DTC4.4k-LA19.8k) was obtained by freeze-drying....

Embodiment 3

[0057] Example 3 Synthesis of Block Polymer PEG5k-P(TMC15k-DTC2k)-Sp

[0058] PEG5k-P(DTC2k-TMC15k)-NPC synthesized by the same method as in Example 1 was dissolved in 3 mL of DCM, then added dropwise to 3 mL of DCM with spermine (26 mg, 0.13 mmol), and reacted at 30°C for 48 hours Afterwards, dialyze (MWCO 7000) in DCM and methanol (volume ratio 1:1) for 48 hours, precipitate with glacial ether twice, filter with suction, and dry in vacuo to obtain PEG5k-P(DTC2k-TMC15k)-Sp. Yield: 94.7%. NMR and TNBSA showed that the grafting rate of Sp was 97%. Table 1 lists the preparation conditions of each polymer and the NMR characterization results of the product, and the targeting molecule can be connected through the linking group.

[0059] Table 1 The preparation conditions of each polymer and the NMR characterization results of the products

[0060]

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Abstract

The invention discloses application of a reduction response polymersome nano-drug in preparation of brain tumor treatment drugs. Block copolymers PEG-P(TMC-DTC), PEG-P(LA-DTC), PEG-P(TMC-DTC)-PEI, PEG-P(LA-DTC)-PEI, PEG-P(TMC-DTC)-Sp, PEG-P(LA-DTC)-Sp and targeted polymers thereof are combined in different ratios, and dual-targeted reduction-sensitive reversible crosslinked vesicles of different targeted molecular proportions can be prepared. Through the hydrogen-bond interaction or other electrostatic interaction between great hydrophilic inner cavities of the crosslinked vesicles and / or PEI-spermine and protein drugs or gene drugs, efficient encapsulation of micromolecular chemotherapeutic drugs, the protein drugs and the gene drugs can be achieved. By means of the in-vivo dual-targeteddrug-carrying crosslinked vesicles, more efficient blood brain barrier crossing, higher tissue penetration depth and endocytosis of more glioma cells can be achieved, and the reduction response polymersome nano-drug is very potential in treating brain gliomas and efficient.

Description

technical field [0001] The invention belongs to the technical field of polymer nano-medicines, and specifically relates to the application of a dual-targeted reduction-responsive polymer vesicle drug-carrying system that can penetrate the blood-brain barrier, penetrate deep into tumor tissue, and target brain tumor cells. Background technique [0002] Worldwide, cancer is the leading cause of human death. Although the incidence rate of brain tumor is low, it has extremely high mortality rate and poor prognosis. Despite the continuous development of medical technology, there has not been a major breakthrough in the treatment of brain tumors. This is mainly due to the following reasons: 1. The unique physiological and pathological characteristics of brain tumors. Brain tumors infiltrate and grow, and are often in the restricted area of ​​surgery. Surgical resection Very difficult. The existence of the blood-brain barrier makes the accumulation of chemotherapy drugs in the br...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): A61K9/127A61K47/34A61K47/42A61K31/704A61P35/00
CPCA61K9/1273A61K31/704A61K47/34A61K47/42
Inventor 钟志远张建姜宇孟凤华
Owner SUZHOU UNIV