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Application of reduction response polymersome nano-drug in preparation of brain tumor treatment drugs

A technology of nano-drugs and therapeutic drugs, which is applied in the direction of anti-tumor drugs, drug combinations, and non-active ingredients of polymer compounds, which can solve the problems of limiting the therapeutic effect of brain tumors and the limited penetration depth of brain tissue, so as to reduce the adsorption of proteins , enrichment and drug release rate increase, the effect of improving efficiency

Active Publication Date: 2018-05-08
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 reduction response polymersome nano-drug in preparation of brain tumor treatment drugs
  • Application of reduction response polymersome nano-drug in preparation of brain tumor treatment drugs
  • Application of reduction response polymersome nano-drug in preparation of brain tumor treatment drugs

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0047] Example 1 Synthesis of block copolymers PEG5k-P (DTC2k-TMC15k) and PEG5k-P (DTC2k-TMC15k)-bPEI1.8k

[0048] In the nitrogen glove box, weigh out 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) and dissolved in dichloromethane (DCM, 7.0 mL), stir and quickly add the catalyst diphenyl phosphate Ester (DPP, DPP / OH molar ratio is 10 / 1). The airtight reactor was sealed and placed in a 40 degree oil bath under magnetic stirring to react for 2 days. After termination of triethylamine, precipitation in ice ether twice, suction filtration, and vacuum drying, PEG5k-P (DTC2k-TMC15k) was obtained.

[0049] PEG5k-P (DTC2k-TMC15k) terminal hydroxychloroformic acid p-nitrophenyl ester NPC activation, and then with branched PEI (bPEI) primary amine to prepare. Specifically, PEG5k-P (DTC2k-TMC15k) (0.4 g, hydroxy 0.017 mmol) and NPC (50 mg, 0.09 mmol) were dissolved in dry DCM and reacted at 0°C for 24 hours, then precipitated in ice e...

Embodiment 2

[0051] Example 2 Synthesis of Targeting Polymer

[0052] There are many ways to synthesize targeting polymers, depending on the functionalized end groups of PEG. The target diblock polymer ApoE-PEG7.5k-P (DTC4.4k-LA19.8k) is synthesized in two steps. The first step is similar to the synthesis of PEG5k-P (DTC4.4k-LA19.8k). First, Use Mal-PEG-OH (Mn = 7.5 kg / mol) instead of MeO-PEG-OH ( M n = 5.0 kg / mol) initiates the ring-opening polymerization of DTC and LA to obtain Mal-PEG7.5k-P (DTC4.4k-LA19.8k). The second step is to react according to the peptide ApoE (sequence LeuArg Lys Leu Arg Lys Arg Leu Leu Arg Lys Leu Arg Lys Arg Leu Leu Cys) and Mal-PEG7.5k-P (DTC2k-LA15k) at a ratio of 1.2:1, Under nitrogen, ApoE dissolved in DMSO was added dropwise to Mal-PEG7.5k-P (DTC2k-LA15k) dissolved in DMSO, and the reaction was stirred at 37°C for 8 hours. After dialysis with DMSO for 24 hours and then with 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 DCM, then added dropwise to 3 mL DCM with spermine (26 mg, 0.13 mmol), and reacted at 30°C for 48 hours After that, it was dialyzed (MWCO 7000) in DCM and methanol (volume ratio 1:1) for 48 hours, precipitated with ice ether twice, filtered with suction, and dried in vacuum to obtain PEG5k-P(DTC2k-TMC15k)-Sp. Yield: 94.7%. NMR and TNBSA methods characterize the Sp grafting rate of 97%. Table 1 lists the preparation conditions of each polymer and the NMR characterization results of the product, and the targeting molecule can be attached through the linking group.

[0059] Table 1 Preparation conditions and NMR characterization results of each polymer

[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 nanomedicine, and specifically relates to the application of a dual-target reduction-responsive polymer vesicle drug-carrying system that can penetrate the blood-brain barrier, penetrate into tumor tissue and target brain tumor cells. Background technique [0002] Worldwide, cancer is the leading cause of human death. Although brain tumors have a low incidence, they have extremely high mortality and a very poor prognosis. Despite the continuous development of medical technology, no major breakthroughs have been made 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, often in the restricted area of ​​surgery, and surgical resection The difficulty is great. The existence of the blood-brain barrier makes the concentration of chemotherapeutic drugs in the brain tumor...

Claims

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Application Information

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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
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