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Use of single targeted reduction-responsive vesicle nano-drug in preparation of drug for treating brain tumors

A technology of nano-drugs and therapeutic drugs, applied in anti-tumor drugs, drug combinations, pharmaceutical formulations, etc., can solve the problems of low efficacy of nano-drugs, blood-brain barrier hindering chemotherapeutic drugs, and reduced enzymatic degradation activity of drugs, etc. The effect of good tumor cell and biological safety, enrichment, and drug release rate improvement, high drug activity

Active Publication Date: 2018-06-08
SUZHOU UNIV
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  • Summary
  • Abstract
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AI Technical Summary

Problems solved by technology

If chemotherapy is given to patients with brain tumors, the existence of the blood-brain barrier seriously hinders the chemotherapy drugs from entering the brain and reaching the lesion site
In addition, the blood-brain barrier is disrupted before administration, and high-dose chemotherapy or radiotherapy for brain tumor patients will also bring huge toxic side effects
In the past few decades, the application of nano-drug delivery systems in the treatment of brain tumors has become a research focus. Low; at the same time, there are still problems such as unstable circulation in the body of the drug-loaded nanosystem, difficulty penetrating the blood-brain barrier, low uptake by brain tumor cells, and low intracellular drug concentration; the drug is degraded by enzymes during the circulation process. The inability to quickly escape from endosomes leads to low efficacy of nano-drugs, which greatly limits the application of nano-drug delivery systems in the treatment of brain tumors
In addition, even when using targeted drug delivery systems for brain tumor therapy, the results are often suboptimal
For example, transferrin (Tf) is a classic tumor-targeting target, and there are many brain-targeting drug delivery systems constructed using it. Partially inactivated, so the effect in the treatment of brain tumor disease models is not ideal; and the drug-loaded liposomes with dual targeting effects have limited brain tumor treatment effects

Method used

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  • Use of single targeted reduction-responsive vesicle nano-drug in preparation of drug for treating brain tumors
  • Use of single targeted reduction-responsive vesicle nano-drug in preparation of drug for treating brain tumors
  • Use of single targeted reduction-responsive vesicle nano-drug in preparation of drug for treating brain tumors

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0052] Example 1 Synthesis of PEG5k-P (DTC4.4k-LA19.8k) and ApoE-PEG7.5k-P (DTC 4.4k-LA19.8k) block copolymer

[0053] In a nitrogen glove box, weigh MeO-PEG-OH ( M n = 5.0 kg / mol, 0.50 g, 100 μmol), LA (2.0 g, 13.9 mmol) and DTC (0.50 g, 2.60 mmol) were dissolved in dichloromethane (DCM, 7.0 mL), and the catalyst diphenyl phosphate was added with stirring (DPP, DPP / OH molar ratio is 10 / 1). The airtight reactor was sealed and placed in an oil bath at 40° C. for 2 days under magnetic stirring. Triethylamine terminated the reaction, precipitated twice in glacial ether, filtered with suction, and dried under vacuum at room temperature to obtain PEG5k-P (DTC4.4k-LA19.8k).

[0054] The synthesis of 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), using Mal-PEG-OH (Mn =7.5 kg / mol) instead of MeO-PEG-OH ( M n = 5.0 kg / mol) initiated the ring-opening polymerization of DTC and LA to obtain Mal-P...

Embodiment 2

[0055] Example 2 Synthesis of block copolymers PEG5k-P (DTC2k-TMC15k) and PEG5k-P (DTC2k-TMC15k)-bPEI1.8k

[0056] 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 with stirring (DPP, DPP / OH molar ratio is 10 / 1). The airtight reactor was sealed and placed in an oil bath at 40° C. 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).

[0057] 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 precipitated ...

Embodiment 3

[0059] Example 3 Synthesis of Targeted Copolymer

[0060] Targeting polymers can be synthesized in various ways, depending on the terminal functionalization groups of PEG. ANG-PEG7.5k-P(DTC2k-TMC15k) was synthesized in two steps. The first step is similar to the synthesis of PEG5k-P (DTC2k-TMC15k) in Example 1, but with Mal-PEG-OH (Mn=7.5 kg / mol) instead of MeO-PEG-OH ( M n = 5.0 kg / mol) as the initiator to initiate the ring-opening polymerization of DTC and TMC to obtain Mal-PEG7.5k-P (DTC2k-TMC15k). In the second step, the Michael addition reaction occurs between the latter and the sulfhydryl group of the polypeptide ApoE in a molar ratio of 1:1.2. Add the DMSO solution of the targeting polypeptide ApoE dropwise to the DMSO solution of Mal-PEG7.5k-P (DTC2k-TMC15k) under nitrogen gas, stir and react at 37 degrees for 8 hours, then dialyze in DMSO for 24 hours and then dialyze with secondary water At 12 o'clock, the product ApoE-PEG7.5k-P (DTC2k-TMC15k) was obtained by ly...

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Abstract

The invention discloses a use of a single targeted reduction-responsive vesicle nano-drug in preparation of a drug for treating brain tumors. Through reduction-responsive reversibly crosslinked vesicles of block polymers such as PEG-P(TMC-DTC), PEG-P(LA-DTC), PEG-P(TMC-DTC)-PEI, PEG-P(LA-DTC)-PEI, PEG-P(TMC-DTC)-Sp and PEG-P(LA-DTC)-Sp and a targeting polymer using ApoE as a targeting molecule, small-molecule chemotherapeutic drugs, protein drugs and gene drugs sensitive to brain glioma cells are efficiently encapsulated. The drug-carrying targeting vesicles can efficiently target multiple receptors (including LRP-1, LRP-2 and LDLR) that are highly expressed on the surfaces of brain microvascular endothelial cells in tumor regions thereby efficiently penetrating the blood-brain barrier andbeing efficiently enriched in the brain tumor region. ApoE-targeting related receptors are also highly expressed on the surfaces of glioma cells so that the drug-carrying targeting vesicles can be efficiently endocytosed by glioma cells and fast release drugs to induce apoptosis.

Description

technical field [0001] The invention belongs to the technical field of polymer nano-medicines, and in particular relates to the application of a reduction-responsive polymer vesicle drug-carrying system capable of penetrating the blood-brain barrier and targeting brain tumor cells. Background technique [0002] Brain tumor is a major disease that threatens human health. Because of the special location of the lesion and the characteristic of infiltrative growth of the brain tumor, the operation is difficult and the recurrence will be rapid after the operation. If chemotherapy is given to patients with brain tumors, the existence of the blood-brain barrier seriously hinders the chemotherapy drugs from entering the brain and reaching the lesion. In addition, the blood-brain barrier is disrupted before administration, and high-dose chemotherapy or radiotherapy for brain tumor patients will also bring huge toxic and side effects. In the past few decades, the application of nano...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K47/64A61K47/60A61K47/59A61K47/69A61K45/00A61P35/00
CPCA61K45/00
Inventor 张建钟志远姜宇史亚南孟凤华
Owner SUZHOU UNIV
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