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Application of targeted reduction response vesicular nanometer medicines in preparation of brain tumor treatment medicines

A technology of nano-drugs and therapeutic drugs, applied in anti-tumor drugs, drug combinations, pharmaceutical formulations, etc., can solve the problems of limited and poor therapeutic effects of brain tumors, and achieve prolonging the circulation time in the body, good biological safety, and preventing drugs. leaked effect

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

However, the cRGD-modified drug-loading system cannot penetrate the blood-brain barrier and enter brain tumor cells, so it is very ineffective in the treatment of brain tumor diseases; Treatment is also limited

Method used

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  • Application of targeted reduction response vesicular nanometer medicines in preparation of brain tumor treatment medicines
  • Application of targeted reduction response vesicular nanometer medicines in preparation of brain tumor treatment medicines
  • Application of targeted reduction response vesicular nanometer medicines in preparation of brain tumor treatment medicines

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0055] Example 1 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 under magnetic stirring for 2 days; triethylamine was terminated, precipitated twice in glacial ether, filtered by suction, and dried 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 2

[0059] Example 2 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). Then, under nitrogen, the DMSO solution of ANG was added dropwise to the DMSO solution of Mal-PEG7.5k-P (DTC2k-TMC15k) according to the latter molar ratio of 1.2:1, stirred at 37 degrees for 8 hours, and then dialyzed in DMSO for 24 hours. Hours and then dialyzed with secondary water for 12 hours, freeze-dried to obtain ANG-PEG7.5k-P (DTC2k-TMC15k), with a yield of 92%. It can be known by NMR integration that the molecular weight of the polymer is 7.5-(2.0-14.7) kg / mol. The ...

Embodiment 3

[0062] Example 3 Synthesis of Block Polymer PEG5k-P(TMC15k-DTC2k)-Sp

[0063] 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 ANG can be connected through the linking group.

[0064] Table 1 The preparation conditions of each polymer and the NMR characterization results of the products

[0065]

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Abstract

The invention discloses application of targeted reduction response vesicular nanometer medicines in preparation of brain tumor treatment medicines. Reduction sensitive reversible crosslinking vesiclesbased on block polymers PEG-P(TMC-DTC), PEG-P(LA-DTC), PEG-P(TMC-DTC)-PEI, PEG-P(LA-DTC)-PEI, PEG-P(TMC-DTC)-Sp or PEG-P(LA-DTC)-Sp and targeting polymers with ANG as the targeting molecules can efficiently wrap small-molecular chemotherapy medicines, protein medicines and gene medicines sensitive to brain glioma cells. The medicine-carrying vesicles can efficiently permeate through a blood brainbarrier in vivo to enter tumor substances and can also rapidly release medicines after entering tumor cells to induce cell apoptosis. The system has the advantages that the process is simple, the carrier biocompatibility is good, the enrichment of medicines at brain tumor parts is remarkably improved, and the concentration of medicines in brain tumor cells is increased. By means of the system, medicines can be conveyed to brain glioma selectively and efficiently.

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 nano-medicine that can penetrate the blood-brain barrier and target brain tumor cells. Background technique [0002] Glioma is a serious disease of the central nervous system. Because the central nervous system plays an important role in human physiological activities, surgical resection of brain tumors is difficult, high-risk, impossible to completely remove, and prone to recurrence. Both radiotherapy and chemotherapy will bring obvious toxic and side effects, and even directly endanger life. Treatment is also poor. With the development of new nano-drug delivery systems, there are better options for the treatment of brain tumors. However, the existing nano drug-loading system has low drug loading efficiency, complex process, and damage to the activity of protein drugs and gene drugs in the pro...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K9/127A61K47/34A61K47/42A61K31/704A61P35/00
CPCA61K9/1273A61K31/704A61K47/34A61K47/42
Inventor 张建钟志远姜宇史亚南孟凤华
Owner SUZHOU UNIV
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