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Brain targeting gene delivery system based on polymethacrylate

A polymethacrylate, brain-targeted technology, applied in the biological field, can solve problems affecting the application potential of gene delivery, achieve the effects of increasing transfection efficiency and expression level, good application feasibility, and prolonging blood circulation time

Active Publication Date: 2014-03-12
FUDAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, it still has a certain hemolytic defect when PDMAEMA is used alone, thus affecting the potential of gene delivery applications

Method used

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  • Brain targeting gene delivery system based on polymethacrylate
  • Brain targeting gene delivery system based on polymethacrylate
  • Brain targeting gene delivery system based on polymethacrylate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0073] Add 2mmol of methoxy-polyethylene glycol (Me-PEG), 20ml of CH 2 Cl 2 , 1ml TEA, cooled in an ice-water bath, mixed 8.37mol of 2-bromoacetobutyryl bromide with 20ml CH 2 Cl 2 After mixing, it was slowly added dropwise into a four-neck flask, and the addition was completed in 30 minutes, and reacted at room temperature for 48 hours to generate MPEG-Br.

[0074] In the vacuum reactor A, add the complexing agent bipyridine, vacuumize, under N 2 Add catalyst copper bromide (CuBr) and DMAEMA under protection, magnetically stir, cool with liquid nitrogen, vacuumize - pass N 2 , repeated three times. Initiator (MPEG-Br), solvent isopropanol and water are added to vacuum reactor B, cooled by liquid nitrogen, vacuumed - N 2 , repeated three times. Then melt the contents of the two reactors A and B at room temperature, transfer the initiator solution in B to A with a sampler, cool with liquid nitrogen, evacuate - pass N 2 , repeated three times. Complete the deaeration sea...

Embodiment 2

[0079] Dissolve 2.0 mg of the prepared MePEG-PDMAEMA and Maleimide-PEG-PDMAEMA in 0.5 ml of deuterated chloroform, identify the structure of the carrier material with a 400 MHz superconducting nuclear magnetic resonance spectrometer, and obtain a nuclear magnetic resonance spectrum. The results are shown in the attached figure 1 . After the reaction of PDMAEMA and Me-PEG, the characteristic absorption peak of methoxy group appeared at 3.4ppm, and the characteristic absorption peak of polyethylene glycol appeared at 3.6ppm, indicating that Me-PEG was successfully modified on PDMAEMA (ie MePEG-PDMAEMA) Simultaneously, after PDMAEMA reacted with Maleimide-PEG, in addition to the characteristic absorption peak of polyethylene glycol appeared at 3.6ppm, the characteristic absorption peak of maleimide group also appeared at 6.7ppm, indicating that Maleimide-PEG was successfully connected onto PDMAEMA (ie Maleimide-PEG-PDMAEMA).

Embodiment 3

[0081] Precisely weigh an appropriate amount of lyophilized Maleimide-PEG-PDMAEMA, dissolve it in PBS (pH 7.0), and prepare a stock solution with a nitrogen atom concentration of 100nmol / μL; at the same time, prepare a pH 7.0 PBS stock solution of the brain-targeting functional group TGN, The concentration is 100nmol / μL containing cysteine. Measure equal volumes of the two stock solutions into vials and stir at room temperature for 4 h. The maleimide group specifically binds to the sulfhydryl group on cysteine ​​to form TGN-PEG-PDMAEMA. Dissolve 2.0mg of the prepared TGN-PEG-PDMAEMA gene delivery carrier in 0.5ml of deuterated chloroform, and identify its structure with a 400MHz superconducting nuclear magnetic resonance spectrometer. The results are shown in the attached figure 1 . After the reaction of Maleimide-PEG-PDMAEMA with brain-targeting functional group TGN, the characteristic absorption peak of maleimide group at 6.7ppm disappeared, indicating that TGN was success...

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Abstract

Belonging to the field of biological technology, the invention and relates to a brain targeting gene delivery system based on polymethacrylate and a preparation method thereof. A vector of the gene delivery system comprises a cationic chain segment polymethacrylate, an electrically neutral segment and a brain targeting functional base TGN in covalent connection, and the vector further conducts self-assembling with an anionic plasmid DNA into nano-micelles through electrostatic interaction. The system provided by the invention can transfer gene drugs across the blood-brain barrier into the brain to play a role. Through noninvasive intravenous injection administration test, the system significantly improves the brain targeting performance of the gene delivery system and expression of the gene in the brain; the particle size, surface charge and modification degree of targeting functional groups are controllable, so as to facilitate optimization of the gene delivery system. The gene delivery system constructed by the invention has the advantages of low cytotoxicity and high brain targeting efficiency.

Description

technical field [0001] The invention belongs to the field of biological technology and relates to a drug delivery system, in particular to a polymethacrylate-based brain-targeted gene delivery system and a preparation method thereof. technical background [0002] With the intensification of population aging process, many brain diseases such as Parkinson's disease and Alzheimer's disease are more and more plagued by human beings, seriously affecting people's health and quality of life. Gene therapy has gradually become a very potential treatment for the above diseases, but due to the existence of the blood-brain barrier (BBB), therapeutic genes cannot autonomously enter the brain lesions and play a therapeutic role. In some studies, hyperosmotic shock, carotid artery injection and direct intracerebroventricular injection were used as invasive routes of administration. Although the effect is good, it is easy to cause brain infection and BBB damage. Therefore, how to increase ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K48/00A61K47/32A61P25/00
Inventor 张奇志钱勇蒋新国
Owner FUDAN UNIV
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