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Ph-sensitive brain tumor two-stage targeting NANO drug delivery system, and preparation method and application thereof

A nano-drug delivery system and brain tumor technology, which is applied in anti-tumor drugs, pharmaceutical formulations, medical preparations of non-active ingredients, etc., can solve the problem of the preparation method and Application and other issues, to achieve the effect of facilitating subsequent development and industrialization, broad application prospects, and improving the degree of targeted concentration

Inactive Publication Date: 2014-03-26
FUDAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] So far, there is no relevant literature report on the preparation method and application of pH-sensitive brain tumor dual-stage targeting nano drug delivery system

Method used

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  • Ph-sensitive brain tumor two-stage targeting NANO drug delivery system, and preparation method and application thereof
  • Ph-sensitive brain tumor two-stage targeting NANO drug delivery system, and preparation method and application thereof
  • Ph-sensitive brain tumor two-stage targeting NANO drug delivery system, and preparation method and application thereof

Examples

Experimental program
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Effect test

Embodiment 1

[0055] Preparation of pH-sensitive tumor cell-targeting functional materials (II)

[0056] Using the solid-phase peptide synthesis method, the Rink amino resin was deprotected with trifluoroacetic acid (TFA) for 1 min, and the amino acids were protected with Fmoc to respond sequentially to the RGD peptide of the sequence CRGDKGPDC, and the cysteines at both ends were cyclized to form RDG cyclic peptide c (CRGDKGPDC), further using Fmoc to protect amino acids in the -NH of c(CRGDKGPDC) 2 The end group introduces 10 histidines (poly(histidine) 10 ) and a cysteine; after removing the protective group of the above-mentioned thiolated pH-sensitive polypeptide with piperidine DMF solution, the polypeptide was cleaved from the resin with hydrofluoric acid, and separated and purified with acetonitrile / water (containing 0.1% TFA) ; HPLC and ESI-MS were used to characterize the purity and molecular weight of the pH-sensitive tumor cell targeting polypeptide CC20 (CHHHHHHHHHH-c(CRGDKGPD...

Embodiment 2

[0060] Preparation of pH-sensitive dual-stage targeting polymeric micelles for brain tumors and evaluation of their pH sensitivity

[0061] Brain targeting molecule R1-angiopep (TFFYGGSRGKRNNFKTEEY) was synthesized by solid-phase peptide synthesis method, and its -NH 2 The end group is connected with cysteine ​​to obtain the sulfhydrylated brain-targeting molecule R1. React it with maleimide-polyethylene glycol-polylactic acid (maleimide-PEG-PLA) in PBS at pH 7.4 overnight, dialyze to remove unreacted small molecules, and freeze-dry to obtain the brain target To the functional material angiopep-PEG-PLA;

[0062] The brain-targeting functional material angiopep-PEG-PLA (1.4 mg), the pH-sensitive tumor cell-targeting functional material CC20-PEG-PLA (1.4 mg) and the amphiphilic polymer material mPEG-PLA (17.2 mg) were dissolved in In 3 mL of acetonitrile, hydrate under reduced pressure to form a film for 2 hours, then use 3 mL of hydration medium for hydration, and filter the ...

Embodiment 3

[0064] Example 3 In vivo targeting evaluation of pH-sensitive brain tumor dual-stage targeting polymer micelles

[0065] Referring to the method described in Example 1, a pH-sensitive tumor cell targeting functional material CC30-PEG-PLA was synthesized, wherein the pH-sensitive molecule poly(histidine) 20 Contains 20 histidines.

[0066] The brain-targeting functional material angiopep-PEG-PLA (1.4mg), the pH-sensitive tumor cell-targeting functional material CC30-PEG-PLA (1.4mg) and the amphiphilic polymer material mPEG-PLA (17.2mg) were dissolved in Add 15 μg of near-infrared probe DiR to 3 mL of acetonitrile, hydrate under reduced pressure to form a film for 2 hours, use 3 mL of hydration medium for hydration, and filter the obtained polymer micelles with a 0.45 μm microporous membrane to obtain pH-sensitive brain tumors Two-stage targeting polymer micelles angio-PEG-PLA / CC30-PEG-PLA; ordinary mPEG-PLA micelles without targeting functional materials and brain targeting an...

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Abstract

The invention belongs to the technical fields of high molecular materials and pharmaceutic preparations, and relates to a pH-sensitive brain tumor two-stage targeting nano drug delivery system, and a preparation method and an application thereof. The nano drug delivery system is composed of a brain targeting functional material, a pH-sensitive tumor cell targeting functional material, an amphiphilic polymer material and an anti-tumor drug; after the nano drug delivery system crosses the blood-brain barrier and enters the brain, the nano drug delivery system is capable of responding to the slightly acidic environment of brain tumor so that the tumor cell targeting functional material molecules extends outwards to further target to the brain tumor cells. In vitro and vivo activity evaluation results indicate that the system is capable of specifically delivering the anti-tumor drug to the brain tumor part and also capable of obviously improving the accumulation of the drug in the brain tumor tissue, and has an obvious anti-brain tumor effect; and the system also has the characteristic of intelligently responding to the pathological environment to realize specifically targeted drug delivery, and thus is wide in application prospect.

Description

technical field [0001] The invention belongs to the technical field of polymer materials and pharmaceutical preparations, and relates to a pH-sensitive dual-stage targeting nano-drug delivery system for brain tumors and its preparation method and application, in particular to a novel brain-targeted and pH-sensitive tumor A brain tumor dual-stage targeted nano drug delivery system with cell targeting integrated, its preparation method and application. Background technique [0002] Brain tumors include primary brain tumors and brain metastases, and are common malignant diseases of the central nervous system. Because the tumor is located close to the central nervous system of the patient, it is difficult to completely remove it by general surgery and it is easy to cause tumor recurrence. Surgical resection of brain tumors combined with chemotherapy is used to prevent and treat tumor recurrence. [0003] So far, targeted drug delivery systems for the treatment of brain tumors m...

Claims

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Application Information

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IPC IPC(8): A61K47/30A61K47/42A61K47/34A61K47/32A61K48/00A61P35/00
Inventor 陆伟跃沈洁谢操魏晓丽占昌友李翀
Owner FUDAN UNIV
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