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Preparation method of crosslinked nanomedicine based on active reaction one-step method

A nano-drug, reactive technology, applied in the direction of drug combination, pharmaceutical formula, non-active ingredient medical preparations, etc., can solve the problems of complex multi-step preparation of chemically bonded nano-drugs, non-crosslinking of chemically-bonded nano-drugs, etc. Achieve the effect of avoiding non-crosslinking, increasing maximum tolerance, and reducing drug leakage

Active Publication Date: 2021-06-18
SUZHOU UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] The purpose of the present invention is to provide a preparation method of cross-linked nano-medicine based on the active reaction type one-step method (referred to as the reaction-loading method), and the nano-medicine with stable drug bonding and circulation stability can be obtained through simple preparation, which solves the problem of In the prior art, the preparation of chemically bonded nano-medicines is complex, requiring catalysts and multi-step preparation; and the product prepared by the present invention has a stable cross-linked structure, which avoids the problem of non-cross-linking of existing chemically-bonded nano-medicines

Method used

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  • Preparation method of crosslinked nanomedicine based on active reaction one-step method
  • Preparation method of crosslinked nanomedicine based on active reaction one-step method
  • Preparation method of crosslinked nanomedicine based on active reaction one-step method

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0042] cRGD-PS-DM1 cross-linked nanomedicine was directly formed by co-polymer PEG-P(TMC-DTC) and cRGD-PEG-P(TMC-DTC) (w / w 80 / 20) encapsulating DM1 while self-assembling, The invention creatively realizes sulfur-sulfur-sulfhydryl exchange reaction and sulfur-sulfur cross-linking simultaneously.

[0043] The overall reaction idea of ​​this embodiment is:

[0044]

[0045] Under nitrogen protection, NHS-PEG-OH ( M n = 7.5 kg / mol, 75 mg, 10 μmol), TMC (200 mg, 1.6 mmol) and DTC (50 mg, 0.26 mmol) were dissolved in 1.1 mL of anhydrous dichloromethane, followed by adding diphenyl phosphate (DPP, 25 mg, 100 μmol) in a closed reactor at 30°C for 72 h, terminated, precipitated twice in glacial ether, filtered with suction and dried in vacuo overnight to obtain NHS-PEG-P(TMC-DTC). Yield: 84.6%. 1 H NMR (600 MHz, CDCl 3 ): PEG: δ 3.64; TMC: δ 2.06, 4.24; DTC: δ 3.02, 4.19; NHS: δ 2.52. M n ( 1 HNMR) =31.8 kg / mol. M n (GPC) = 34.8 kg / mol, M w / M n = 1.14; then the o...

Embodiment 2

[0065] According to Example 1, the polymers PEG-P (TMC-DTC) and MAL-PEG-P (TMC-DTC) were prepared, and the targeting molecule Anti-CD19-PEG of the anti-CD19 antibody was prepared from the latter -P(TMC-DTC), the chemical structure is as follows:

[0066]

[0067] Further preparation of cross-linked nano-drugs and targeted cross-linked nano-drugs, which are vesicle structures with a particle size of about 90-100 nm; loaded with maytansine DM1, the drug loading DLC ​​can reach 10-15wt.%; MTD research results show The MTD values ​​of cross-linked vesicle nanomedicine and targeted cross-linked vesicle nanomedicine are nearly 4 times higher than that of free DM1; the tumor inhibition rate (TIR ) respectively exceeded 60% and 90%; the median survival of mice exceeded 35 days and 60 days (PBS was 25 days), and the toxic and side effects on the main organs of mice were very small.

Embodiment 3

[0069] According to Example 1, TMC was replaced with LA to prepare polymers PEG-P (LA-DTC) and NHS-PEG-P (LA-DTC), and the targeting molecule was prepared from the latter to target polymerization of EGFR targeting polypeptide GE11 Material GE11-PEG-P (LA-DTC), the chemical structure is as follows:

[0070]

[0071] Further preparation of cross-linked nano-drugs and targeted cross-linked nano-drugs, which are vesicle structures with a particle size of about 50-70 nm; loaded with the drug 6-mercaptopurine (6MP) with its own mercapto group, and the drug loading DLC ​​is 5- 10 wt.%; MTD results showed that the MTD value of cross-linked vesicle nano-drugs and targeted cross-linked vesicle nano-drugs was 6 times that of free 6MP; The tumor inhibition rate (TIR) ​​of triple-negative breast cancer MDA-MB-231 subcutaneous tumors exceeded 60% and 85% respectively; the median survival of mice exceeded 47 days and 58 days (PBS was 30 days), and the main effect on mice Visceral almost ...

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Abstract

The invention discloses a method for preparing a cross-linked nano-medicine based on an active-response one-step method, which specifically includes the following steps: after adding a polymer and a drug with a sulfhydryl group into a solution and mixing them, dialyzing to obtain a cross-linked nano-medicine; the polymer The side chain contains a dithiolane structure. The present invention can obtain nano-medicines with stable circulation through simple preparation, which solves the defects of complex preparation of chemically bonded nano-medicines and the need for catalysts in the prior art; moreover, the products prepared by the present invention have a stable cross-linked structure, avoiding the existing chemical bond The problem of non-crosslinking of composite nanodrugs; on the B16F10 melanoma-bearing model, it showed good therapeutic effect, and the tumor inhibition rate exceeded 90%, indicating that the active targeting crosslinking nanodrug has great potential application in cancer chemotherapy .

Description

technical field [0001] The invention belongs to the technical field of polymer nano-medicines, and in particular relates to a preparation method of a cross-linked stable nano-medicine based on an active-response one-step method, and the circulation-stable nano-medicine can be obtained through simple preparation. Background technique [0002] Chemotherapy is the most common means of treating malignant tumors. In the past few decades, in order to improve the selectivity of chemotherapy drugs and reduce the side effects, researchers have explored various polymer nanocarriers. Generally speaking, there are two ways to encapsulate drugs in polymer nanocarriers, one is physical embedding, and the other is to form polymer-drug conjugates through chemical bonds. For example, NK105 and Genexol-PM are two typical examples of using micelles to encapsulate paclitaxel (PTX), while NK911 is a model of chemically bonded nano-drugs. Physically embedded nanomedicines are more prone to prob...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): A61K47/69A61K47/68A61K47/64A61K47/54A61K47/61A61K31/537A61P35/00
CPCA61K31/537
Inventor 钟志远孟凤华孟浩张玥
Owner SUZHOU UNIV
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