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Acid sensitive polymer prodrug, nanoparticles of prodrug and application of nanoparticles

A technology of acid-sensitive polymers and nanoparticles, applied in the field of medical materials, can solve the problems of easy excretion of human body side effects, low cell endocytosis efficiency, low bioavailability, etc., to achieve strong killing of cancer cells and drug resistance Sexual cancer cells, improve the therapeutic effect, improve the effect of endocytic efficiency

Active Publication Date: 2013-09-11
SUZHOU UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, most of the current anticancer drugs are small molecules, which have the disadvantages of large toxic side effects and poor water solubility, which greatly limits the clinical application of anticancer drugs.
[0004] In order to solve the problems of small molecule anticancer drugs such as low water solubility (strong hydrophobicity), low bioavailability, easy excretion, and large toxic and side effects on the human body, various polymer prodrugs or drug carriers have been studied to change the anticancer drug. How drugs enter the body and how they are distributed in the body
[0005] Although polymer prodrugs can greatly improve the solubility of hydrophobic drugs, several water-soluble prodrugs that have entered the clinical trial stage still have problems such as low drug loading and low endocytosis efficiency. And the drug is released slowly only by the degradation of the polymer, which makes cancer cells prone to drug resistance; polymer nano drug carriers usually have a high drug content and are enriched in tumor cells through the EPR effect, but they are stable in vivo. Problems such as poor sex and easy early release of drugs

Method used

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  • Acid sensitive polymer prodrug, nanoparticles of prodrug and application of nanoparticles
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  • Acid sensitive polymer prodrug, nanoparticles of prodrug and application of nanoparticles

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0048] paclitaxel prodrug PEG 113 -P(AA 20 - g -PTX) preparation, attached figure 1 Synthesize a schematic diagram for it:

[0049] in N 2 Under protection, the initiator AIBN (3.12 mg, 0.019 mmol), macromolecular RAFT reagent PEG-DMP (0.48 g, 0.095 mmol), acrylic acid (163 μL, 2.375 mmol) and 6 mL of solvent 1,4-dioxane Rings were added to the 25mL sealed reactor, and continued to flow for 30 minutes under N 2 , and then the reactor was placed in an oil bath at 70°C and stirred for 48 hours. After the reaction, it was precipitated in glacial ether, and the sample was vacuum-dried for 24 hours to obtain the target diblock copolymer PEG 113 -PAA 20 , and the yield was 85%. 1 H NMR (400 MHz, D 2 O): PEG (-CH 2 -CH 2 -O-: δ 3.63; CH 3 -O-: δ 3.38), PAA (-CH 2 -CH-COO-): δ 2.37; -CH 2 -CH-COO-: δ 1.6-1.9). M n ( 1 H NMR) = 6.4 kg / mol.

[0050] Polymer PEG 113 -PAA 20 (0.3 g, 0.93 mmol COOH), dissolved in 10 mL of anhydrous 1,4-dioxane, added to a 50 ml two-nec...

Embodiment 2

[0053] paclitaxel prodrug PEG 113 -P(AA 20 - g -PTX) preparation

[0054] in N 2 environment, the PEG with a vinyl ether functionalization degree of 12 prepared in Example 1 113 -PAA 20 (100.0 mg, equv. 164.8 μmol EGVE unit) was dissolved in 10 mL of anhydrous DMF, and then sequentially added PTX (70.4 mg, 82.4 μmol), p -TSA (0.32 mg, 1.65 μmol), freshly dried over 4? molecular sieves. After reacting for 4 days, the reaction solution was filtered and then dialyzed with DMF (molecular weight cut-off 3500) to remove unreacted paclitaxel. After dialysis in DMF for 24 hours, it was transferred to water for dialysis for 48 hours. After dialysis, it was freeze-dried to obtain a white solid with a yield of about 73.5%. NMR and HPLC test results showed that the content of PTX in the prodrug was about 27.6 wt.%.

Embodiment 3

[0056] paclitaxel prodrug PEG 113 -P(AA 20 - g -PTX) preparation

[0057] in N 2 environment, the PEG with a vinyl ether functionalization degree of 12 prepared in Example 1 113 -PAA 20 (100.0 mg, equv. 164.8 μmol EGVE unit) was dissolved in 10 mL of anhydrous DMF, and then sequentially added PTX (140.8 mg, 164.8 μmol), p -TSA (0.32 mg, 1.65 μmol), freshly dried over 4? molecular sieves. After reacting for 4 days, the reaction solution was filtered and then dialyzed with DMF (molecular weight cut-off 3500) to remove unreacted paclitaxel. After dialysis in DMF for 24 hours, it was transferred to water for 48 hours for dialysis. After dialysis, it was freeze-dried to obtain a white solid with a yield of about 78.2%. NMR and HPLC test results showed that the content of PTX in the prodrug was about 42.8 wt.%.

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Abstract

The invention discloses an acid sensitive polymer prodrug, nanoparticles of the prodrug and application of the nanoparticles. In the acid sensitive polymer prodrug, a polymer precursor is a vinyl ether-functionalized water-soluble A-B type two-block polymer; drug molecules are linked with the A-B type two-block polymer through an acetal bond; the acid sensitive polymer prodrug is self-assembled in water solution to form predrug micellar nanoparticles in which a polyethylene glycol hydrophilic chain segment serves as an outer surface and an anti-cancer drug bound to a polymer main chain through the acetal bond serves as a hydrophobic core. The pH sensitive prodrug and the nanoparticles of he prodrug are simple in preparation method, and good in tumor inhibitory effect; the nanoparticles also can efficiently encapsulate another hydrophobic anticancer drug; the kill capability to the cancer cell is enhanced; and the efficiency of endocytosis of the cell to the nanoparticles can be enhanced by coupling specific target molecules onto the surfaces of the nanoparticles. Thus, the inhibitory effect on the tumor cell is enhanced.

Description

technical field [0001] The invention relates to an acid-sensitive polymer prodrug, a nanoparticle prepared therefrom and the application of the nanoparticle as a drug carrier, belonging to the field of medical materials. Background technique [0002] Globally, more than 7 million people die from cancer every year, and this number is increasing year by year. The treatment of cancer is the biggest test and problem facing mankind in the 21st century. [0003] With the continuous development and progress of science and technology, human beings continue to explore related sciences such as oncology, molecular biology, pharmacy and chemistry, which has made great progress in the research of anti-tumor drugs. Many effective anti-cancer drugs have been used Designed and developed. However, most of the current anticancer drugs are small molecules, which have the disadvantages of high toxicity and poor water solubility, which greatly limit the clinical application of anticancer drugs...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K47/34A61K47/32A61K47/22A61K9/14A61K31/337A61K31/136A61K31/12A61K31/704A61P35/00
Inventor 孟凤华顾裕丹钟志远
Owner SUZHOU UNIV
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