Fully-degradable and anti-tumor macromolecular drug with multi-drug synergistic effect and preparation method of fully-degradable and anti-tumor macromolecular drug

Abstract

The invention discloses a fully-degradable and anti-tumor macromolecular drug with a multi-drug synergistic effect and a preparation method of the fully-degradable and anti-tumor macromolecular drug.The anti-tumor macromolecular bonded drug takes polylactide as a main chain, a hydrophilic branch chain of polyethylene glycol is introduced, and various anti-tumor drugs are grafted. The preparationmethod of the anti-tumor drug comprises the steps as follows: firstly, polylactide containing norbornene side groups is prepared, methoxypolyethylene glycol branch chains are introduced through an azide-ene click reaction sequentially, azide side groups are modified by a photo-click reaction and an esterification reaction of thio-ene, and finally, anti-tumor drug molecules are introduced by a force actuated azide-alkyne cycloaddition reaction. According to the method, the anti-tumor macromolecule bonded drug is synthesized with various click reactions, and the method has the characteristics ofsimplicity, high efficiency, mild reaction conditions, large drug loading amount, high purity and the like; the anti-tumor macromolecular bonded drug has the advantages that the anti-cancer activityis improved through the synergistic action of multiple drugs, and the dosage of each drug can be reduced due to the combined action of the multiple drugs, and accordingly, toxic and side effects of chemotherapy are reduced.

Description

technical field [0001] The invention relates to an anti-tumor drug, in particular to a fully degradable anti-tumor polymer bonded drug with multi-drug synergy and a one-pot preparation method thereof; it belongs to the field of biomedical polymer materials. Background technique [0002] Malignant tumor has always been a global public health problem, which greatly endangers human health, and has become the leading cause of human death in the new century. Improving the cure rate of cancer and the survival time of cancer patients is the focus and difficulty of scientific research workers. Chemotherapy, as one of the five major treatment methods for tumors, is currently the most important method in cancer treatment. Although common chemotherapy has achieved certain results, there are still poor biocompatibility of anticancer drugs in practical applications, low cell absorption in patients, and long-term use will cause adverse effects of drug resistance, resulting in the actual ...

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Problems solved by technology

In the prior art, there are few reports of bonded polymer anti-tumor drugs with multi-drug synergy

[0004] At present, there are reports in the literature (International Journal of Pharmaceutics 2015 488 44-58) using chemical bonds to bond a drug through a polymer carrier, and then physically wrapping a drug to form a multi-drug polymer micelle. This method is simple and convenient And the drug loading is high, but because of the physical package, the release in the body is unstable, the release rate cannot be automatically controlled, and it is prone to early release, burst release, etc.

Another document (Biomaterials Science 2017 5 1889-1897) used a hydrophobic drug and a hydrophilic drug to synthesize an amphiphilic multi-drug molecule. The relevant protection of cancer drugs will cause them to be easily cleared by the immune system in the human body, reducing the utilization efficiency of drugs, and long-term exposure of drugs will easily cause drug denaturation and lose its curative effect

In this literature report (Colloids and Surfaces B:Biointerfaces2017 155 51-60), the hydrophilic and strong PEG was used to improve the hydrophilicity and stimuli responsiveness of small-molecule anticancer drugs, making the two modified drugs in aqueous environment It can self-assemble into micelles and achieve the effect of intelligent release, but the actual content ratio of the two drugs cannot be effectively controlled by the feeding ratio, so that the synergy between the drugs cannot achieve the best effect

In this literature study (Chemistry-A European Journal 2017 23 9397-9406), it uses a sensitive polymer as a carrier to encapsulate a variety of drugs to achieve a synergistic anti-tumor effect, but because the drug is not bonded, it has a burst release and the issue of early release

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