| Cancer is a disease threatening human life and health.The morbidity and mortality caused by cancer are increasing year by year.Among many cancer treatments,chemotherapy is an important means of cancer treatment,but its toxic and side effects on normal tissues are urgent problems to be solved.Although polymer micelles can effectively reduce drug toxicity during drug delivery,spontaneous dissociation occurs when their concentration is lower than their critical micellar concentration(CMC),which limits their further wide application.Polymer micelles with tunable stability can break through the limitations of CMC and demonstrate stability in physiological environments and degradability in tumor environments.Therefore,polymeric micelles with adjustable stability show potential application value in the field of anti-tumor drug delivery.In this paper,a multi-stimulus responsive polymer micelle drug delivery system(DDSs)with adjustable stability of nuclear crosslinking and shell crosslinking was prepared by introducing 0n2+ into imidazole block copolymer.The main research work of this paper is as follows:1、A two-block copolymer[PImPM10/Zn2+-b-P(P(EG)5MA)9]containing imidazole groups was synthesized.Due to the hydrophobicity of imidazole block and the hydrophilicity of polyethylene glycol block,it was able to self-assemble into polymer micelles in selective solvent water.pH-responsive polymer micelles with adjustable stability of nuclear cross-linked nuclear drug delivery were prepared by Zn2+coordination crosslinking.The CMC of this polymer micelle(0.00052 mg/mL)was significantly lower than that of non-cross-linked polymer micelles.It was placed in a weakly acidic system simulating the tumor microenvironment to remove Zn2+and disrupt the nuclear cross-linked structure,which caused the polymeric micelles to uncouple and thus release the drug they were loaded with.The polymer micelles showed a significant cumulative drug release in the simulated system at pH 5.0,which was about 12.6 times higher than that at pH 7.4.It has been confirmed by in vitro cell experiments that the IC50 value of drug-loaded nuclear crosslinked polymer micelles is low,showing obvious toxicity.Therefore,Zn complex-induced nuclear cross-linked polymer micelles with adjustable stability show certain potential applications in the field of cancer therapy.2、On the basis of the above work,synthesized the triblock copolymer[PNBMA5-b-PImPM10/Zn2+-b-P(P(EG)5MA)9],which can self-assemble into coreshell-crown polymer micelles in selective solvent water,with PNBMA5 as the core,PImPM10 as the shell and P(P(EG)5MA)9 as the crown.After the Zn2+ coordination cross-linked PImPM10 shell,tunable stable photostable/pH-responsive polymer micelles shell cross-linked nuclear drug delivery were obtained.It was found that the CMC of this shell cross-linked polymer micelles(0.00071 mg/mL)was significantly lower than that of the non-cross-linked polymer micelles.The polymeric micelles were delocalized by placing them in a weak acidic system simulating a tumor microenvironment to remove Zn2+and disrupt the shell cross-linked structure,and by irradiating them with UV light to exfoliate the o-nitrophenyl groups,thus releasing the loaded drug.The polymer micelles showed obvious cumulative drug release under the combined stimulation of pH 5.0 with UV lamp irradiation,which was about 7.5 times of that under the condition of pH 7.4.In vitro cell experiments have confirmed that the drug-loaded polymer micelles show significant toxicity.Therefore,based on the dual protection strategy of photoresponsive nuclear protection and pH-responsive shell protection,the polymer micelles can effectively deliver anti-tumor drugs,which has broad prospects in cancer treatment. |
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