Study On Folate-targeted Pluronic/PLA Polymersomes Co-delivery Anti-tumor Drugs

Compared with traditional chemotherapy,targeted nanomedicines have the characteristics of high bioavailability,specific distribution in vivo,long circulating time and less systemic toxic and side effects.With the increasingly serious problem of multidrug resistance in cancer,the efficacy of many chemotherapy drugs is reduced or even ineffective,which puts forward higher requirements for targeted nanomedicines.The targeted nanomedicine co-delivery system embedded with two drugs at the same time is expected to delay the adaptation process and related mutation of cancer through the synergistic effect of drugs targeting multiple signal pathways and metabolic pathways,so as to further improve the therapeutic effect of cancer.In this thesis,the folate-targeted Pluronic/polylactic acid（FA-F127-PLA）polymersomes were used as drug carriers,and doxorubicin hydrochloride（DOX）and paclitaxel（PTX）were embedded to construct a polymersome co-delivery anti-tumor drug system.The structure,in vitro drug release,targeting behavior and the synergistic effect of the co-delivery system were studied in detail.Two polymer materials PLA-F127-PLA and FA-F127-PLA were synthesized by ring-opening polymerization.Polymersomes were prepared by the nano-precipitation method,and characterized by particle size analyzer and transmission electron microscope.The results showed that the size of blank polymersomes was 60-70 nm,and the size of double-embedded polymersomes（120-140 nm）was larger than that of single-embedded polymersomes（80-90 nm）.All polymersomes showed the core-shell structure with negative charge and good dispersion.In vitro release experiments showed that folate-targeted Pluronic/PLA polymersomes had the characteristics of slow release after sudden release in the initial stage,and the cumulative drug release rate improved in acidic environment.It was beneficial to prolonging the drug circulation time in vivo and drug accumulation in tumor sites.In this study,human ovarian cancer OVCAR-3 cells with excessive folate receptor expression were selected as the cell model.The MTT assay was used to explore the cytotoxicity and synergistic effects of PTX and DOX co-delivered by polymersomes on tumor cells.The experimental results showed that the cytotoxicity of double-embedded polymersomes was stronger than that of the corresponding free drug combination.Furthermore,the cytotoxicity effect of PTX₁/DOX₅ Ps with the mass ratio 1:5 of PTX to DOX was greater than that of PTX₁/DOX₁ Ps and PTX₅/DOX₁Ps in turn,showing the best synergistic effect.The results of quantitative cell experiments showed that the cellular uptake of double-embedded polymersomes was higher than that of single-embedded polymersomes and free drugs.The cellular uptake of PTX₁/DOX₅ Ps was the highest.This is consistent with the result of cytotoxicity.The cellular uptake and distribution of polymersomes were observed by fluorescence qualitative experiment.The results showed that C-6/DOX Ps were mainly distributed in cytoplasm.With the prolongation of incubation time,DOX loaded in C-6/DOX Ps was gradually released and transferred from cytoplasm to nucleus.In summary,the research shows that the folate-targeted Pluronic/PLA polymersome is a good co-delivery drug carrier.It has potential application prospects to encapsulate simultaneously hydrophilic drugs and hydrophobic drugs,so that the drug efficacy can achieve better synergistic effect.