| Traditional chemotherapy drugs in the treatment of various tumor have their advantages,but there are some significant problems,such as poor water solubility,multi-resistant.These limit their clinical application.Evolution of drug resistance in cancer cells has been attributed as a major factor in the failure of many forms of monotherapy.To prevent evolutionary development,it often requires a high drug dose to kill the whole cancer cell population,whereas it always induces severe side effects.The limitations of monotherapy can be circumvented by synergistic combination of multiple anticancer agents which allows for reduction of the drug dose and offers a potential benefit to simultaneously act on several anticancer targets,therefore preventing or delaying the emergence of drug resistance.However,the traditional combination strategy,namely the drug cocktail,shows limited success in clinics due to the non-coordinated distributions of drugs after administration.Pharmacokinetic interactions are also observed in these combination therapies,raising concern about the synergistic toxicity of these cocktails.Nanocarriers have been developed as an important strategy for drug delivery due to their capabilities of enhancing drug solubility,improving pharmacokinetics and preferentially accumulating in tumor by the enhanced permeability and retention(EPR)effect.Therefore,the nanocarrier-based combination therapy not only has the loading potency of the multiple agents,but also accommodates their biodistribution and plasma elimination,realizing an extremely simple dose optimization.Polymeric micelle is one of the most common nanoparticle systems for codelivery of multiple drugs due to their physicochemical stability and low toxicity.In this thesis,nanomedicine and nanodrug delivery system have been introduced,and the research process of its application in treatment of tumor is also summarized.According to the targeting modes,nanodrug delivery system is categorized into passive targeting,active targeting and stimuli responsive.In Chapter Ⅱ,there is the synthesis of mPEG-BC-PGluCPT.The formulation of mPEG-BC@PGluCPT micelles was confirmed based on critical micelle concentration(CMC),partical size,and morphology observations.The average hydrodynamic diameter of mPEG-BC@PGluCPT micelles was approximately 181 ± 3 nm with narrow size distribution.Transmission electron microscopy(TEM)image displays mPEG-BC@PGluCPT spherical micelles.The stability of micelles stored at 4 ℃ was determined.Self-assembled micelles mPEG-BC@PGluCPT,mPEG@PGluCPT and Dox-loaded micelles mPEG-BC@PGluCPT-Dox showed sustained drug release profiles over 48 h.Only approximately 14%of CPT was released from mPEG-BC@PGluCPT and mPEG@PGluCPT with or without boronate ester bonds at pH 7.4 during 48 h.However,when the pH was 5.5,44%of CPT was released from mPEG-BC@PGluCPT and only 9%of CPT was released from mPEG@PGluCPT.It implied that boronate ester bonds of mPEG-BC@PGluCPT could be disrupted in acid condition.Dox-loaded micelles mPEG-BC@PGluCPT·Dox released Dox more slowly with pH increasing from 4.5 to 7.4.This accelerated release under an acidic condition was attributed to the shedding of mPEG shells resulting from cleavage of boronate ester bonds and re-protonation of the amino group of Dox resulting in its higher aqueous solubility at a lower pH value.In Chapter Ⅲ,the cytotoxicity of mPEG-BC@PGluCPT and mPEG-BC@PGluCPT-Dox micelles against HepG2 cells and colo 205 cells was evaluated,and the cellular uptake of mPEG-BC@PGluCPT-Dox micelles into HepG2 cells and HL 7702 cells was evaluated by flow cytometry(FCM).Sialyl Lewis X is more abundant on the surface of HepG2 cells than HL 7702 cells.Intracellular fluorescence intensity of mPEG-BC@PGluCPT-Dox micelles was strong in HepG2 cells and increased as the pH decreased from 7.4 to 6.0.However,the fluorescence intensity of mPEG-BC@PGluCPT-Dox micelles in HL-7702 cells remained low and showed little change.These were attributed to the exposure of boronic acid segment resulting from the cleavage of boronate ester bonds under simulated tumor microenvironment.The exposed boronic acid could interact with Sialyl Lewis X,realizing the receptor-mediated endocytosis and resulting in enhanced cellular uptake.The cytotoxicity of mPEG-BC@PGluCPT micelles exhibited slightly weaker than that of mPEG-BC@PGluCPT-Dox micelles at different pH values.It implies as a co-delivery system,Dox-loaded micelles mPEG-BC@PGluCPT·Dox has enhanced proliferation inhibition of tumor cells.In summary,the dual-drug delivery micelles have the great potential for treatment tumor. |
