Design,Synthesis And Application Of Lipid Molecular Anticancer Conjugates Responsive To Tumor Microenvironment

Cancer,also known as malignant tumor,is one of the life-threatening diseases in the world.Chemotherapy is one of the most effective approach for the treatment of cancer.Platinum-based drugs and doxorubicin,as the most widely used chemotherapeutic drugs,have achieved good anticancer effects,but also accompanied with serious toxic and side effects.In recent years,studies have found that natural plant-based artesunate has been found to shown potent anticancer activity with minimal side effects in vivo.However,its low aqueous solubility,poor bioavailability,instability with a short half-life and drug resistance greatly limit its application in the cancer treatment.One efficient approach to address these challenges is to encapsulate drugs in a nanoparticle-based carrier.Nanoparticles accumulate at tumor cells through EPR effect and selectively release anticancer drugs in response to stimulation in tumor microenvironment,and finally achieve cancer treatment.In this paper,three different anticancer prodrug nano-drug delivery systems were designed based on cisplatin,doxorubicin and artesunate respectively,and were constructed and evaluated in vitro and in vivo.The experimental results showed that the three nano-drug delivery systems constructed could effectively improve the efficacy of anticancer drugs,and effectively reverse the drug resistance of tumor cells,providing a promising anticancer therapy.The research of this paper includes the following three aspects:?1?A new type of negatively charged tetravalent platinum prodrug?C12-Pt-DFO?was synthesized,and nanoparticles with small particle size,high drug loading and excellent stability were prepared through assembly with negatively charged hydropHilic polymer mPEG-b-PGA.Through ATP-dependent and clathrin-mediated endocytosis pathways,this nano-drug delivery system can effectively entered cells,rapidly released and reduced divalent platinum under reduction conditions.Cell cycle is mainly arrested in S pHase and DNA replication is destroyed to cause apoptosis,which overcomes the resistance of A549/DDP and7404/DDP cells to cisplatin.?2?A doxorubicin-N,N??bis?dodecyl??L?glutamic diamide?DOX-LGC12?prodrug with double-long lipid chains was synthesized,and pH-responsive doxorubicin prodrug nanoparticles were prepared by mPEG-DSPE.The nano-drug delivery system can effectively enter the cell,rapidly released the original drug under the acidic conditions in the intracellular lysosome,interacted with the DNA in the nucleus,arrested the cell in the G2/M phase,inhibited cell proliferation,exerted cytotoxicity,and effectively reversed the drug resistance of MCF7 cells.?3?An artesunate-N,N??bis?dodecyl??L?glutamic diamide?ART-LGC12?prodrug with double-long lipid chains was synthesized,and mitochondrial targeted nanoparticles were prepared by mPEG-DSPE.They entered cells efficiently and the endoperoxide bridge of ART was broken by intracellular Fe²⁺ions to generate highly toxic ROS for killing cancer cells,which could eventually effectively promote anticancer efficiency of ART.Cells with the treatment of NPs-TPP exhibited the MMP loss,induce cell cycle arrest and leading to apoptosis.