Application Of Nano-drugs Based On Amphiphlic Tetravalent Platinum Prodrugs In Cancer Therapy

Cancer is a great threat to human health.Chemotherapy,radiotherapy and surgery are commonly used to treat cancers.As a kind of chemotherapeutic drugs,platinum drugs are widely used in clinic because of their good therapeutic effect.However,the concomitant side effects and drug resistance are the main reasons for the failure of chemotherapy.In recent years,many nanodelivery systems have been developed to effectively improve the systemic toxicity and drug resistance of platinum drugs.Because of the octahedral structure,Pt(Ⅳ)has a certain chemical stability,it will not reduce until ingested by cells and decreases the probability of binding to human normal proteins,so that toxic and side effects of Pt(Ⅳ)will be reduced.Based on this,amphiphilic Pt(Ⅳ)prodrugs containing groups with different chemical structures and functions were designed and then assembled with polymer via electrostatic complexation or self-assembled into nano-delivery system to improve the therapeutic effect of platinum drugs and overcome drug resistance,.The research contents are as follows:(1)A negatively charged Pt(Ⅳ)prodrug with lipid tails can self-assemble into nanoparticles via electrostatic complexation with a positively charged hydrophilic polymer.Results showed that NPs had a small and uniform size,moreover,they could rapidly release platinum drugs in reductive conditions.In comparison to cisplatin,NPs exhibited significantly enhanced intracellular uptake as well as higher cytotoxic and could overcome cisplatin resistance.Further more,NPs could disturb cell cycle,result in cell apoptosis.In summary,the novel strategy for platinum drug delivery based on electrostatic complexation provided a potential method for cancer therapy;(2)An imidazole group and a long lipid tail were introduced into the axial positions of Pt(Ⅳ),which could assemble into nartoparticles via electrostatic complexation with a negatively charged hydrophilic polymer.The nano-delivery system was confirmed to be pH-responsive and mitochondrial targeting,which makes it possible to search for other targets than nuclear DNA.Further,nanoparticles showed high cytotoxicity,and overcame cisplatin resistance significantly;(3)An amphiphilic Pt(Ⅳ)with a lactose molecule and a long lipid tail in axial pisitions was synthesized,which could self-assemble into nanoparticles.The platinum drugs were encapsulated in the core of the micelles,while the hydrophilic lactose molecule was located in the surface.Due to the liver-targeting ligand lactose,the nanoparticles could self-target to liver tumor cells.The experimental results showed that nanoparticles could effectively target the lactose receptors on 7404 cells.Compared to eisplatin,the nanoparticles exhibited higher cytotoxicity and overcame cisplatin resistance effectively.In summary,different nano-delivery systems based on platinum drugs were constructed by designer Pt(Ⅳ)prodrugs with different structures and functions.These transformations not only improved platinum drugs’ cytotoxicity and overcame cisplatin resistance,but also broadened it’s versatility,providing new strategies for the further application of platinum drugs.