Folic Acid-targeted Dual Drug-loaded Polymer Vesicles And Their Anti-tumor Research

Cancer is one of the most dangerous and highly lethal diseases that seriously threaten human health.Chemotherapy is one of the most important non-operative methods in the treatment of cancers.In recent years,many clinical research results show that single drug chemotherapy is often difficult to effectively control the cancer disease,multidrug resistance may also appear in the last stage of treatment,while the combination of different chemotherapy drugs can improve the anticancer effect,delay the emergence of drug resistance and reduce drug toxicity.The combination of free drug cocktail treatment has been widely used in clinical treatment,but the distinct pharmacokinetics of combined drugs and non-specific drug distribution slow down the development in the clinic.The polymersome architecture,with its large hydrophilic reservoir and its thick hydrophobic lamellar membrane,provides significant storage capacity for both water soluble and insoluble substances in the synergistic treatment of cancer.It can change the drug distribution in vivo and pharmacokinetic properties,and achieve the effect of drug enrichment on the lesion site by active and passive targeting modification.It is an ideal carrier for simultaneously encapsulating of both hydrophobic and hydrophilic chemotherapeutic drugs for the combination treatment of tumors.In this study,Poly(?-caprolactone)-poly(ethylene glycol)-poly(?-caprolactone)(PCL-PEG-PCL,PCEC)amphiphilic triblock copolymers were synthesized by ring-opening polymerization of ?-CL in the presence of PEG with Sn(Oct)2 as catalyst.The PCEC has good biocompatibility and biodegradability as carrier material.Then,paclitaxel(PTX)and doxorubicin hydrochloride(DOX HCl)are used as model hydrophobic and hydrophilic anticancer drug,respectively.Folate(FA)receptor-targeted polymersomes with apparent bilayered lamellar structure were successfully developed to co-encapsulate the hydrophobic-hydrophilic chemotherapeutic drug pair(PTX and DOX)in a single vesicle for enhancing the combination chemotherapeutic effect.Hydrophobic PTX was loaded into the thick hydrophobic lamellar membrane by the self-assembly of triblock copolymer PCL-PEG-PCL,while hydrophilic DOX was encapsulated into the hydrophilic reservoir using a trans-membrane ammonium sulfate gradient method.TEM photographs showed that PCL-PEG-PCL triblock copolymers with fPEG(w)of 33%was found to form polymersomes,which was characterized with a hydrophobic bilayer membrane and aqueous core.Cellular uptake study indicated that FA-targeted Co-delivery polymersomes had higher internalization efficiency in FA receptor-overexpressing BEL-7404 cells than non-targeted Co-delivery polymersomes.In vitro cytotoxicity assay demonstrated that FA-targeted Co-delivery polymersomes exhibited less cytotoxic effect than free drug cocktail,but suppressed the growth of tumor cells more efficiently than non-targeted Co-delivery polymersomes.Ex vivo imaging biodistribution studies revealed that FA-targeted Co-delivery polymersomes led to highly efficient targeting and accumulation in the BEL-7404 xenograft tumor.Furthermore,the in vivo antitumor study showed that FA-targeted Co-delivery polymersomes exhibited less cytotoxic effect than free drug cocktail,but exhibited significantly higher tumor growth inhibition than free drug cocktail.Therefore,the newly developed FA-targeted co-delivery polymersomes hold great promise for simultaneous delivery of multiple chemotherapeutics and would have great potential in tumor-targeting and combination chemotherapy.