Construction Of Phosphorylcholine-based Drug Delivery Systems For Tumor Therapy

Chemotherapy is one of the main treatment methods for cancer,but the traditional chemotherapy has many problems such as low utilization rate of drugs and high toxic and side effects.Nanocarriers can improve the biodistribution and tumor targeting properties of drugs in vivo,which is an effective way to improve the curative effect of cancer.Phosphorylcholine is an electrically neutral zwitterionic group found in the outer surface of biofilms.Because of their great blood compatibility,phosphorylcholine-based polymers provide a new idea for the safe and effective nanocarrier systems.Firstly,we investigated the effect of branching on blood circulation and tumor targeting of polymer nanovehicles in vivo.For the purpose,star-branched polylactic acid and poly(2-methacryloyloxyethyl phosphorylcholine)(PLA-PMPC)copolymers with AB₃,(AB₃)₂,and(AB₃)₃architecture were designed by coupling at the PLA core.Nanomicelles self-assembled from these copolymers were used to evaluate the effect of core branching on blood circulation and tumor targeting.The results showed that branching changed the behavior of polymeric self-assembly in solution,thereby changed the stability,particle size,and surface anti-fouling performance of the polymeric micelles.Moreover,star-branched copolymer micelles with highest branching degree made their payload persist best in blood and allowed for highest concentrations in the tumor site.These studies suggested that raising the branching degree of amphiphilic copolymer potentially offered a promising strategy to design carriers of enhanced circulation and targeting in vivo.Secondly,we developed tumor-microenvironment-responsive nanocapsules for therapeutic antibodies(t Abs)by in situ radical polymerization employing MPC as monomers and diallyl disulfide as crosslinkers.Due to the protective effect of the hydration layer formed by PMPC,the nanocapsules could effectively protect t Abs from the capture of the reticuloendothelial system,prolong the blood circulation time of t Abs,and improve the biological distribution of t Abs in vivo.The cetuximab-loaded nanocapsules nano(cetuximab)efficiently delivered cetuximab to tumor tissue via the EPR effect and released cetuximab with the reductive condition of the tumor.The released cetuximab acted on vascular endothelial cells to destroy the blood-tumor barrier and realized the self-augmentation of the EPR effect,which in turn contributed to further tumor accumulation of long-circulating nano(cetuximab).Compared with single-dose administration of native cetuximab,that of nano(cetuximab)showed a more effective tumor-suppressive effect for three weeks.This novel self-augmentation of the EPR effect endowed by the biological characteristics of t Abs and nanotechnology properties might contribute to the improvement of the therapeutic effects of t Abs and inspire new ideas for antibody-based tumor therapy.Finally,a p H-responsive,superparamagnetic nanoparticles(SPMNs)-based method was developed for the precise and mild separation of blood Tf R+exosomes.Briefly,multiple SPMNs labeled with transferrins(Tf)could precisely bind to blood Tf R+exosomes to form an exosome-based cluster(SMNC-EXOs)due to the specific recognition of Tf R by Tf.Under an external magnetic field,SMNC-EXOs could be separated.Taking advantage of the p H-responsive dissociation of Tf and Tf R,blood Tf R+exosomes with high purity were obtained by the mild collapse of SMNC-EXOs.The blood Tf R+exosomes showed excellent bio-safety and enabled the efficient delivery of chemotherapeutics to tumors,facilitating the clinical translation of exosome-based drug delivery systems.