Investigation Of PH-sensitive Nano-sized Zwitterionic Carrier Of Anticancer Drug Doxorubicin

Drug delivery system (DDS) based on nano drug vehicle (NDV) is the main strategy to improve the solubility, lower the side effect and enhance the therapeutic efficacy of the anticancer drug. The biocompatibility and bio-distribution of NDVs are mostly determined by the surface modification of the’nonfouling’materials. At present, polyzwitterionic materials with excellent ’nonfouling’ property and biocompatibility, and better stability than polyethylene glycol (PEG), are believed as an ideal candidate materials as polymeric drug carrier. In this dissertation, based on the structural characteristics of zwitterionic materials, we designed, prepared and further evaluated both polycarboxybetaine (PCB) based polymeric prodrug NDVs with response to micro environmental changes and a pure drug self-assembled NDV with zwitterionic surface. Following three systems were investigated:1. We demonstrated an approach to neutralize the positive charge imparted to a NDV by a conjugated basic drug (DOX) and the residue functional group on a charge balanced zwitterionic polymer (PCBMA) based system by including a negatively charged monomer (SMA). By introducing the SMA component, the NDV with a slightly negative surface charge achieved prolonged circulation time and good anticancer therapeutic efficacy without causing obvious systemic toxicity.2. We developed an instantly resistance-switchable NDVs through net charge reversal for tumor triggered cell targeting. The NDVs exhibit a prolonged circulation time, because of the nonfouling nature of the zwitterionic surface at physiological pH. The surface charge then switches to a positively charged state with increased protonated carboxyl group in response to the lower extracellular pH found in malignant tumors. This change promotes the adhesiveness to the tumor cell and it facilitates internalization by tumor cell. When combined, the NDV inhibits tumor growth to the same extent as free DOX, while reducing the unwanted side effects seen in other healthy tissues. We developed pure drug composed nano vesicles with extremely high drug loading content and drug loading efficiency by self-assembly of two types of amphiphilic drug, vitamin E succinate (VES) and doxorubicin hydrochloride (DOX·HCl), with opposite charge. Those nano vesicles with zwitterionic surface showed:acid simulated DOX release, more effective killing of MCF-7/ADR cells by a synergitic effect of VES, DOX and nano structure, and prolonged circulation time comparing to the free DOX. Those primary results suggested the promising potential of this new NDV with zwitterionic surface composed by the amphiphilic drug with opposite charge.