(579d) Combined Modality Doxorubicin-Based Chemotherapy and Chitosan-Mediated p53 Gene Therapy Using Double-Walled Microspheres for Cancer Treatment

Cancer is a leading cause of death and has become the number one killer in many countries. Despite several attempts in the development of new anti-cancer drugs, drug combinations or treatment regimens, the progress in traditional cancer therapy remains dim. Many cancers develop cross-resistance to a number of anti-cancer agents following the exposure to one such drug. Moreover, the efficacy of anti-cancer drugs is restricted by their unfavorable properties, including poor solubility, narrow therapeutic window and intensive cytotoxicity to normal tissues, which are some of the causes of treatment failure in cancer.

In this study, a novel synergistic therapy strategy for cancer treatment is developed on the basis of combining chemotherapy and gene therapy using double-walled microspheres as delivery carriers for controlled and sustained release. Double-walled PLLA(PLGA) microspheres consisting of encapsulated doxorubicin in the poly(DL-lactic-co-glycolic acid) (PLGA) core surrounded by encapsulated chitosan-p53 nanoparticles in the poly(L-lactic acid) (PLLA) shell have been successfully fabricated. The precision particle fabrication technique, based on previous works, employs a coaxial nozzle to produce a jet of core polymer surrounded by an annular stream containing a second polymer which is disrupted into uniform nascent double-walled droplets by an ultrasonic transducer. The effective restoration of the tumor suppressor gene p53 function allows reestablishment of normal cell growth control and restores appropriate response to doxorubicin. Thus, when the therapeutic gene is released by the double-walled microspheres, the chemotherapeutic drug can be delivered to the cancer cells simultaneously with the aim to keep targeted cells sensitive to the drug during the treatment period. The microspheres provide an additional advantage of releasing the agents in tandem by selectively loading them into the core and shell phases, thereby optimizing drug device formulation and enhancing drug efficacy.

The chitosan-DNA nanoparticles and double-walled microspheres were synthesized and characterized. In vitro release tests were conducted for the microspheres to determine the release characteristics of both drug and chitosan-DNA nanoparticles. The microspheres were also tested in hepatocellular carcinoma (HCC), mainly HepG2 (wt-p53) and Hep3B (null-p53) cells, by comparing their cell viability, cell apoptosis, p53 gene expression and activation of p53 pathway.