Nanoparticle-Mediated p53 Gene Therapy for Breast Cancer

Abstract

Abstract : Gene expression with non-viral vectors is usually transient and lasts only for few days. Therefore, repeated injection of the expression vector is required to maintain a therapeutic protein concentration in the target tissue. Biodegradable nanoparticles ( 200 nm diameter) formulated using biocompatible polymer, poly(D,L-lactide-co-glycolide) (PLGA) have the potential for sustained gene delivery. Our hypothesis is that the nanoparticle-mediated gene delivery would resuft in sustained gene expression, and hence better efficacy with a therapeutic gene. Nanoparticles loaded with wt-p53 DNA demonstrated greater and sustained antiproliperative activity in vitro as compared to that with naked DNA and DNA-liposome complex. The greater efficacy of wt-p53 DNA-loaded nanoparticles was attributed to sustained intracellular DNA delivery and gene expression. A single-dose intratumoral administration of wt-p53 DNA-loaded nanoparticles demonstrated significant inhibition of tumor growth in MDAMB-435-induced subcutaneous breast cancer mouse model that also resulted in prolonged animal survival than controls. The mechanism of inhibition of tumor growth with wt-p53- DNA-loaded nanoparticles was attributed to higher apoptosis of tumor cells than that in controls, and also the induction of antiangiogenic protein, thrombospondin-I that inhibited tumor angiogenesis. The studies thus demonstrate the efficacy of nanoparticles as a non-viral gene expression vector and their potential application in breast cancer therapy.