Jornal de Nanomedicina e Nanotecnologia

Abstrato

Nanoparticle-facilitated Intratumoral Delivery of Bcl-2/IGF-1R siRNAs and p53 Gene Synergistically Inhibits Tumor Growth in Immunocompetent Mice

Anil Philip Kunnath, Nur Izyani Kamaruzman and Ezharul Hoque Chowdhury

Breast cancer, the leading cause of cancer-related deaths in women, is usually treated with surgery, radiation therapy, hormone-blocking/chemotherapy drugs, monoclonal antibodies or combinations of these approaches and agents depending on the cancer stage and the existence of specific receptors, with accompanying various adverse effects. Silencing of the genes responsible for cancer development and progression with small interfering RNA (siRNA) in combination with overexpression of the genes with tumor suppressing activities could be an attractive concept for precisely treating breast cancer with minimal side effects. However the short half-life in plasma due to nuclease-mediated degradation and renal clearance, and the inefficiency in penetrating the plasma membrane limit the applications of siRNA and DNA as therapeutic molecules. Recently, we have developed pH-sensitive carbonate apatite nano-carrier to efficiently deliver siRNA or DNA across the cell membrane facilitating them to escape endosomal acidic compartment and specifically cleave a cytoplasmic mRNA transcript or enable gene expression after nuclear translocation, respectively. Moreover, we demonstrated nanoparticle-accelerated delivery of the siRNAs targeting cyclin B1, PLC-gamma-2/ calmodulin1, HER2/ErbB2, ABCG2/ABCB1 and cROS1 mRNAs sensitizes cervical adenocarcinoma and breast cancer cells towards conventional anti-cancer drugs. Here, we report that co-delivery of the siRNAs targeting IGF-1R and Bcl-2 gene transcripts and the pasmid DNA containing p53 gene with the help of carbonate apatite nanoparticles synergistically induces inhibition of growth/proliferation of breast cancer cell lines as well as regression of the breast tumor induced in Balb/c mice. Additionally, concerted delivery of nanoparticle-associated IGF-1R/Bcl-2 siRNAs and p53 gene apparently slows down the growth of the established tumor in presence of doxorubicin or paclitaxel compared with the individual free drugs. Thus, the combination of IGF-1R/Bcl-2 knockdown and restoring of normal p53 function could be a highly promising approach that should be further investigated through pre-clinical trials to establish the therapeutic role of this combination therapy for breast cancer.