A combinatorial delivery of survivin targeted siRNA using cancer selective nanoparticles for triple negative breast cancer therapy

Triple-negative breast cancer (TNBC) is one major type of cancer for which there has been no effective therapy to date. An important reason for it being the lack of expression of important receptors such as estrogen, progesterone and human epidermal growth factor receptor-2 (HER-2). There is no FDA approved targeted treatment available till date leading to high rate of proliferation and multi-drug resistance. Here, we developed doxorubicin (Dox) (chemotherapeutic) and lycopene (LCP) (chemo-protective) loaded polyamidoamine (PAMAM) dendrimer as an extensive anti-survivin siRNA nanocarrier (DLP/siRNA). The developed dendriplex was characterized by FTIR, DSC, NMR, Zetasizer and AFM. In vitro study depicted an elevated apoptosis rate and tumor cell uptake rate for this formulated dendriplex. Additionally, the gel retardation technique confirmed the siRNA-protecting ability of dendrimer from nuclease. Most importantly, the silencing of survivin siRNA as observed in the cancer cell population with the combined effect of chemotherapeutic and chemo-protective agents inhibited the cancer cell stemness and suppressed the tumor growth without causing cardiac toxicity in the TNBC xenograft model. Altogether, this combinatorial approach of gene delivery and chemotherapy with an application of chemo-protective effect suggests an enhanced therapeutic efficacy in the treatment of triple-negative breast cancer. [Display omitted]