Delivery and Biodistribution of siRNA for Cancer Therapy: Challenges and Future Prospects

Abstract

RNAi-based approaches provide a promising therapeutic modality for the treatment of cancer. The inaccessibility of tumors in different cancer types necessitates the development of safe, specific and efficient systemic delivery systems to meet therapeutic need. The translation of siRNA-based cancer therapeutics to the clinic is hindered by several challenges associated with the cargo (siRNA) and the delivery system, including susceptibility to nucleases; insufficient circulation half-life due to phagocytosis by the reticuloendothelial system, transient and poor biodistribution in the tumor tissue; cellular uptake; inability to escape endosomes and release into the cytosolic compartment for an RNAi-mediated effect; microRNA-like unintended off-target effects; undesirable immune stimulation; and carrier-related toxicity. This review provides an overview of the pharmacokinetic and biodistribution challenges witnessed in the delivery of siRNA when administered systemically. It also describes the current delivery approaches using liposome-, polymer- and peptide-based delivery systems shown to elicit significant gene silencing and tumor growth regression in proof-of-concept studies. As part of future perspectives, delivery agents that showed significant efficacy in preclinical rodent models and clinical trials are also reviewed.