Designing of Tumor-Targeted HuR siRNA Nanoparticle as a Therapeutic for Lung Cancer

Abstract

Small interfering (si) RNA has emerged as a valuable laboratory tool not only for studying the function of a gene but also as a therapeutic for cancer treatment. siRNA-based therapies are being developed and tested against a plethora of human cancers in laboratories around the world and serve as an alternate strategy for conventional therapy, in particular for cancers that have developed resistance to therapy. Preclinical studies have convincingly demonstrated that siRNA therapy when combined with conventional therapies and small molecule inhibitors produce enhanced antitumor activity. While siRNA therapy is attractive, there are also several hurdles that need to be overcome for successfully translating to the clinic. One major hurdle is the availability of a biodegradable delivery vehicle that can efficiently protect the siRNA from rapid degradation when administered in vivo. siRNA therapy, like conventional and molecularly targeted therapies, requires specificity and targeted delivery to the rapidly growing tumor such that the tumor therapeutic efficacy is high while normal tissue toxicity is low. Recent advances made in the field of nanotechnology have led to the synthesis of nanocarriers of various compositions. These nanocarriers, often referred to as nanoparticles, can carry different payloads including siRNA. Among several nanocarriers that have been tested till date, lipid-based nanoparticles have been the most widely tested due to their excellent biocompatibility, low immunogenicity, safety, and enhanced efficacy. In the present study, we describe a lipid-based nanoparticle that is targeted toward human lung cancer cells expressing the folate receptor. The therapeutic payload carried by the nanoparticle is an siRNA that targets the human antigen R (HuR). HuR is an mRNA-binding protein that regulates the stability and translation of several oncoproteins and is overexpressed in lung cancer. Thus HuR is a druggable target and its inhibition should result in global knockdown of several oncoproteins resulting in therapeutic efficacy. The present chapter provides an overview of various lipid-based nanoformulations including tumor-specific targets for nanoparticle delivery, challenges in siRNA delivery, and molecular targets against which siRNA is developed and finally discusses about our rationally designed folate-targeted nanoparticle carrying siRNA for HuR (HuR-FNP) gene silencing and its promising potential in the treatment of lung cancer.