Abstract 3669: Engineering the biointerface of synthetic high density lipoprotein nanoparticles enables efficient nucleic acid loading, delivery, and target gene regulation in cancer cells
Authors: McMahon Kaylin M. , Vander Griend Don , Volpert Olga , Thaxton C. Shad 
Published: August 2015

Local treatment of cancer confined to the primary organ can be curative. However, other than a few success stories, locally advanced and metastatic cancer remains incurable. Ideally, new therapies are needed that specifically target cancer cells and derive efficacy by targeting molecular pathways that are unique to distinct tumor profiles and individual patients. Toward this end, we focus on the use of biomimicry to exploit mechanisms by which cancer cells uptake molecular cargo. Naturally, some cancer cells are dependent upon exogenous cholesterol for cellular signaling, growth, and in some cancers, such as prostate, steroidogenesis. However, cholesterol is a highly hydrophobic molecule that requires a delivery vehicle for systemic circulation and cellular delivery. High-density lipoproteins (HDLs) are natural nanostructures that engage cancer cells to deliver exogenous cholesterol. In addition to cholesterol, HDLs bind and deliver nucleic acids, such as microRNAs. Importantly, HDLs are targeted to a surface receptor, scavenger receptor type B-1 (SR-B1), whereupon binding allows for particle uptake and cargo delivery. SR-B1 has been shown to be overexpressed in human cancers, thus making HDLs a highly attractive delivery vehicle for therapeutic nucleic acid cargo. Because of the propensity of HDL to bind, stabilize, and deliver RNA our group has developed ways to synthesize lipoproteins nanoparticles and use them as therapeutic RNA delivery vehicles. Importantly, natural HDLs are highly dynamic species, which frequently undergo exchange of molecular surface components other lipoprotein species, as well as, HDLs. Recent work is focused on chemically tailoring the surface of synthetic HDL nanoparticles (HDL NPs) to understand RNA binding, stabilization, and cellular delivery. In addition, manipulating the surface chemical features of HDL also provides a way to better understand intermolecular exchange with native serum lipoproteins. Data demonstrate that by tailoring the surface chemistry of the HDL NP one can modulate the efficiency by which siRNAs can be incorporated onto the particle surface and delivered to target cells to reduce target gene expression in cancer cells. Further, data show the tendency for nanoparticle lipids to transfer to natural HDLs; however, siRNA formulated on the surface of the HDL NP remains bound, even when exposed to serum for prolonged periods. In short, exploration of HDL NPs for the systemic delivery of siRNAs may be a promising approach for targeted patient-specific cancer therapies.

Citation Format: Kaylin M. McMahon, Don Vander Griend, Olga Volpert, C. Shad Thaxton. Engineering the biointerface of synthetic high density lipoprotein nanoparticles enables efficient nucleic acid loading, delivery, and target gene regulation in cancer cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3669. doi:10.1158/1538-7445.AM2015-3669