Developing Lipid Nanoparticle-Based siRNA Therapeutics for Hepatocellular Carcinoma Using an Integrated Approach

Abstract

Successful siRNA therapeutics requires the optimal integration of multiple components, including an efficient delivery system, a disease indication that is appropriate for siRNA-based therapy, and a potent and nontoxic siRNA against a robust therapeutic target. Although all currently available delivery systems have limitations, it is important to recognize that a careful selection of the disease indication, therapeutic target, and siRNA molecule could partially compensate for deficiencies associated with the delivery system and makes it possible to advance a therapeutic siRNA regimen. In this study, we present the development of siRNA therapeutics for hepatocellular carcinoma using an integrated approach, including the development of an efficient lipid nanoparticle delivery system, the identification of a robust therapeutic target that does not trigger liver toxicity upon target knockdown, and the selection of potent and nonimmunogenic siRNA molecules against the target. The resulting siRNA-containing lipid nanoparticles produced significant antitumor efficacy in orthotopic hepatocellular carcinoma models, and, thus, represent a promising starting point for the development of siRNA therapeutics for hepatocellular carcinoma.

APOE polymorphism in ATTR amyloidosis patients treated with lipid nanoparticle siRNA

“…In this study, we confirmed by in vitro experiments that expression of APOE is a major determinant of Patisiran-mediated knockdown. Human hepatoma cell line HepG2 was chosen which was previously used to evaluate other siRNAs and various LNP formulations [19,20]. Our data indicate that downregulation of APOE significantly deteriorates silencing of TTR.…”

Pharmacokinetics and biodistribution of recently-developed siRNA nanomedicines

“…In fact, intratumoral VEGF expression was not reduced by VEGF-siRNA/DOTAP complexes but rather increased [129]. More recently, Shen et al screened several lipid NPs for optimal siRNA delivery to HCC and identified a combination of lipids that showed significant anti-tumor effect with cancer-targeting siRNA’s [130]. An interesting note in this study is that good in vitro transfection efficiency did not necessarily translate to good in vivo silencing effect in orthotopic HCC tumors, which indicates the significance of circulation stability of gene-carrier complexes [130].…”

Delivery of Therapeutic siRNA to the Lung Endothelium via Novel Lipoplex Formulation DACC

“…11 Furthermore, the correlation between, and the relevance of results from in vitro and in vivo knock down experiments are much better understood, especially with respect to the impact of PEG shielding, and hence use for the modulation of PK properties critical for in vivo delivery. 12 We have previously reported on a newly synthesized cationic lipid, referred to as AtuFECT01, as part of the lipid system AtuPLEX, which exhibits more efficient siRNA binding activity and delivery to cells of the vascular endothelium as compared to other commercially available cationic lipids such as DOTAP or DOTMA. 5 Nevertheless, such nanoparticles tend to accumulate in filtering organs of the reticuloendothelial system.…”