Therapeutic Gene Silencing Using Targeted Lipid Nanoparticles in Metastatic Ovarian Cancer

Lipid nanoparticles encapsulating small interfering ribonucleic acids are developed that block two essential pathways for cancer cell survival. Targeting of metastasized ovarian cancer cells is further enhanced by coating nanoparticles with hyaluronan. Robust gene silencing in key tissues involved in ovarian cancer pathophysiology in an advanced ovarian cancer mouse model is demonstrated and improved median and overall survival observed. AbstractOvarian cancer is an aggressive tumor owing to its ability to metastasize from stage II onward. Herein, lipid nanoparticles (LNPs) that encapsulate combination of small interfering RNAs (siRNAs), polo-like kinase-1 (PLK1), and eukaryotic translation-initiation factor 3c (eIF3c), to target different cellular pathways essential for ovarian cancer progression are generated. The LNPs are further modified with hyaluronan (tNPs) to target cluster of differentiation 44 (CD44) expressing cells. Interestingly, hyaluronan-coated LNPs (tNPs) prolong functional activity and reduce growth kinetics of spheroids in in vitro assay as compared to uncoated LNPs (uNPs) due to ≈1500-fold higher expression of CD44. Treatment of 2D and 3D cultured ovarian cancer cells with LNPs encapsulating both siRNAs result in 85% cell death and robust target gene silencing. In advanced orthotopic ovarian cancer model, intraperitoneal administration of LNPs demonstrates CD44 specific t umor targeting of tNPs compared to uNPs and robust gene silencing in tissues involv...
Source: Small - Category: Nanotechnology Authors: Tags: Research Article Source Type: research