PLGA siVAV1 nanoparticles for the treatment of pancreatic ductal adenocarcinoma

Pancreatic ductal adenocarcinoma (PDAC) is among the leading causes of cancer-related death worldwide due to late diagnosis and aggressive metastatic nature. The tumor’s complex extracellular matrix is resistant to chemotherapeutic agents, and only ~10% of patients are suitable for surgical resection¹. Overexpression of VAV1 protein in PDAC is associated with decreased survival and contributes to the tumorigenic properties of pancreatic cancer (PC) cells². We aim to develop spatial and systemic drug delivery systems, which are composed of siRNA encapsulated in polymeric nanoparticles (NPs) against VAV1 for PDAC therapy.

NPs composed of the biocompatible and biodegradable polymer, PLGA (Poly (DL-lactide-co-glycolide)) have been successfully prepared by the double-emulsion solvent-diffusion (DESD) technique, characterized with high siRNA encapsulation yield (up to ~90%), spherical shape of ~100nm, neutral charge, and good stability as a lyophilized powder (up to 2.5 years, at -20°C). In vitro cell assays demonstrated rapid engulfment by PC cells, low cytotoxicity at the effective concentration range, and were shown to significantly decrease VAV1 gene expression (up to 75%). In addition, we developed an injectable delivery system of NPs in a thermo-reversible gel suitable for local administration via a laparoscopic catheter. Enhanced spatial retention of the gel-embedded NPs in mice’s pancreas was observed. Ongoing research is evaluating local vs. systemic delivery of siVAV1 in orthotopic PDAC rodent models, for an effective and safe therapy.

Reference:

(1) Adamska A, Domenichini A, Falasca M. Int J Mol Sci. 2017:18,1338-1381.

(2) Katzav S. Oncotarget. 2015:6,28731- 28742.