Work

Targeting siRNA nanoparticles with ApoB peptide: Formulation, biodistribution, and bioactivity in pancreatic tumor-bearing mice

Year: 2025

Type: article

Abstract: Pancreatic cancer (PC) is one of the most lethal cancers, with limited therapeutic means mainly due to its distinctive extracellular matrix (ECM). Polymeric nanoparticles (NPs) containing siRNA against VAV1 protein, which is overexpressed and involved in PC progression and metastases formation, have been shown as a promising approach. For enhanced tumor accumulation of the siRNA and effective therapy, targeted NPs is a valuable approach. Herein, poly(lactic-co-glycolic acid) (PLGA)-based NPs encapsulating siVAV1 were linked with an ApoB-derived peptide. This targeting ligand possesses a high affinity for proteoglycans and low-density lipoprotein receptors, which are overexpressed on the PC cell surface and within the ECM. We have characterized the physicochemical properties of ApoB-targeted NPs (T-NPs), examined their affinity properties in 2D/3D cell cultures, and assessed their biodistribution and therapeutic bioactivity in an orthotopic PC mouse model. T-NPs displayed favorable physicochemical properties in terms of nano-size, low polydispersity index, neutral charge, homogenous spherical morphology, and efficient siRNA encapsulation. High affinity and increased internalization of T-NPs were observed in cell cultures. Treatment of PC-bearing mice with siVAV1-laden T-NPs revealed superior tumor accumulation, resulting in increased survival rates following significant suppression of tumor growth and metastases. The therapeutic effect was mediated via the knockdown of both VAV1 mRNA and protein levels. These findings validate our hypothesis that targeted ApoB-PLGA NPs can address PC therapeutic challenges, suggesting an effective and safe targeting approach. • Targeted NPs via ApoB-peptide have favorable physicochemical properties. • High affinity and increased internalization of targeted NPs by cancer cells. • Enhanced tumor accumulation of targeted NPs in pancreatic tumor-bearing mice model. • SiVAV1 targeted NPs inhibit pancreatic cancer & metastases via VAV1 mRNA knockdown. • Increased survival of pancreatic tumor-bearing mice treated with siVAV1-laden NPs.

Source: Journal of Drug Delivery Science and Technology

DOI: 10.1016/j.jddst.2025.106900

Authors: Majd Agbaria, Doaa Jbara-Agbaria, Gershon Golomb

Institution: Hebrew University of Jerusalem

Language: English

Topic: RNA Interference and Gene Delivery

Subfield: Molecular Biology

Field: Biochemistry, Genetics and Molecular Biology

Domain: Life Sciences

SDG: Good health and well-being

Open Access status: hybrid

Estimated APC paid: $3,810