VEGF Overexpression Significantly Increases Nanoparticle-Mediated siRNA Delivery and Target-Gene Downregulation

Abstract

The availability of nanoparticles (NPs) to deliver small interfering RNA (siRNA) has significantly expanded the specificity and range of ‘druggable’ targets for precision medicine in cancer. This is especially important for cancers such as triple negative breast cancer (TNBC) for which there are no targeted treatments. Our purpose here was to understand the role of tumor vasculature and vascular endothelial growth factor (VEGF) overexpression in a TNBC xenograft in improving the delivery and function of siRNA NPs using in vivo as well as ex vivo imaging. We used triple negative MDA-MB-231 human breast cancer xenografts derived from cells engineered to overexpress VEGF to understand the role of VEGF and vascularization in NP delivery and function. We used polyethylene glycol (PEG) conjugated polyethylenimine (PEI) NPs to deliver siRNA that downregulates choline kinase alpha (Chkα), an enzyme that is associated with malignant transformation and tumor progression. Because Chkα converts choline to phosphocholine, effective delivery of Chkα siRNA NPs resulted in functional changes of a significant decrease in phosphocholine and total choline that was detected with 1H magnetic resonance spectroscopy (MRS). We observed a significant increase in NP delivery and a significant decrease in Chkα and phosphocholine in VEGF overexpressing xenografts. Our results demonstrated the importance of tumor vascularization in achieving effective siRNA delivery and downregulation of the target gene Chkα and its function.

Nano-drug delivery system for pancreatic cancer: A visualization and bibliometric analysis

“…However, it is important to note that therapeutic miRNAs can also accumulate in healthy tissues due to interstitial fluid pressure and shearing stress promoting NPs extravasation, which may lead to their degradation ( Zhang et al, 2019a ), and cause toxic and other adverse reactions ( Kara et al, 2022 ). Effective delivery and cell uptake of siRNA are major challenges in therapeutic applications ( Wang et al, 2016 ; Arnold et al, 2017 ; Tan et al, 2022 ). PEGylated ligand-targeted liposomes or micelles avoid nonspecific clearance of siRNA by the reticuloendothelial system and protect siRNA from the degradation of nuclease ( Charbe et al, 2020 ), which makes it possible to address these major obstacles.…”