Dual drug delivery via integrin-targeted nanoparticles enhances therapeutic efficiency in BRAFV600E colon cancer.

Abstract

Colorectal cancer (CRC) patients possessing the BRAFV600E mutation often fail to respond to current first line therapies and are associated with poor prognosis, despite the advent of orally delivered small molecule inhibitors (SMIs) targeting the RAS-RAF-MEK-ERK signaling pathway. Thus, further improvements are required at a formulation and delivery level in order to enhance survival of these patients. Here we have formulated nanoparticles (NPs) made from biodegradable pegylated poly(lactide-co-glycolide) (PEG-PLGA) polymers, co-loaded with the SMIs, encorafenib (a BRAFV600E inhibitor) and trametinib (a MEK1/2 inhibitor) and decorated with the integrin targeting moiety, cyclic arginine-glycine-aspartate (cRGD), that are capable of significantly enhancing therapeutic effectiveness upon intravenous (IV) delivery in a xenogeneic CRC model when compared to the soluble SMIs delivered IV at equivalent doses. Pharmacokinetic analyses revealed actively targeted NPs could deliver the SMIs more efficiently to the tumor than IV administered SMIs in soluble form while also reducing their accumulation in the skin, an off-target site often associated with the dose-limiting side-effects of trametinib. This work is the first to demonstrate the therapeutic benefit of targeted nano-based co-delivery of SMIs in BRAFV600E-CRC and warrants further progression toward clinical studies in order to improve CRC patient survival outcomes.

Abstract as supplied by the indexing source. © the authors / publisher.