Molecular engineering of ultrasmall silica nanoparticle-drug conjugates as lung cancer therapeutics

Abstract

Purpose: Small-molecule inhibitors have had a major impact on cancer care. While treatments have demonstrated clinically promising results, they suffer from dose-limiting toxicities and the emergence of refractory disease. Considerable efforts made to address these issues have more recently focused on strategies implementing particle-based probes that improve drug delivery and accumulation at target sites, while reducing off-target effects. Experimental Design: Ultrasmall (<8 nm) core-shell silica nanoparticles, C0 dots, were molecularly engineered to function as multivalent drug delivery vehicles for significantly improving key in vivo biological and therapeutic properties of a prototype epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, gefitinib. Novel surface chemical components were used to conjugate gefitinib-dipeptide drug-linkers and deferoxamine (DFO) chelators for therapeutic delivery and PET imaging labels, respectively. Results: Gefitinib-bound C0 dots (DFO-Gef-C0 dots), synthesized using the gefitinib analogue, APdMG, at a range of drug-to-particle ratios (DPR; DPR ¼ 11-56), demonstrated high stability for DPR values≤ 40, bulk renal clearance, and enhanced in vitro cytotoxicity relative to gefitinib (LD50 ¼ 6.21 nmol/L vs. 3 mmol/L, respectively). In human non-small cell lung cancer mice, efficacious Gef-C0 dot doses were at least 200-fold lower than that needed for gefitinib (360 nmoles vs. 78 mmoles, respectively), noting fairly equivalent tumor growth inhibition and prolonged survival. Gef-C0 dot-treated tumors also exhibited low phosphorylated EFGR levels, with no appreciable wild-type EGFR target inhibition, unlike free drug. Conclusions: Results underscore the clinical potential of DFOGef-C0 dots to effectively manage disease and minimize off-target effects at a fraction of the native drug dose.