Use of Size and a Copolymer Design Feature To Improve the Biodistribution and the Enhanced Permeability and Retention Effect of Doxorubicin-Loaded Mesoporous Silica Nanoparticles in a Murine Xenograft Tumor Model

TLDR

A key challenge for improving the efficacy of passive drug delivery to tumor sites by a nanocarrier is to limit reticuloendothelial system uptake and to maximize the enhanced permeability and retention effect. The study shows that reducing MSNP size and coating them with a polyethyleneimine–polyethylene glycol copolymer lowers opsonization and boosts passive delivery of 50 nm doxorubicin‑loaded MSNP to a human squamous carcinoma xenograft, and suggests that adding targeting ligands and nanovalves could further improve cell‑specific targeting and controlled release. Using near‑infrared fluorescence imaging and elemental Si analysis, the authors demonstrated passive accumulation of ~12 % of the injected particle load at the tumor site, where the 50 nm MSNP were effectively taken up by KB‑31 cells and delivered doxorubicin. The 50 nm copolymer‑coated MSNP induced apoptosis, accelerated tumor shrinkage versus free doxorubicin, and markedly reduced systemic toxicity, confirming that size reduction and steric/electrostatic surface modification enable effective passive tumor targeting.

Abstract

A key challenge for improving the efficacy of passive drug delivery to tumor sites by a nanocarrier is to limit reticuloendothelial system uptake and to maximize the enhanced permeability and retention effect. We demonstrate that size reduction and surface functionalization of mesoporous silica nanoparticles (MSNP) with a polyethyleneimine–polyethylene glycol copolymer reduces particle opsonization while enhancing the passive delivery of monodispersed, 50 nm doxorubicin-laden MSNP to a human squamous carcinoma xenograft in nude mice after intravenous injection. Using near-infrared fluorescence imaging and elemental Si analysis, we demonstrate passive accumulation of ∼12% of the tail vein-injected particle load at the tumor site, where there is effective cellular uptake and the delivery of doxorubicin to KB-31 cells. This was accompanied by the induction of apoptosis and an enhanced rate of tumor shrinking compared to free doxorubicin. The improved drug delivery was accompanied by a significant reduction in systemic side effects such as animal weight loss as well as reduced liver and renal injury. These results demonstrate that it is possible to achieve effective passive tumor targeting by MSNP size reduction as well as by introducing steric hindrance and electrostatic repulsion through coating with a copolymer. Further endowment of this multifunctional drug delivery platform with targeting ligands and nanovalves may further enhance cell-specific targeting and on-demand release.