Codelivery of an Optimal Drug/siRNA Combination Using Mesoporous Silica Nanoparticles To Overcome Drug Resistance in Breast Cancer <i>in Vitro</i> and <i>in Vivo</i>

TLDR

The study aims to use a multifunctional mesoporous silica nanoparticle carrier to co‑deliver doxorubicin and P‑gp‑targeting siRNA to overcome doxorubicin resistance in a multidrug‑resistant breast cancer xenograft. The authors developed a 50‑nm PEI‑PEG‑functionalized mesoporous silica nanoparticle that, after high‑throughput siRNA screening, delivers doxorubicin and P‑gp siRNA with improved tumor biodistribution and an 8 % enhanced permeability‑retention effect. In vivo, the dual delivery system achieved synergistic tumor growth inhibition, significant P‑gp knockdown at heterogeneous sites, and demonstrated that tumor microenvironment heterogeneity—not P‑gp expression—drives delivery efficacy, proving the concept of a dual drug/siRNA nanocarrier to overcome doxorubicin resistance.

Abstract

We used a multifunctional mesoporous silica nanoparticle (MSNP) carrier to overcome doxorubicin (Dox) resistance in a multidrug resistant (MDR) human breast cancer xenograft by codelivering Dox and siRNA that targets the P-glycoprotein (Pgp) drug exporter. The Pgp siRNA selection from among a series of drug resistance targets was achieved by performing high throughput screening in a MDR breast cancer cell line, MCF-7/MDR. Following the establishment of a MCF-7/MDR xenograft model in nude mice, we demonstrated that a 50 nm MSNP, functionalized by a polyethyleneimine–polyethylene glycol (PEI-PEG) copolymer, provides protected delivery of stably bound Dox and Pgp siRNA to the tumor site. The effective biodistribution and reduced reticuloendothelial uptake, as a result of our nanocarrier design, allowed us to achieve an 8% enhanced permeability and retention effect at the tumor site. Compared to free Dox or the carrier loaded with either drug or siRNA alone, the dual delivery system resulted in synergistic inhibition of tumor growth in vivo. Analysis of multiple xenograft biopsies demonstrated significant Pgp knockdown at heterogeneous tumor sites that correspond to the regions where Dox was released intracellularly and induced apoptosis. We emphasize that the heterogeneity originates in the tumor microenvironment, which influences the vascular access, rather than heterogeneous Pgp expression in the MDR cells. Taken together, these data provide proof-of-principle testing of the use of a dual drug/siRNA nanocarrier to overcome Dox resistance in a xenograft. The study also provides the first detailed analysis of the impact of heterogeneity in the tumor microenvironment on the efficacy of siRNA delivery in vivo.