Layer-by-layer nanoparticles for systemic codelivery of an anticancer drug and siRNA for potential triple-negative breast cancer treatment.

Abstract

A single nanoparticle platform has been developed through the modular and controlled layer-by-layer process to codeliver siRNA that knocks down a drug-resistance pathway in tumor cells and a chemotherapy drug to challenge a highly aggressive form of triple-negative breast cancer. Layer-by-layer films were formed on nanoparticles by alternately depositing siRNA and poly-l-arginine; a single bilayer on the nanoparticle surface could effectively load up to 3500 siRNA molecules, and the resulting LbL nanoparticles exhibit an extended serum half-life of 28 h. In animal models, one dose via intravenous administration significantly reduced the target gene expression in the tumors by almost 80%. By generating the siRNA-loaded film atop a doxorubicin-loaded liposome, we identified an effective combination therapy with siRNA targeting multidrug resistance protein 1, which significantly enhanced doxorubicin efficacy by 4 fold in vitro and led to up to an 8-fold decrease in tumor volume compared to the control treatments with no observed toxicity. The results indicate that the use of layer-by-layer films to modify a simple liposomal doxorubicin delivery construct with a synergistic siRNA can lead to significant tumor reduction in the cancers that are otherwise nonresponsive to treatment with Doxil or other common chemotherapy drugs. This approach provides a potential strategy to treat aggressive and resistant cancers, and a modular platform for a broad range of controlled multidrug therapies customizable to the cancer type in a singular nanoparticle delivery system.

• Authors: Zhou J Deng, Stephen W Morton, Elana Ben-Akiva, Erik C Dreaden, Kevin E Shopsowitz, Paula T Hammond
• Journal: ACS nano (ACS Nano) Vol. 7 Issue 11 Pg. 9571-84 (Nov 26 2013) ISSN: 1936-086X [Electronic] United States
• PMID: 24144228 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Biopolymers
• Drug Carriers
• Liposomes
• RNA, Small Interfering

Topics

• Administration, Intravenous
• Animals
• Antineoplastic Agents (administration & dosage, therapeutic use)
• Biopolymers (chemistry)
• Breast Neoplasms (drug therapy, genetics)
• Cell Line, Tumor
• Drug Carriers
• Drug Resistance, Neoplasm (genetics)
• Female
• Humans
• Liposomes (chemistry)
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• Nanomedicine (methods)
• Nanoparticles (chemistry)
• Neoplasm Transplantation
• RNA, Small Interfering (metabolism)
• Triple Negative Breast Neoplasms (drug therapy, genetics)