Abstract P6-14-10: Treatment of Breast Cancer Using Multistage Delivery of PI3K/mTOR Inhibitors
Authors: Blanco E , Sangai T , Martinez JO , Meric-Bernstam F , Ferrari M. 
Published: April 2011

Background: Current chemotherapeutic strategies are not without substantial shortcomings, including non-specific drug distribution and toxicity to normal cells. Breakthroughs in the understanding of underlying molecular mechanisms of tumorigenesis has led to the discovery and design of several drugs capable of exerting effects on key targets essential for tumor propagation. Consider rapamycin and LY294002, drugs that target the PI3K/mammalian target of rapamycin (mTOR) signaling pathway, a pathway found to be dysregulated in breast cancer. The objective is to generate a nanoscale platform capable of site-specifically delivering a powerful payload of PI3K/mTOR inhibitors for the synergistic treatmentof breast tumors. The novel, injectable nanocarrier consists of three components: 1) mesoporous silicon particles (MSPs) that will be injected into the bloodstream and housing; 2) nanoparticles (polymer micelles) loaded with; 3) PI3K/mTOR inhibitors. We hypothesize that this platform will provide for enhanced bioavailability and drug synergy at tumor sites.

Materials and Methods: The amphiphilic block copolymers that comprise the micelles consist of a pegylated formulation of poly(ε-caprolactone) (PEG-PCL, MW = 5k-1k). Drug-containing micelles were fabricated using a film sonication technique. The yield, loading efficiency, and percentage of loaded drug was calculated. Nanoparticle size and zeta potential was determined using dynamic light scattering (DLS), while size and morphology was corroborated via TEM. Release studies of drugs from micellar formulations was performed to determine the kinetics of release. Dried APTES-modified MSPs were incubated with the micellar formulations for ∼3 h. Nanoparticle loading and release was analyzed via HPLC. The in vitro antitumor efficacy of the platform was evaluated in MCF-7 and MDA-MB-468 breast cancer cells via a sulforhodamine B assay.

Results: Micelles produced by the film sonication technique were found to have an average zeta potential of -9.29 mV, and an average diameter of 34.4 ± 2.7 nm. This size was confirmed via TEM. Drug loading densities of paclitaxel, rapamycin, and LY294002 within polymer micelles was shown to be 4.6 ± 0.4, 4.1 ± 0.6, and 3.2 ± 0.6 %, respectively. Factoring in a theoretical loading of 5% for all drugs, the loading efficiency using this procedure is very high. The release kinetics were shown to be slow for rapamycin and paclitaxel (20% release over 4 days) while very fast for LY294002 (&gt;60%). Loading of micelles within the MSPs was shown to be approximately 40%. Upon incubation of the micelles with MCF-7 and MDA-MB-468 breast cancer cells, the multistage platform was effective at suppressing tumor growth after a 4 d incubation. Discussion: We have proposed herein a novel nanotherapeutic platform that aims to effectively target the PI-3K/mTOR pathway in breast tumors, bringing about tumor eradication by delivering drugs in a site-specific fashion in order to maximize drug synergy. We believe that the long blood circulation and the site-specific delivery afforded by the nanocarrier platform will translate in vitro synergy findings to the in vivo setting. Current work is underway to examine the in vivo efficacy of the platform.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P6-14-10.