Abstract P6-11-11: Multistage Delivery of Paclitaxel: Increased Drug Stability and Sustained Release Results in Enhanced Efficacy in Breast Cancer

Abstract

Abstract Background: A significant challenge for effectively treating cancer is overcoming biological barriers that reduce circulation times and increase degradation of possible treatments. We established an innovative approach to address this issue by embedding drug-containing nanoparticles within the pores of a larger mesoporous silicon particle (MSP) in order to optimize site-specific localization and release of therapeutic agents. The objective is to develop a nanotherapeutic-based multistage platform for breast cancer treatment, wherein paclitaxel, a mitotic inhibitor used in the treatment of breast tumors, will be loaded into polymeric micelles, which in turn will be loaded within MSPs. We hypothesize that this nested incorporation of drugs within MSPs, combined with enhanced tumor transport, will result in a more pronounced and sustained antitumor effect. Materials and Methods: Micelles were assembled from amphiphilic block copolymers consisting of poly(ethylene glycol)-poly(∈-caprolactone) (PEG-PCL, MW = 5k-5k). Nanoparticle size, zeta potential, and morphology was determined, and PTX loading and release kinetics from micelles analyzed. Drug-containing micelles were incorporated into MSPs by a previously established dry-loading method, wherein nanoparticles were incorporated into pores via capillary action. Loading of fluorescent micelles was used to verify loading within MSPs via fluorescence microscopy and flow cytometry analysis. Sulforhodamine B assays were used to evaluate the in vitro antitumor efficacy of the platform in MCF-7 and MDA-MB-468 breast cancer cells. In vivo efficacy was evaluated in MDA-MB-468 breast tumors in female nu/nu mice. Results: Resulting micelles had an average size of 20 nm, as confirmed through TEM, with paclitaxel loaded into micelles very effectively. Release kinetics showed that 50% of the drug was released within 4 hours and 80% released within 24 hours. Loading of micelles into MSPs depended largely on electrostatic interactions, with micelles loading better within pores of MSPs displaying increased positive charge. Micelle loading into MSPs was successful as demonstrated by flow cytometry, and release was significantly retarded (< 30% of drug released over 4 d). Incubation of micelle-containing MSPs with breast cancer cells in vitro showed that MSPs could be internalized by cells, after which a sustained and delayed release of the payload was observed in cells. Breast tumors treated with MSPs demonstrated sustained tumor suppression (169 mm3 compared to initial starting volume of 200 mm3) at day 35 following a single injection. It is important to note that sustained tumor efficacy was achieved with nanoparticle and free drug formulations, however, with the caveat of repeated administrations. Discussion: A novel multistage approach to chemotherapy effectively allows a secondary payload to be loaded and preserved within the MSPs until reaching the tumor site. This prevents premature release of the drug and allows for a sustained release which may potentially result in fewer patient side effects. Future studies will involve loading of multiple nanoparticle types into MSPs and addition of targeting and diagnostic components. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P6-11-11.