Abstract PO-216: Design, fabrication, and evaluation of dual-loaded biodegradable nanoparticles for breast cancer treatment

Abstract

Abstract Introduction: The purpose of this study was to design, fabricate and determine the cytotoxic effects of dual-loaded (paclitaxel and 17-AAG) stealth polymeric nanoparticles. HSP90 inhibitors, such as 17-AAG, sensitize lung and breast cancer cells to paclitaxel induced cytotoxicity both in vitro and in vivo. Concurrent exposure to 17-AAG and paclitaxel is required for the synergistic activity of the two drugs. Further, clinical evaluations of 17-AAG in combination with approved therapies such trastuzumab and other drugs have shown enhancement or synergistic effects. Stealth nanoparticles are capable of providing site-specific tumor targeting thereby reducing toxicity in healthy cell, improving the solubility of anticancer drugs and synchronizing the disposition of encapsulated drugs (varying biodistribution/pharmacokinetics of combination drugs through cocktail administration has been attributed to their ineffectiveness in the clinic). Further, therapeutic nanoparticles could overcome drug resistance due to P-glycoprotein efflux pump. The stealth property of nanoparticles (PEG on the surface) will prevent capture by the reticuloendothelial system (RES) and will facilitate tethering ligands (mAbs) to the surface of the nanoparticles for receptor mediated endocytosis (active targeting). Dose reduction coupled with a better quality of life during treatment would also improve patient compliance. Experimental Procedures: A central composite face-centered statistical experimental design (CCF) in three independent factors and seventeen runs was implemented for the fabrication nanoparticles by dispersion polymerization technique using biodegradable poly-ϵ-caprolactone and a pH (acid) sensitive crosslinker, followed by computer optimizations. Numerical and graphical optimizations were carried out to select the factor combination to minimize the particle size, to minimize the time (h) for maximum release of paclitaxel and 17-AAG, to maximize paclitaxel and 17-AAG loading efficiency and to maximize paclitaxel and 17-AAG encapsulation efficiency. The optimal formulation was used for nanoparticle fabrication for biological studies in SKBR3 cell line (HER-2- overexpressing human breast cancer cell line) and MCF7 cell line (human breast cancer cell line). Results and Conclusion: The dispersion polymerization method was successfully used to fabricate an optimized dual-loaded nanoparticle formulation using an acid (pH) sensitive crosslinker and a macromonomer. The cytotoxic effects of the paclitaxel treatment and that of the drug combination (free drugs or nanoparticles) observed were similar in both SKBR3 and MCF7 cell lines suggesting synergistic or potentiation effects. Also, since paclitaxel and 17-AAG in the combination were half their concentrations, when used alone, and still yielded similar cytotoxic effects, we have been able to reduce the dose of paclitaxel without lowering its therapeutic efficacy. 17AAG on its own was not as effective as paclitaxel. Citation Format: Emmanuel O. Akala. Design, fabrication, and evaluation of dual-loaded biodegradable nanoparticles for breast cancer treatment [abstract]. In: Proceedings of the AACR Virtual Conference: Thirteenth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2020 Oct 2-4. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(12 Suppl):Abstract nr PO-216.