Abstract P6-13-14: Temporospatial delivery of chemotherapeutics from nanoparticles for synergy enhancement
Authors: V Segura-Ibarra, S Wu, FE Cara, F Meric-Bernstam, M Ferrari, E Blanco
Journal: Cancer Research (2016)

Abstract INTRODUCTION Chemotherapeutic synergy enhancement can be obtained when drugs are delivered in a sequential manner. However, clinical translation of synergistic combinations is not feasible due to different pharmacokinetic properties arising from distinct drug formulations that negate proper sequential delivery. Our laboratory has developed a platform for temporospatial delivery of agents in a sequential fashion for purposes of enhancing site-specific synergy. The system comprises a drug-containing poly(lactic-co-glycolic acid) (PLGA) core and an outer shell of drug complexed with β-cyclodextrin (β-CD). In this study, we demonstrate the therapeutic potential of this nanoparticle system by encapsulating two drugs, rapamycin (RAP) and paclitaxel (PTX). This combination has been shown to result in cell-killing synergy enhancement in when administered sequentially, and in a time staggered manner, in triple negative breast cancer (TNBC) in in vitro cell-based models. EXPERIMENTAL METHODS The final platform was fabricated by resuspending PLGA-PTX nanoparticles in an aqueous solution of RAP cyclodextrin complexes (RAP-CD) under sonication. Nanoparticles were characterized for size and surface charge. Drug concentration and release kinetics were determined by HPLC. In vitro growth inhibition in SUM159 TNBC cells was determined via MTT assay. Western blotting was used to confirm target knockdown. For in vivo efficacy analysis, SUM159 breast cancer cells (3×106) were inoculated in the mammary fat pads of 4- to 6-week–old female nu/nu mice, and treatments were administered intravenously once a week for a duration of 21 days. RESULTS AND DISCUSSION Nanoparticles had a mean diameter of 140 nm and zeta potential of -30 mV. After complexation with RAP-CD, the surface charge became 25 mV. Release kinetics depicted a fast release of RAP at early timepoints, while PTX showed a prolonged release. Nanoparticles showed concentration dependent cell-killing efficacy in SUM159 breast cancer cells in vitro, with knockdown of pS6, characteristic of RAP treatment, observed. Upon administration of NNPs to murine models of TNBC, NNPs showed significant tumor growth inhibition compared to controls, and knockdown of pS6. CONCLUSION We have developed a novel nanoparticle for the temporospatial release of drugs. The ability to localize agents site-specifically and deliver them sequentially should enable clinical translation of synergistic regimens observed in in vitro scenarios, in turn yielding more efficacious more efficacious outcomes following combination chemotherapy. Citation Format: Segura-Ibarra V, Wu S, Cara FE, Meric-Bernstam F, Ferrari M, Blanco E. Temporospatial delivery of chemotherapeutics from nanoparticles for synergy enhancement. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P6-13-14.