Delivery of Drug Combination Therapy in Polymeric Nanoparticles for Treatment of Breast Cancer

The development of resistance and the serious side effects associated with the commercial preparation of paclitaxel (PTX) necessitate the development of new PTX formulations that have a better safety profile. The use of synergistic drug combination therapies has emerged as one promising avenue towards reducing the toxicities associated with high doses of single agents while maintaining therapeutic efficacy. The molar ratios at which the drugs are administered have significant impact on their synergistic effects. In this thesis, for the first time, we provide a systematic assessment of the synergistic effects of PTX and everolimus (EVER) combination and define the optimal synergistic ratio. Polymeric nanoparticles represent an effective nanocarrier platform for the delivery of drug combinations to the tumor site at the optimal synergistic ratio, allowing for selective delivery and sparing normal tissues from exposure to their cargo and the toxicities that result. This thesis describes the design and characterization of a dual-targeted polymeric nanoparticle formulation based on poly(ethylene glycol)-b-poly(lactide-co-glycolide) (PEG-b-PLGA) co-encapsulating PTX and EVER at the optimal synergistic molar ratio (Dual-NPs). HER2 and EGFR-targeted antibody Fab fragments were conjugated to the surface of the NPs to enhance specific delivery and facilitate NP internalization in breast cancer co-overexpressing HER2 and EGFR. Dual-targeting of HER2 and EGFR resulted in a significant increase in the cellular uptake and cytotoxicity of the Dual-NPs in breast cancer cells relative to untargeted and HER2 mono-targeted NPs. Cellular uptake was dependent on the level of expression of HER2 and EGFR, confirming receptor-mediated internalization of the NPs. Limited in vivo stability is one of the main practical challenges in the application of polymeric NPs for the delivery of PTX to the tumor site. Importantly, Dual-NPs maintained their stability in mouse models which is a essential to exploit the EPR effect, leading to increased tumor accumulation and reduced toxicities. As a result, the levels of body weight loss were significantly reduced and neurotoxicity was overall reduced with Dual-NP treatment relative to the free-drug combination. In conclusion, Dual-NPs represent a promising tool for the delivery of PTX and EVER drug combination therapy to BC while reducing the toxicities of the drugs.Ph.D.2020-11-13 00:00:0