Novel drug delivery systems: pH-responsive expansile nanoparticles & drug concentrating devices as tools for treating cancer

Thesis (Ph.D.)--Boston UniversityNew strategies for treatment and methods of drug delivery are required for patients suffering from cancer-the second leading cause of death worldwide. Current chemotherapeutic treatments frequently suffer from poor water solubility, systemic toxicity, poor accumulation within the target tissues and an inability to eradicate all remaining tumor following resection procedures. Nanoparticles (NPs) are extensively investigated as a means to increase drug solubility, alter biodistribution, target specific sites within the body, and minimize drug side effects and, as such, numerous NP formulations are being investigated as drug delivery devices to assist in the treatment and management of cancer. We have developed a pH-responsive expansile nanoparticle (eNP) that can encapsulate the hydrophobic chemotherapeutic agent Paclitaxel (Pax) (a poorly water soluble, yet potent chemotherapeutic agent), and deliver it specifically to the intracellular compartment of tumor cells. Paclitaxel-loaded-eNPs (Pax-eNPs) localize specifically to regions of intraperitoneal (IP) tumors and, once taken up by tumor cells, undergo a conformational change upon exposure to the mildly acidic cellular endosome that results in eNP swelling and intratumoral drug release. In this work, we describe: 1) the clinical problem and cost (both humanitarian and fmancial) of local cancer recurrence following tumor resection; 2) the eNP delivery system and, specifically, we characterize the swelling of eNPs using microscopy and tunable resistive pulse sensing techniques; 3) the in vitro activity of Pax-eNPs in breast cancer cells; 4) the improved efficacy of Pax- eNPs compared to the standard clinical formulation of Pax (i.e., Pax dissolved in Cremophor/Ethanol) in a murine model of established peritoneal mesothelioma; and, 5) the ability of eNPs to act as intratumoral, intracellular drug concentrating devices. Further investigation of this NP-based drug delivery system will facilitate a greater understanding of the materials and devices used in the delivery of chemotherapeutic agents and may lead to the clinical translation and application of eNPs