ABSTRACT A common point of treatment failure in intraperitoneal mesothelioma is cancer recurrence following debulking surgery. To address this unmet clinical need, a unique nanoparticle-based solution is proposed which employs: 1) A functional pH-responsive “expansile” nanoparticle (eNP) delivery platform, which leverages fundamental pathophysiological properties of tumors (e.g., mildly acidic extracellular environment and high metabolic rate) to induce compositional and architectural changes (e.g., particle swelling) that result in tumor-specific accumulation with enhanced particle penetration and retention both in the extracellular and intracellular tumoral environment. This “Materials-Based Targeting” approach overcomes limitations of traditional strategies (e.g., enhanced permeability and retention (EPR) effect, and antibody-based targeting). In addition, the reduced nanoparticle complexity, compared to antibody labeled nanoparticles, will facilitate large-scale, GMP production of material necessary for the initiation of future clinical trials. 2) Use of a biodegradable drug-conjugate polymer of paclitaxel (PGC-PTX) that, when co-formulated with the eNP polymer will afford an ultra-high drug-loaded nanoparticle. These nanoparticles provide exceptionally high drug loading (40-70 wt%) which will enable delivery of an unprecedented local dose of drug. Furthermore, the covalent conjugation of paclitaxel ensures prolonged (>60+ days) delivery of paclitaxel with negligible burst release (<10% in the first 10 days) while avoiding systemic toxicities. *We hypothesize that the properties of a nanoparticle delivery platform (i.e., PGC-PTX-eNPs) with Materials- Based Targeting can be optimized to deliver an ultra-high local dose of paclitaxel to peritoneal tumors and thereby prevent tumor recurrence following surgical resection in mesothelioma cancer models. Importantly, key preliminary data support the proposed studies, well-characterized materials and rigorous experimental designs are established, and essential cross-disciplinary collaborations and expertise (nanotechnology, polymer chemistry, cell metabolism, autophagy, and surgical oncology) are in place to address this hypothesis. The specific aims of this five year proposal are to: 1) Perform mechanistic studies to determine how chemical properties, nano-architecture and drug incorporation of PGC-PTX-eNPs impact the Materials-Based Targeting functionality (e.g., tumor-specificity and intracellular trafficking); 2) Optimize the nanoparticle formulation of PGC- PTX-eNPs to achieve the maximum antitumor effect against three normal and drug-resistant mesothelioma cell lines and six patient samples; and, 3) Evaluate the optimized PGC-PTX-eNP formulation to determine the biodistribution, toxicity, PK, and PD/efficacy in a PDX model of recurrent mesothelioma.