Continuous flow manufacturing of antibody-loaded nanoparticles for non-opioid oral cancer pain therapy

About This Grant

PROJECT SUMMARY/ABSTRACT Oral cancer affects over 59,000 Americans annually and causes severe, debilitating pain that significantly impairs patients' ability to eat, speak, and maintain quality of life. Current treatment relies primarily on opioids, which carry substantial risks including addiction, tolerance, constipation and respiratory depression. The ongoing opioid crisis has intensified the urgent need for effective, non-opioid cancer pain therapies. Recent work has shown that persistent cancer pain is mediated by protease-activated receptor 2 (PAR2) signaling from endosomal compartments within sensory neurons, rather than from cell surface receptors as previously believed. While anti- PAR2 monoclonal antibodies (mAbs) show therapeutic promise, their clinical translation has failed, potentially because conventional mAbs cannot penetrate cells to reach these intracellular targets. However, nanoparticles are readily endocytosed by cells and trafficked to endosomal compartments, providing an opportunity to deliver anti-PAR2 mAbs directly to the site of persistent pain signaling. This proposal addresses two critical gaps: the urgent need for non-opioid cancer pain therapies and the lack of scalable manufacturing processes for nanoparticle-based biologics delivery systems. Current delivery nanotechnologies suffer from low therapeutic loadings, poor encapsulation efficiency, and rely on unscalable production methods that prevent clinical translation. To overcome these limitations, I propose to develop the Biologics Sequential NanoPrecipitation (BioSNaP) process, a novel continuous flow manufacturing process to efficiently encapsulate biologics, including mAbs, into polymeric nanoparticles. BioSNaP represents a fundamental advancement in biologics delivery through several innovations: it operates as a continuous flow process, uses scalable micromixers enabling straightforward industrial scale-up, minimizes the biologic solvent exposure to preserve activity, and uses biocompatible non-ionic triblock copolymers. The resulting core-shell- corona nanoparticles are specifically designed for cellular uptake and endosomal delivery, directly addressing the challenge of intracellular mAb targeting. Our three specific aims will: (1) determine how triblock copolymer architecture influences nanoparticle properties for optimal mAb delivery, (2) optimize BioSNaP process parameters to maximize encapsulation efficiency while preserving mAb activity, and (3) demonstrate therapeutic efficacy of anti-PAR2 mAb nanoparticles in oral cancer pain models. This research is innovative in combining cutting-edge pain biology with advanced nanotechnology to target previously inaccessible intracellular signaling pathways. The work is significant because it will establish BioSNaP as a transformative platform technology for biologics delivery while providing the first effective, non- opioid therapy specifically designed for cancer pain. Success will validate endosomal PAR2 targeting as a therapeutic strategy with broad implications for chronic pain treatment and establish a scalable manufacturing platform applicable across multiple therapeutic areas requiring biologics delivery.