Continuous flow manufacturing of antibody-loaded nanoparticles for non-opioid oral cancer pain therapy
openNIBIB - National Institute of Biomedical Imaging and Bioengineering
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.
Up to $187K
health research