Targeting Fluid Stress-induced Chemoresistance in a 3D Carcinomatosis Perfusion Model Using Mechanism-based Photo-immunoconjugate Nanoparticles

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ABSTRACT The prognosis for patients with advanced stage and recurrent ovarian cancer has remained dismal for decades. The poor response rates result in part from resistance to chemotherapy, particularly platinum- and taxane-based agents. Ovarian cancer often metastasizes via transcoelomic routes along currents of ascitic fluid in the peritoneal cavity. We have engineered a 3D adherent perfusion model to mimic ovarian nodules that stud peritoneal surfaces and recapitulate resistant disease, thereby providing a unique platform to develop targeted therapies. Our studies showed that physiologically relevant fluid shear stress (FSS) induces a pro- metastatic phenotype and confers resistance to platinum agents. Photoimmunotherapy (PIT) has shown promise in selectively imaging and treating disseminated tumors, and it can resensitize chemoresistant cancer cells to platinum agents. However, the high thresholds of intracellular photoimmunoconjugate required for cell death have hindered the effectiveness of PIT in physiologically relevant models. Therefore, the main goal of this proposal is to develop a multi-purpose nanoplatform that breaks the selectivity-uptake trade-off of photoimmunoconjugates and enables multi-tier cancer targeting under peritoneal FSS. We have recently shown that successful conjugation of photoimmunoconjugates onto nanoparticles can effectively enhance intratumoral photoimmunoconjugate delivery and improve PIT outcomes in mice. We hypothesize that nanoscale engineering enables high-payload co-delivery of photoimmunoconjugate and chemotherapy in a manner that is safe and efficacious in overcoming FSS-induced chemoresistance. This approach will significantly enhance the therapeutic index of platinum agents for ovarian cancer patients. In Aim 1, a panel of photoimmunoconjugate-nanoconstructs (PICNC) will be developed to target biomarkers altered by FSS in a 3D perfusion model of ovarian cancer. In Aim 2, we will assess the effects on chemosensitization, T cell sparing, and destruction of immune supporting tumor-associated macrophages following PICNC-PIT under FSS in 3D perfusion models. In Aim 3, to improve the safety and consistency of the treatment, we will develop image- guided strategies to inform the timing and dosing of PICNC-PIT in mouse models. In Aim 4, the anti-tumor efficacy of PICNC-PIT will be evaluated in cell line-based syngeneic (immunocompetent) and xenograft mouse models, as well as PDX models, for ovarian cancer. The PIs envision a simple and feasible modification to the standard treatment framework, where PICNC will be delivered intraperitoneally after surgical debulking, and activated by light, triggering PIT and releasing chemotherapy. The knowledge gained could play a transformative role in the development of improved therapeutic regimens tailored to the molecular profile of disseminated tumors in individual patients. To accomplish these aims, we will deploy our multi-disciplinary team of nanoparticle engineering, 3D tumor perfusion model, cancer biology, tumor immunology, biostatistics, and gynecologic oncology experts to examine the impact of our technology on ovarian cancer treatment.