Abstract
An outstanding problem in cancer therapy is the battle against treatment-resistant disease. This is especially true for ovarian cancer, where the majority of patients eventually succumb to treatment-resistant metastatic carcinomatosis. Limited perfusion and diffusion, acidosis, and hypoxia play major roles in the development of resistance to the majority of front-line therapeutic regimens. To overcome these limitations and eliminate otherwise spared cancer cells, we utilized the cationic photosensitizer EtNBS to treat hypoxic regions deep inside in vitro 3D models of metastatic ovarian cancer. Unlike standard regimens that fail to penetrate beyond ∼150 µm, EtNBS was found to not only penetrate throughout the entirety of large (>200 µm) avascular nodules, but also concentrate into the nodules' acidic and hypoxic cores. Photodynamic therapy with EtNBS was observed to be highly effective against these hypoxic regions even at low therapeutic doses, and was capable of destroying both normoxic and hypoxic regions at higher treatment levels. Imaging studies utilizing multiphoton and confocal microscopies, as well as time-lapse optical coherence tomography (TL-OCT), revealed an inside-out pattern of cell death, with apoptosis being the primary mechanism of cell killing. Critically, EtNBS-based photodynamic therapy was found to be effective against the model tumor nodules even under severe hypoxia. The inherent ability of EtNBS photodynamic therapy to impart cytotoxicity across a wide range of tumoral oxygenation levels indicates its potential to eliminate treatment-resistant cell populations.
Highlights
The last several decades have seen countless advances in our ability to detect and treat cancer
Ovarian cancer (OvCa) cells were cultured on the surface of an extracellular matrix (ECM)-rich gel bed (Matrigel), and developed into nodules varying in sizes over the course of days
As therapies for OvCa have developed from many careful clinical trials, the mainstay of future OvCa management will likely rest on the three major therapeutic options used today: surgery, platin therapeutics, and taxol-based treatment regimens
Summary
The last several decades have seen countless advances in our ability to detect and treat cancer. The mortality associated with certain cancers, such as ovarian, remains unacceptably high. Ovarian cancer (OvCa) represents a major therapeutic challenge, as tumors too often evade front-line treatments, causing the majority of patients to eventually succumb to treatment-resistant disease. OvCa is typically diagnosed at an advanced stage, where patients present with disseminated metastatic lesions coating the surfaces of the peritoneal cavity. It is impossible to remove all lesions surgically, leaving behind significant sub-millimeter sized residual tumors. Resistant OvCa face a poor quality of life and a dismal five-year survival rate of 30% [1]
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