Abstract
Fluence rate is an effector of photodynamic therapy (PDT) outcome. Lower light fluence rates can conserve tumor perfusion during some illumination protocols for PDT, but then treatment times are proportionally longer to deliver equivalent fluence. Likewise, higher fluence rates can shorten treatment time but may compromise treatment efficacy by inducing blood flow stasis during illumination. We developed blood-flow-informed PDT (BFI-PDT) to balance these effects. BFI-PDT uses real-time noninvasive monitoring of tumor blood flow to inform selection of irradiance, i.e., incident fluence rate, on the treated surface. BFI-PDT thus aims to conserve tumor perfusion during PDT while minimizing treatment time. Pre-clinical studies in murine tumors of radiation-induced fibrosarcoma (RIF) and a mesothelioma cell line (AB12) show that BFI-PDT preserves tumor blood flow during illumination better than standard PDT with continuous light delivery at high irradiance. Compared to standard high irradiance PDT, BFI-PDT maintains better tumor oxygenation during illumination and increases direct tumor cell kill in a manner consistent with known oxygen dependencies in PDT-mediated cytotoxicity. BFI-PDT promotes vascular shutdown after PDT, thereby depriving remaining tumor cells of oxygen and nutrients. Collectively, these benefits of BFI-PDT produce a significantly better therapeutic outcome than standard high irradiance PDT. Moreover, BFI-PDT requires ~40% less time on average to achieve outcomes that are modestly better than those with standard low irradiance treatment. This contribution introduces BFI-PDT as a platform for personalized light delivery in PDT, documents the design of a clinically-relevant instrument, and establishes the benefits of BFI-PDT with respect to treatment outcome and duration.
Highlights
In photodynamic therapy (PDT), light, photosensitizer and oxygen interact to produce tissue-damaging reactive oxygen species (ROS)
When tumor blood flow recovers after PDT, the surviving treatment-spared tumor cells can proliferate to result in tumor regrowth
Modulation of light delivery improves PDT efficacy compared to standard treatment with continuous high irradiance, while limiting treatment times to less than those needed for continuous illumination at low irradiance. We explore these ideas using two preclinical murine tumor models, radiation-induced fibrosarcoma (RIF) and malignant mesothelioma (AB12)
Summary
In photodynamic therapy (PDT), light, photosensitizer and oxygen interact to produce tissue-damaging reactive oxygen species (ROS). Vascular damage is often beneficial to achieving a complete response, but the timing of vascular damage relative to the period of light delivery is critical [3,4]. Functional deterioration of tumor blood vessels after light delivery is favorable when it deprives remaining tumor cells of oxygen and nutrients. Therapeutic effects can be compromised when vascular damage manifests as temporary ischemia during light delivery; under these circumstances, a resultant decrease in oxygen supply during PDT can reduce. When tumor blood flow recovers after PDT, the surviving treatment-spared tumor cells can proliferate to result in tumor regrowth. For these reasons, the extent and time-course of PDT-induced vascular damage can critically impact therapeutic effect
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