PDT Dose Parameters Impact Tumoricidal Durability and Cell Death Pathways in a 3D Ovarian Cancer Model

Abstract

The successful implementation of photodynamic therapy (PDT)-based regimens depends on an improved understanding of the dosimetric and biological factors that govern therapeutic variability. Here, the kinetics of tumor destruction and regrowth are characterized by systematically varying benzoporphyrin derivative (BPD)-light combinations to achieve fixed PDT doses (M × J/cm2). Three endpoints were used to evaluate treatment response: 1.) Viability evaluated every 24 hours for 5 days post-PDT; 2.) Photobleaching assessed immediately post-PDT; and 3.) Caspase-3 activation determined 24-hours post-PDT. The specific BPD-light parameters used to construct a given PDT dose significantly impact not only acute cytotoxic efficacy, but also treatment durability. For each dose, PDT with 0.25 μM BPD produces the most significant and sustained reduction in normalized viability compared to 1 μM and 10 μM BPD. Percent photobleaching correlates with normalized viability for a range of PDT doses achieved within BPD concentrations. To produce a cytotoxic response with 10 μM BPD that is comparable to 0.25 μM and 1 μM BPD a reduction in irradiance from 150 mW/cm2 to 0.5 mW/cm2 is required. Activated caspase-3 does not correlate with normalized viability. The parameter-dependent durability of outcomes within fixed PDT doses provides opportunities for treatment customization and improved therapeutic planning.

Impact of treatment response metrics on photodynamic therapy planning and outcomes in a three-dimensional model of ovarian cancer

“…Previous studies from our group have demonstrated that BPD-PDT significantly decreases the size of 3-D OvCa nodules 20 and synergistically enhances carboplatin efficacy. 21 These and other studies 31,59,61,68 suggest a role for 3-D models in improved treatment planning, including for PDT regimens. The myriad of variables that influence PDT outcomes, including the marginal benefit gained from dose escalation, PS concentration, fluence, and the metrics used to evaluate treatment response require further optimization.…”

“…The myriad of variables that influence PDT outcomes, including the marginal benefit gained from dose escalation, PS concentration, fluence, and the metrics used to evaluate treatment response require further optimization. 59 Furthermore, many efforts have been made to standardize treatment response criteria, most notably by the World Health Organization (WHO), the RECIST group, and recently in a study by Wolchok et al 1,4,69 These treatment response criteria have been regularly revised to account for important effects of newer modalities in order to avoid exclusion of otherwise promising regimens from the translational research pipeline. 1,3,70 These concepts related to critical evaluation of treatment response metrics can be translated to HTS platforms as bioengineered 3-D tumor models become increasingly sophisticated and could complement current treatment planning approaches.…”

“…56 Among these, 3-D platforms have emerged as attractive tools for treatment planning because they restore essential biological and structural features of tumors observed in-vivo and enable physiologically relevant, inexpensive, and highly reproducible studies. 5,[57][58][59] We 20,21,31,60-62 and others 18,58,[63][64][65][66][67] have used tumor models that restore critical cues from the extracellular matrix to evaluate and optimize treatments for OvCa and other cancers. Previous studies from our group have demonstrated that BPD-PDT significantly decreases the size of 3-D OvCa nodules 20 and synergistically enhances carboplatin efficacy.…”

Duramycin-porphyrin conjugates for targeting of tumour cells using photodynamic therapy

“…A number of studies in the literature have investigated the effect of PDT on ovarian and pancreatic cancer in a variety of models including cell lines [61], 3D cell culture [62][63][64], transplanted mice [65,66] and Phase I/II human trials [67,68]. A benzoporphyrin derivative (BPD) at 0.25 μM was able to reduce cell viability and volume in the human ovarian carcinoma cell line OVCAR5 and penetrate well through OVCAR5 3D cell culture [62,63].…”

“…A benzoporphyrin derivative (BPD) at 0.25 μM was able to reduce cell viability and volume in the human ovarian carcinoma cell line OVCAR5 and penetrate well through OVCAR5 3D cell culture [62,63]. In another study in which OVCAR5 cells were grown in a culture film a fibre optic delivery system was used where the PS (pheophorbide) and oxygen gas was delivered separately [64].…”