Photodynamic therapy of tumors with controlled delivery of photosensitizer hematoporphyrin

Taranets L.1, Chepurna O.2, Cholin V.2, Gamaleia N.F.1

L. Taranets1, O. Chepurna2, V. Cholin2, N. Gamaleia1

1R.E. Kavetsky Institute of Experimental Pathology, Oncology and Radiobiology, NAS of Ukraine, Kyiv, Ukraine

2SME “Fotonika Plus”, Cherkasy, Ukraine

Introduction: Photodynamic therapy (PDT) is a tumor treatment modality, which is grounded on application of a photosensitizing drug (PS) and light of appropriate wavelength which activates PS leading to tumor cell destruction. To enhance PDT antitumor effect, a number of approaches are now under investigation, including elaboration of targeting techniques, such as use of metal or polymeric nanoparticles, and development of novel regimens of light and PS delivery. One of the promising approaches, which we exploited in this study, may be called metronomic or chronic PDT. It is based on continuous low level photoirradiation of a tumor and delivery of PS over extended period of time — from several hours to a few days. Aim: To establish a chronic regimen of PDT, providing controlled release and prolonged accumulation of PS in tumors by employment of natural polymeric materials with simultaneous low-intensity light illumination, and to evaluate PDT effects on murine Lewis lung carcinoma (LLC) tumor growth and metastatic dissemination. Methods: C57Bl6 female mice (6 per qroup) with intracutaneous transplanted LLC were used. A special photodiode panel was developed for continuous low-intensity blue-light irradiation of tumor-bearing animals. Photosensitizer hematoporphyrin was loaded into 4% hyaluronic acid hydrogel which was inoculated intratumorally twice: on the 1st and 3rd days of light treatment. On the whole, mice were illuminated for 6 days. Before the start of experiments, kinetics of hematoporphyrin release from hyaluronic acid gel, introduced to mice, was determined by recording its fluorescence in tumors for 5 days using USB 4000 fiber optic spectrometer (“Ocean Optics”, USA). All procedures involving animals were performed in accordance with the Institutional Animal Care and Use Committee. Results: Hyaluronic acid hydrogel during three days provided controlled release and higher accumulation (up to 7 times) of hematoporphyrin compared to free hematoporphyrin. This enabled us to use the gel-carrier for controlled release of hematoporphyrin in PDT experiments. For accomplishment of this chronic PDT, six-day illumination of LLC-bearing mice with hematoporhyrin-containing hydrogel was carried out. Remarkable inhibition up to 80% of tumor growth was observed in a group of treated animals compared to untreated ones. Moreover, the number of lung metastases in treated animals was 24-fold lower than in control group, indicating clear antimetastatic effect of chronic PDT. Conclusion: A feasibility of controlled continuous release of hematoporphyrin photosensitizer from hyaluronic acid hydrogel was demonstrated. Six-day blue-light low-level illumination of tumors concomitant to controlled hematoporphyrin release resulted in remarkable antitumor and antimetastatic effect, indicating significance of this approach to PDT of tumors.

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