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Chronobiological approaches to antiangiogenic photodynamic therapy of tumors: the first experimental evaluation
N F Gamaleia1, I A Lisnyak, E D Shishko
1Kavetsky Institute for Experimental Pathology, Oncology and Radiobiology NAS of Ukraine, Kiev 03022, Ukraine. gamaleia@onconet.kiev.ua
Unlabelled:
In research of the last decade, rhythmic (circadian) variations of vascular endothelial growth factor (VEGF) production by tumors were discovered. The present paper authors have earlier synthesized and characterized a new derivative photosensitizer - an immunoconjugate of hematoporphyrin with antiVEGF antibodies.
Aim:
To elaborate and to test a novel modification of the photodynamic therapy of tumors (PDT) method, founding upon a timed introduction of the immunoconjugated photosensitizer to tumor-bearing animals, so that this coincides with a maximum content of VEGF in tumor tissues.
Methods:
Circadian variations of VEGF contents in murine transplanted tumors, Lewis lung carcinoma and sarcoma 180, were determined by ELISA method. Immunoconjugated photosensitizer concentrations in tumors were estimated by spectrofluorometry. Photoirradiation of the tumors was carried out with a red light (wavelength of 635 nm) from a semiconductor laser. Light doses were chosen, calculating on a partial inhibition of tumor growth, in order that a dependence of PDT efficiency on a daily time-moment (circadian rhythm phase) of the treatment could be observed distinctly.
Results:
Circadian variations of the VEGF levels in Lewis lung carcinoma and sarcoma 180 were demonstrated with the maximum at 14:00 h and the minimum at 02:00 h. Intra-abdominal introduction into tumor-bearing mice of the immunoconjugated photosensitizer resulted in a greater accumulation of the immunoconjugate in tumors at 14:00 h than at 02:00 h. Laser irradiation of carcinomas and sarcomas at 14:00 h or 02:00 h after introduction of the immunoconjugated photosensitizer to mice the day before at the same time points, induced a significantly enhanced inhibition of tumor growth in animals treated at day-time versus those treated at night-time.
Conclusion:
The obtained results justify further attempts to transfer principles of tumor chronochemotherapy onto photodynamic therapy.
Insights
This study shows that timing photodynamic therapy (PDT) to match peak vascular endothelial growth factor (VEGF) levels in tumors enhances treatment effectiveness. Optimizing PDT timing improves tumor growth inhibition in mice.
Area of Science:
- Oncology
- Pharmacology
- Chronobiology
Background:
- Tumor production of vascular endothelial growth factor (VEGF) exhibits circadian variations.
- An immunoconjugate of hematoporphyrin with anti-VEGF antibodies was developed as a photosensitizer.
Purpose of the Study:
- To develop and test a modified photodynamic therapy (PDT) approach.
- Timed administration of an immunoconjugated photosensitizer to coincide with maximal VEGF levels in tumors.
Main Methods:
- Quantified circadian VEGF variations in murine tumors (Lewis lung carcinoma, sarcoma 180) using ELISA.
- Measured immunoconjugated photosensitizer levels in tumors via spectrofluorometry.
- Administered red light (635 nm) laser irradiation, with doses chosen to observe PDT efficacy dependence on circadian phase.
Main Results:
- VEGF levels in tumors peaked at 14:00 h and were lowest at 02:00 h.
- Higher accumulation of the immunoconjugated photosensitizer was observed in tumors at 14:00 h compared to 02:00 h.
- Day-time PDT (14:00 h) resulted in significantly greater tumor growth inhibition than night-time PDT (02:00 h).
Conclusions:
- Circadian-timed photodynamic therapy shows promise for enhanced tumor treatment.
- The findings support the transfer of chronochemotherapy principles to photodynamic therapy.
