Motivation for the study
Glioblastoma is the most aggressive and lethal brain cancer with an average prognosis of 15 months. Fluorescence-guided surgery (FGS) for glioblastoma was FDA-approved in 2017, while photodynamic therapy (PDT) remains an active area of clinical investigation with very promising results so far. The aim of PDT is to eradicate the invasive cancer cells within 2 cm of the resected area where the glioblastoma most often recurs. However, a significant hurdle of this therapy modality is the limited light penetration depth in brain tissue.
5-aminolevulinic acid metabolized into protoporphyrin IX (PpIX) is photosensitizer that is activated at 635 nm wavelength and currently used for both photodynamic diagnosis and therapy. Benzoporphyrin derivative (BPD) is another photosensitizer that is activated at longer 689 nm wavelength which could lead to deeper tissue penetration. Liposomal formulation of BPD (Visudyne) was FDA-approved in 2001 for treatment of wet age-related macular degeneration and is also being actively studied for oncological indications. This study aimed to compare the penetration depth of 635 nm and 689 nm light between nanoliposomal formulations of PpIX and BPD photosensitizers in rat brains.
Nanoliposomal formulations of BPD (Nal-BPD) and PpIX (Nal-PpIX) were manufactured to improve solubility and bioavailability of the photosensitizers. Capillary tubes filled with 5 µM of Nal-BPD or Nal-PpIX were inserted into the ex vivo brain tissue samples at varying depths (0-2 cm). Brain tissues were then superficially illuminated with 635 nm (PpIX) or 689 nm (BPD) light from a ML6600 laser system. Capillaries were then removed and fluorescence emission recorded to determine the level of photobleaching, which is an indicator of how much light has penetrated into the brain to bleach the photosensitizer.
Significantly higher penetration depth in brain was achieved with 689 nm (NaI-BPD) than with 635 nm (NaI-PpIX). A negligible (<2%) photobleaching of NaI-PpIX was observed at 1 cm depth in brain, while at this depth 27% of Nal-BPD was photobleached and some photobleaching was observed even up to a depth of 2 cm. Higher light fluences improved the penetration depth with both photosensitizers but NaI-BPD (689 nm) had higher photobleaching even when two times smaller fluences were used compared to Nal-PpIX (635 nm). Although the activation wavelengths differ only by 55 nm, there is an appreciable drop in light scattering and absorption by up to 40-50% which can explain the results.
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Predictors and Limitations of the Penetration Depht of Photodynamic Effects in the Rodent Brain
Collin T. Inglut, Brandon Gaitan, Daniel Najafali, Irati Abad Lopez, Nina P. Connolly, Seppo Orsila, Robert Perttilä, Graeme F. Woodworth, Yu Chen, Huang-Chiao Huang
Photochem Photobiol, 2020, 96 (2)
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