Maximum and safe removal of malignant gliomas is no easy, and various modalities are used, including photodynamic diagnosis (PDD) using 5-aminolevulinic acid (5-ALA). Fluorescence guided surgery (Fluorescence Guided Surgery: FGS) using 5-ALA is highly useful for malignant gliomas, because it selectively accumulates in the tumor cells and the presence of the tumor cells can be demonstrated in a very simple and real-time manner by the assessment of emitting fluorescence of its metabolite Protoporphyrin IX (PpIX). Recently, the mechanism of PpIX accumulation has been elucidated, and in the future, research to increase the effects of PDD and PDT by increasing the efficiency of accumulation is expected. On the other hand, 5-ALA PDD is not useful in lower-grade gliomas due to problems including false positives and false negatives, and its use requires sufficient knowledge and experience. In order to overcome these problems, PpIX fluorescence quantification using spectral analysis have been developed, and further development of these techniques is expected. Recently, it was shown that PDD is possible using talaporfin sodium, which has been approved as a photodynamic therapy (PDT) treatment in Japan, and more effective surgical treatment will be developed by combining PDD and PDT using talaporfin sodium in the future.
As for photobiomodulation therapy, also known as low-reactive level laser therapy (LLLT), various biological effects have been reported, including the promotion of wound healing and alleviation of inflammation. In this article, we will look back on previous reports on the mechanisms of photobiomodulation therapy and describe the clinical effects that can be achieved, with a focus on plastic surgery and dermatology.
Extension of diagnostic depth in 5-aminolevulinic acid-based photodynamic diagnosis (ALA-PDD) for bladder cancer was investigated by selecting the wavelength of the excitation light. Numerical calculation based on the light attenuation in bladder tissue and the absorption coefficient of PpIX showed that the fluorescence intensity with the green excitation light of 505 nm wavelength was highest for a tumor located at a depth of 0.9 mm or deeper. The diagnostic depth in an extracted porcine bladder tissue using an excitation wavelength of 505 nm was compared with that using the blue-violet excitation light of 405 nm wavelength that is currently used in PDD. The fluorescence intensity at the excitation wavelength of 505 nm was higher for a tumor located at a depth of 0.8 mm or deeper. These results indicate that an extension of the diagnostic depth is achieved with the excitation wavelength of 505 nm.
Photodynamic therapy is expected to be a minimally invasive treatment for cancer. Activatable photosensitizers have attracted considerable attention as one of the strategies for improving the minimally invasive properties. The activatable photosensitizer is in the photo-inactive (OFF) state in normal tissues; however, it is in the photoactive (ON) state in the tumor tissue. In this review, low pH- and sono-activatable photosensitizers are introduced.
Theranostics combining cancer diagnosis and cancer treatment is attracting attention as a field of cancer medicine. Porphyrin derivatives are used as photosensitizing molecules in cancer treatment (photodynamic therapy, PDT) and cancer diagnosis (photodynamic diagnosis, PDD). In the previous report, we developed glycosylated 5,10,15,20-tetrakis(pentafluorophenyl)porphyrin (TFPP) zinc (Zn and 62Zn) complexes as a PDT photosensitizer with positron emission tomography (PET)-tracking functionality. These complexes displayed a high cellular uptake amount, efficient photocytotoxicity, and promising PDT effect. However, they have the disadvantage of slow tumor accumulation. In this study, we synthesized TFPP zinc complexes (Zn-P) bearing two kinds of substituent groups, namely a glucose (Glc) group to improve tissue selectivity and a 2-hydroxyethanethiol (ME) group to enhance cell penetration for theranostics. We show that Zn-P(Glc)2(ME)2 increased the efficiency of singlet oxygen generation under the standard condition of this photocytotoxicity test. The photocytotoxicity of Zn-P(Glc)2(ME)2 was evaluated in HeLa cells, RGK-1 gastric carcinoma mucosal cells, and two human glioblastoma cells (U87 and T98G) at coincubation for 8 hours. Zn-P(Glc)2(ME)2 was found to exhibit photocytotoxicity in a short incubation time (8 hours).
The main tumor killing mechanism of photodynamic therapy (PDT) is apoptosis and necrosis of tumor cells after generation of singlet oxygen species and this effect is mainly dependent on the depth of laser irradiation penetration. PDT using talaporfin sodium as a photosensitizer has already been applied clinically for high-grade glioma treatment and improvement of its further therapeutic effect is highly desired. Recently, basic research and preclinical evaluation of PDT to improve its effect while minimizing surrounding normal tissue damage has been performed, since simply raising laser power to improve PDT effect is not realistic in view of damage to surrounding normal tissue.
The main countermeasure might be the increase in accumulation of already known photosensitizers in tumor tissue. However, the search for mechanisms of tumor-specific accumulation of the photosensitizers and their interactions with key molecules of tumor cells is still underway. Using next generation photosensitizers and combination with immunotherapy, as well as increasing the tumor accumulation of existing photosensitizers, are important issues regarding basic research on and preclinical evaluation of PDT, and application of such new findings will result in the increase of the clinical role of PDT.
Photodynamic therapy (PDT) was approved to be covered by health insurance in Japan on 2013, as an additional intraoperative local treatment for invasive tumor cells after maximum safe resection of the primary malignant brain tumors. This review provides an overview of the clinical trials conducted over the last 40 years, illustrating how PDT is applied in the clinical practice in the world. Furthermore, examples from ongoing clinical trials are presented, and the author proposed the future perspectives of PDT for malignant brain tumors.
Hydrophobic and rigid molecular structure is required for efficient generation of reactive oxygen species upon photoirradiation with longer wavelength region. Lacks in water-solubility of the photosensitizers frequently obstacle in practical use. In this article, we introduce our attempts to solubilize by conjugation of photosensitizer with water-soluble polymer.
Photodynamic therapy, a promising less invasive cancer treatment, can be improved by the development of cancer-selective and effective photosensitizers. In general, porphyrin photosensitizers produce singlet oxygen to damage biomolecules in cancer cell. However, hypoxic environment in tumor may inhibit the activity of photosensitizers. The purpose of this review is the introduction of porphyrin phosphorus(V) complexes, which can photosensitize damage of DNA, protein (including enzyme), folic acid, and nicotinamide adenine dinucleotide through electron transfer. Furthermore, a phosphorus(V) porphyrin demonstrated cancer-selective photocytotoxicity and a tumor-selectivity in an animal experiment.
Photosensitizers have been widely used for diagnosis and therapy for malignant tumors in clinical setting. Porphyrin compounds have been known as not only a photosensitizer but also radiosensitizer. In clinical neurosurgery, 5-aminolevulinic acid (ALA) is available for intraoperative fluorescence marker for malignant gliomas. Recently, combination therapy using 5-ALA and ionizing irradiation for malignant tumors have been investigated. 5-ALA can highly accumulate protoporphyrin IX (PpIX) in mitochondria of tumor cells via the heme biosynthesis. PpIX can induce oxidative stress on mitochondria of tumor cells under the ionizing irradiation exposure. In this review, we discuss radiotherapy using 5-ALA, so called radio-dynamic therapy, for malignant tumors.
Malignant glioma is the adult brain tumor with the poorest prognosis, and its median overall survival is around one year. In the treatment of this disease, the surgical removal rate has the most significant influence on the prognosis, which means that adjuvant therapy such as radiation or chemotherapy has not exerted sufficient effect. Therefore it is indispensable to develop totally different ideas and methods. Among the new attempts, photodynamic therapy (PDT) has been a unique presence. We focused on this and investigated its effect in vitro on PDT using 5-aminolevulinic acid (ALA) as a photosensitizer. In fact, in 2014, PDT was approved for glioblastoma treatment in Japan by the results of clinical trial by the Japanese research group. However, the major problems of PDT are that penetration depth of the light in brain tissue is limited and that craniotomy is necessary. To overcome issue of penetration depth, ultrasound has been expected as alternative energy source to excite the photosensitizer. Several research have shown that various photosensitizers are excited by ultrasound as well. This is so called sonodynamic therapy (SDT). Several studies have confirmed cytotoxic effect of SDT, although its mechanism has not been elucidated. Furthermore, the innovation of transcranial focused ultrasound presented the possibility to avoid craniotomy in SDT. Although there are a lot of problems to be solved, we expect that SDT can be a novel therapy. We think advantages of SDT are low toxic and minimally invasive profiles, hence sustainable treatment. If it is possible to control tumor growth by repeating SDT, we believe there is a possibility of leading to a paradigm shift of treatment of malignant gliomas.