It is widely known that thermal neutron beams for nuclear reactors, cyclotron or synchrotron radiation technology have made remarkable progress in the last 50 years, and that they are being constructed all over Japan and used for cancer irradiation treatment. Since the problems of cancer specificity and cancer recurrence have not been sufficiently resolved so far, synchrotron irradiation is not yet fully adopted as a new cancer treatment method. In order to solve the problem of cancer specificity and cancer recurrence, we applied it as a means to utilize and solve the cancer selectivity of porphyrin rings and evaluated the sensitization of these radiation sources.

¹⁰B decarbonate, a scavenger for thermal neutrons, and a derivative of porphyrin (Compound-B: CB) of Chlorin-E6 derivative were also used as sensitizers for these synchrotron and laser beams.

First, the photosensitizing efficiency of CB in Photodynamic Therapy (PDT) was compared with that of standard methylene blue (MB) and Laserfrin (Talaporfin Sodium) for clinical use. As a result, it was found that approximately 12–35% of photosensitivity can be expected compared to MB and conventional clinical photosensitizers.

Next, in order to verify the sensitization of CB to thermal neutron beams, proton beams, and carbon beam irradiation, C6 brain tumor cultured cells or transplanted mice to which CB was administered were used, and thermal neutron beams were used jointly in Research Reactor Institute of Kyoto University (KUR) and carbon beam microbeams were performed at the Atomic Energy Agency Takasaki Quantum Application of the research institute in vivo system, respectively. Furthermore, synchrotron proton beams were performed at the Wakasa Wan Research Center, the carbon beams were performed at National Institute of Radiological Sciences, and relatively higher-energy X-rays (>75 keV) were examined at the RI Center of the University of Fukui School of Medicine in vivo system, after application for joint use machine time, and the irradiation effects were examined each time, respectively.

As a result, the sensitization effect of CB was confirmed under different irradiation sources and conditions. Furthermore, a synergistic anti-tumor effect was obtained by the additional treatment of combined laser irradiation of photodynamic therapy (PDT), which has been continuously studied. Tumor recurrence could be effectively prevented, and in some cases, the tumors regressed and disappeared.

Therefore, the dual-use sensitizer molecule CB solves the problem of cancer recurrence through its cancer specificity, its sensitizing effect not only on thermal neutron beams but also on synchrotron and cyclotron radiation such as proton beams and carbon beams, and the synergistic effect of combined treatment with PDT.

As a result, the application of CB can be fully adopted as a new coping method (or therapeutic method) for synchrotron radiation to be effective. As a method of realization, it is conceivable to carry a compact semiconductor laser to a treatment facility for BNCT, proton beams, carbon beams, and use PDT in combination after the irradiations.

This review describes conventional photodynamic therapy (PDT) agents, protein-inactivation studies using photosensitizers, and our recent development of the intracellular molecular-targeted photodynamic therapy (IMT-PDT). We have developed a ligand-directed photosensitizer (LDPS) that combines the glucose transporter 1 (GLUT1), a ligand cancer-specific protein, with di-iodinated BODIPY, a cell membrane-permeable organic photosensitizer. The LDPS induced its anti-tumor effect through GLUT1-specific oxidative photoinactivation. This study demonstrates the potential of novel molecular-targeted PDT, a promising technology that can control the selective inactivation of tumor-specific proteins by light in a spatio-temporal manner.

Improving cancer selectivity of photosensitizers is an important issue in developing photodynamic therapy and diagnosis, and an extensive investigation on activatable photosensitizers, as a solution to improve cancer selectivity, have been carried out. The results revealed that the quantum yield of conventional activatable photosensitizers could be controlled by varying the quenching efficiency of the excited state. However, researches on photosensitizers that can control light absorption efficiency have attracted much attention recently. This review presents an overview on the recent activatable photosensitizers.

Photodynamic therapy (PDT) is a non-invasive cancer treatment method. Much effort has been devoted to the development of tumor-accumulating photosensitizers to enhance PDT efficacy. Glycoconjugated photosensitizers seem to be promising candidates as the carbohydrate moieties act as tumor-accumulating devises and are highly hydrophilic elements. This review briefly introduces recent studies involving synthetic glycoconjugated photosensitizers fabricated using click chemistry methods such as Huisgen 1,3-dipolar cycloaddition and thiol-para-fluoro click reactions.

A long-standing goal in the field of cancer therapy is the ability to treat tumors noninvasively. Photodynamic therapy (PDT) has attracted attention as a less invasive method for treating cancer. Thus, we focused on the sugar conjugation of photosensitizers (chlorin, C₆₀ etc.), mainly to improve their biocompatibility and tumor selectivity. We have developed sugar (glucose, mannose, maltotriose etc.)-conjugated chlorins as third-generation photosensitizers for PDT and glucose conjugated chlorin e6 (G-Ce6), especially, shows excellent PDT effects in vitro and in vivo. In addition, excellent PDT effects have been observed in dog cancer models.

A major photosensitizer in urology is protoporphyrin IX (PpIX), which is induced by 5-aminolevulinic acid (5-ALA) and used for photodynamic diagnosis (PDD) of non-muscle invasive bladder cancer (NMIBC). In recent years, evidence for the therapeutic efficacy of PDD-assisted transurethral resection of bladder tumor (TURBT) has also been reported. In addition, as robotic-assisted devices equipped with near-infrared fluorescence imaging systems become more widely used, it is expected that the application and development of photosensitizers that emit near-infrared fluorescence, including indocyanine green (ICG), which is used for intraoperative fluorescence imaging of blood vessels and lymph vessels, will expand. Finally, sunitinib, which has long been used as a tyrosine kinase inhibitor (TKI) for renal cancer, has also been shown to have photosensitizer properties. This article outlines the current status of 5-ALA and ICG and the efficacy of sunitinib against human renal cancer cell lines in vitro.

Photosensitizers, diethoxyP(V)tetrakis(4-octyloxyphenyl)porphyrin (EtP(V)TOPP) and diethoxyP(V)tetrakis(4-butoxyphenyl)porphyrin (EtP(V)TBPP), were synthesized. Singlet oxygen (¹O₂) generating activity of these P(V)porphyrins in ethanol was confirmed. Redox potential measurement demonstrated their tryptophan oxidation ability through photoinduced electron transfer from the thermodynamic point of view. EtP(V)TOPP and EtP(V)TBPP form J-aggregates in an aqueous solution, resulting in the suppression of their photodynamic activity. In the presence of human serum albumin (HSA), their aggregation states were resolved. EtP(V)TBPP effectively photosensitized HSA oxidation through ¹O₂ generation and electron transfer, whereas EtP(V)TOPP barely induced HSA photodamage. Since EtP(V)TOPP has relatively long alkoxyl chain, its steric hindrance possibly inhibits the approach to the tryptophan residue of HSA. In conclusion, the photodynamic activity of P(V)porphyrin through the ¹O₂ generation and the electron transfer mechanism can be controlled by the self-aggregation and dissociation.

A drawback to carrier-based cytosolic delivery of biomolecules and drugs is that endosomal entrapment of cargoes (biomolecules and drugs) often occurs. Photochemical internalization (PCI) can be used to solve this shortcoming. In PCI, a photosensitizer is encapsulated in the endosome together with the cargo. The photosensitizer can then be photoirradiated to induce endosomal escape and cytoplasmic dispersion of the cargo. This method can deliver the cargo into the cytoplasm with almost no damage to the cells by irradiating with minimum necessary light. However, side effects including cytotoxicity are observed with increasing light intensity. Our recent results suggest that the cause of side effects is “photosensitizers adsorbed on the cell surface,” which are not necessary for PCI. In this study, prior to photoirradiation, we attempted to remove or inactivate photosensitizers on the cell surface by washing the cells, treating with serum, and quenching with trypan blue. We investigated the efficacy of these treatments at reducing the side effects of PCI. We used PCI-based photoinduced cytosolic dispersion of RNA (PCDR) to verify reductions in side effects.

Most photosensitizers for photodynamic therapy have a highly planar structure to absorb longer wavelength light. This leads to water insolubility and aggregation tendency to degrade the availability in photodynamic therapy. A drug delivery system is a powerful tool for overcoming such difficulties. In this article, pH-responsive block copolymer, P(BnA-co-DMAEA)-b-PPEGA, has been synthesized from benzyl acrylate (BnA), 2-dimethylaminoethyl acrylate (DMAEA), and polyethylene glycol monomethyl ether acrylate (PEGA) via RAFT polymerization. Polymer micelles were prepared by dialysis method applying to the resulting block copolymer. DLS confirmed the pH-responsive nature of the resulting polymer micelles. Zinc phthalocyanine (ZnPc) was successfully incorporated into the polymer micelles. The photocytotoxicity of ZnPc-loaded polymer micelles was examined in RGK-1 cells. The results indicate the importance of the pH-responsive unit on the polymer micelles as a photosensitizer carrier.