|Hiramatsu, Ryo -|
|Kawabata, Shinji -|
|Miyatake, Shin-Ichi -|
|Kuroiwa, Toshihiko -|
|Vicente, M. Graca H. -|
Submitted to: Lasers in Surgery and Medicine
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: November 16, 2010
Publication Date: January 19, 2011
Citation: Hiramatsu, R., Kawabata, S., Miyatake, S., Kuroiwa, T., Vicente, M., Easson, M.W. 2011. Application of an octa-anionic 5,10,15,20-tetra[3,5-(nido-carboranylmethyl)phenyl]porphyrin (H2OCP) as dual sensitizer for BNCT and PDT. Lasers in Surgery and Medicine. 43:52-58. Interpretive Summary: The prognosis for patients with malignant glioma is poor. The median survival for glioblastoma (GB) patients is 2 years after the initial diagnosis with the most recurrence being at the site of the original tumor, indicating that a more aggressive local therapy is required to eradicate the unresectable tumor cells invading the adjacent normal brain. Two adjuvant therapies with the potential to destroy these cells are photodynamic therapy (PDT) and boron neutron capture therapy (BNCT). Both are bimodal therapies, the individual components of which are non-toxic in isolation but tumoricidal in combination. Boronated porphyrin derivatives have emerged as promising dual sensitizers for both PDT and BNCT, because of their known selectivity for tumor cells, usually low dark toxicity and desirable photophysical properties, including strong light absorptions in the visible and near infrared regions, ability for generation of singlet oxygen upon light activation, and fluorescence properties. Several boronated porphyrins have been synthesized and evaluated in cellular and animal studies; among these the boronated porphyrins BOPP and CuTCPH both containing four boron clusters, have been extensively investigated. The results from these studies show that this type of boronated porphyrin can selectively deliver therapeutic concentrations of boron into tumor cells with low dark cytotoxicity and long retention times within tumors. Porphyrins of high boron content (with up to 16 boron clusters) have been reported and this type of compound could potentially deliver higher amounts of boron to tumors at the same drug dose. In particular, the synthesis and cellular evaluation of the octa-anionic 5,10,15,20-tetra[3,5-(nido-carboranylmethyl)phenyl]porphyrin (H2OCP), containing eight boron clusters have been reported by one of us. These studies showed that H2OCP delivers high amount of boron to human glioma T98G cells with low dark cytotoxicity and therefore has promise for application in BNCT as a boron delivery agent. In this study, we evaluated the potential of H2OCP as dual sensitizer, in the PDT and BNCT of F98 Rat glioma cells. Although several boronated porphyrins have been proposed as boron delivery agents for BNCT, only a few have been investigated as dual sensitizers for both the BNCT and PDT treatment of tumors.
Technical Abstract: The applications of the octa-anionic 5,10,15,20-tetra[3,5-(nidocarboranylmethyl) phenyl]porphyrin (H2OCP) as a boron delivery agent in boron neutron capture therapy (BNCT) and a photosensitizer in photodynamic therapy (PDT) have been investigated. Using F98 Rat glioma cells, we evaluated the cytotoxicity of H2OCP with a colony-forming assay, examined its time-dependent cellular uptake, and compared the cellular uptake/clearance of boron after exposure over time using H2OCP in conjunction with boronophenylalanine (BPA) and sodium borocaptate (BSH), which are currently used in BNCT clinical studies as boron delivery agents. The cell boron concentrations were analyzed quantitatively using inductively coupled plasma atomic emission spectrometry (ICP-AES). Fluorescence microscopy experiments were also performed to visualize the porphyrin within the cells. Our results show that the cell surviving fraction following light irradiation (18 J/cm2 18 h after exposure to 10 µg 10B/ml H2OCP) was 0.05 and that H2OCP accumulated within cells to a greater extent than BPA, and was retained inside the cells as much as BSH.