The prognosis for patients with high-grade cerebral glioma is poor. Most treatment failures are due to local recurrence of tumor, indicating that a more aggressive local therapy could be beneficial. Adjuvant treatments such as porphyrin-sensitized photodynamic therapy (PDT) or boron neutron capture therapy (BNCT) have the potential to control local recurrence. The selective tumor uptake of a boronated porphyrin was studied in CBA mice bearing an implanted intracerebral glioma. Biopsy samples of tumor, normal brain, and blood were analyzed by a fluorometric assay following intraperitoneal and intravenous administration of boronated protoporphyrin (BOPP). This compound was selectively localized to tumor at ratios as high as 400:1 relative to normal brain.Confocal laser scanning microscopy of glioma cells in vitro and in vivo showed that BOPP was localized within mitochondria and excluded from the nucleus of these cells. This discrete subcellular localization was confirmed by density gradient ultracentrifugation after homogenization of mouse tumor biopsies. The selective discrete localization of these compounds within the tumor suggests that this compound may be used as a dual PDT/BNCT sensitizer.Primary cerebral tumors are responsible for -2% of all cancer deaths, with =10,000 persons dying per annum in the United States (1). The majority of these deaths are due to the high-grade gliomas-anaplastic astrocytoma and glioblastoma multiforme. At present there is no satisfactory treatment for these tumors. Surgery provides a definitive histological diagnosis and relief of symptoms of raised intracranial pressure. Radiotherapy and adjuvant chemotherapy are of limited value and most studies utilizing these treatments report median survival times of <1 year (1, 2). Most treatment failures are due to local recurrence of the tumor, suggesting that more aggressive local therapy could be beneficial. Two adjuvant therapies with the potential to control local recurrence are photodynamic therapy (PDT) and boron neutron capture therapy (BNCT).PDT relies on the selective uptake or retention of a photosensitizing chemical in the tumor relative to surrounding normal tissue, followed by treatment with light of the appropriate wavelength to activate the photosensitizer (3). The photoactivation of this sensitizer results in generation of a cytotoxic chemical species, probably singlet excited state oxygen, which leads to selective tumor necrosis (3). Photosensitizers that have been used in most clinical and experimental studies to date are hematoporphyrin derivative (HpD) and its enriched commercial preparation Photofrin II (3), both of which have been shown to selectively localize in glioblastoma multiforme (4, 5). Reports of PDT in the treatment of animal (5-7) and human (5, 7-9) gliomas have been encouraging, although the use of a more tumor-selective photosensitizer than HpD or Photofrin II would be desirable.Like PDT, BNCT is based on selective tumor localization of a sensitizing agent, a compound containing 10B atoms, fo...

A novel, sterically hindered ester of 2,4-bis-(a,P-dihydroxyethyl)deuteroporphyrin IX containing four carborane cages is prepared by the reaction of the acid chloride of 1,2-dicarba-closo-dodecaborane-carboxylic acid with the bis-glycol in the presence of 4-dimethylaminopyridine.

The efficacy of binary cancer therapies such as BNCT and PDT depends critically on the subcellular localization site of the sensitizer. This work presents the synthesis and plasma lipoprotein binding properties of the first reported binary conjugate of a boronated porphyrin with a peptide nuclear localization sequence. The porphyrin-NLS conjugate associates in vitro predominantly with low density lipoproteins. Such association provides a potentially selective entry pathway into malignant cells that overexpress the LDL receptor.

Three structurally similar tetraphenylporphyrins bearing polyhedral borane anions have been synthesized and their toxicological profiles obtained in rats. These conjugates were found to have quite different acute toxicities as manifested at the maximum tolerated dose (MTD). When given at the MTD and observed over 28 days, the most acutely toxic porphyrin was found to be devoid of toxicity, as measured by blood chemistry panels. The remaining two less acutely toxic compounds both elicited significant changes, characterized by moderate to severe thrombocytopenia, failure to gain weight normally and changes in liver enzymes indicative of mild hepatotoxicity. All toxic effects were transient, with platelets rebounding to above normal levels at day 28. We conclude that thrombocytopenia is the dose limiting toxicity for boronated porphyrins in mammals and suggest that these effects may be due to the porphyrin, not the borane or carborane.