Selective tumor uptake of a boronated porphyrin in an animal model of cerebral glioma.

Abstract

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...

Targeted intracellular delivery of photosensitizers to enhance photodynamic efficiency

“…37,38 Long chains and high concentrations appear to predispose PS to lysosomal localization, whereas PS with short chains accumulate predominantly in mitochondria. 39 Mitochondria quite specifically accumulate sulfonated aluminium chlorophthalocyanine, 40 boronated porphyrin, 41 the lipophilic cationic porphyrin derivative 5,10,15,20-tetrakis(1-decylpyridinium-4-yl)-21H.23H-porphine tetrabromide 42 and lipophilic cationic phthalocyanines, of which the most efficient is 2,9,16,23-tetrakis(hexyldimethylammonio) zinc(II) phthalocyanine tetramethylsulphate. 43 Protoporphyrin IX, formed subsequent to the introduction of 5-aminolevulinic acid, localizes both in the endoplasmic reticulum (ER) and mitochondria of melanoma cells, whereas exogenously added protoporphyrin IX is found in lysosomes/endosomes (aggregated PS) or in the outer membrane (monomeric form).…”

Evaluation of porphyrin C analogues for photodynamic therapy of cerebral glioma

“…Such intracellular redistribution has been reported with other porphyrin photosensitisers (Schneckenburger et al, 1988 Kaye et al, 1985). However the demonstration of the extremely high tumour to brain ratios that can be achieved using other porphyrin sensitisers (Hill et al, 1992b) suggests that other factors apart from just BBB breakdown must be critical in mediating uptake. Kinetic studies showed that peak drug uptake levels in tumour occurred at 9 and 6 h after injection for porphyrins 7 and 8 respectively, with maximal tumour to normal brain ratios of 15:1 and 13:1 respectively.…”

Inhibition of human pancreatic cancer growth in nude mice by boron neutron capture therapy

“…In a study of BPA distribution in a rat glioblastoma, Coderre et al (1990Coderre et al ( , 1994) demonstrated a tumour-blood ratio of 4:1 compared with 0.7:1 for BSH. Ratios as high as 400:1 in tumour compared with normal brain were obtained 48 h after intravenous injection of 100 mg kg-' BOPP, while at the same time point, the tumour-blood ratio was only 11:1 (Hill et al, 1992;Malleshe et al, 1993). Damage to brain endothelium may present particular problems, if reactor exposures take place when blood boron levels are high .…”