ALA-PDT of glioma cell micro-clusters in BD-IX rat brain

Abstract

A significant contributory factor to the poor prognosis of patients with glioblastoma multiforme is the inability of conventional treatments to eradicate infiltrating glioma cells. A syngeneic rat brain tumor model is used to investigate the effects of aminolevulinic acid (ALA)-mediated photodynamic therapy (PDT) on small clusters of tumor cells sequestered in normal brain.The intrinsic sensitivity of rat glioma cells to PDT was investigated by exposing ALA-incubated cells to a range of radiant exposures and irradiances using 635 nm light. Biodistribution studies were undertaken on tumor-bearing animals in order to determine the tumor selectivity of the photosensitizer following systemic administration (i.p.) of ALA. Effects of ALA-PDT on normal brain and gross tumor were evaluated using histopathology. Effects of PDT on isolated glioma cells in normal brain were investigated by treating animals 48 h after tumor cell implantation: a time when the micro-clusters of cells are protected by an intact blood-brain-barrier (BBB).Rat glioma cells in monolayer are susceptible to ALA-PDT -lower irradiances are more effective than higher ones. Fluorescence microscopy of frozen tissue sections showed that photosensitizer is produced with better than 200:1 tumor-to-normal tissue selectivity following i.p. ALA administration. ALA-PDT resulted in significant damage to both gross tumor and normal brain, however, the treatment failed to prolong survival of animals with newly implanted glioma cells compared to non-treated controls if the drug was delivered either i.p. or directly into the brain. In contrast, animals inoculated with tumor cells preincubated in vitro with ALA showed a significant survival advantage in response to PDT.

Noninvasive fluorescence monitoring for functional assessment of murine glioma treatment.

“…ALA-based PDT is currently under research as an adjuvant therapy for gliomas and has been extensively studied in preclinical models as both a primary and adjuvant therapy [23,25,31,32]. ALA-based PDT has not been shown to eradicate gliomas when used as a primary, single dose therapy in preclinical models whether the treatment is administered when the tumors are very small or after significant progression has taken place [33,34]. Considerable improvement on ALA-PDT efficacy has been realized when it is administered as a primary, metronomic therapy in preclinical rat and rabbit models, although significant technical challenges make this treatment less desirable as standard therapy [31,35].…”