Selective disruption of hte blood-brain barrier by photochemical internalization

Failure to eradicate infiltrating glioma cells using conventional treatment regimens results in tumor recurrence and is responsible for the dismal prognosis of patients with glioblastoma multiforme (GBM). This is due to the fact that migrating glioma cells are protected by the blood-brain barrier (BBB) which prevents the delivery of most anti-cancer agents. The overall objective of this work was to evaluate the ability of photochemical internalization (PCI) to selectively disrupt the BBB in rats. This will permit access of anti-cancer drugs to effectively target infiltrating tumor cells, and potentially improve the treatment effectiveness for malignant gliomas; PCI treatment, coupling the macromolecule Clostridium perfringens (Cl p) epsilon prototoxin with AlPcS2a-photodynamic therapy (PDT), was performed on non-tumor bearing inbred Fischer rats. T2-weighted and T1-weighted post-contrast magnetic resonance imaging (MRI) scans were used to evaluate the extent of BBB disruption which was inferred from treatment-induced edema and contrast volumes; The PCI effect in rat brain was found to be dependent on light fluence, photosensitizer concentration, Cl p prototoxin concentration and administration route. Selective disruption of the BBB by PCI was observed for intraperitoneal administration of 1:100 stock dilutions of Cl p prototoxin and photosensitizer concentrations and light fluences of 1 mg/kg and 1 J respectively. Single modality treatments consisting of PDT or Cl p resulted in only minimal damage to the BBB; PCI was found to be highly effective for inducing selective and localized disruption of the BBB. The extent of BBB opening peaked on day 3 and was completed restored by day 18 after PCI