Disruption of the blood-brain barrier following ALA-mediated photodynamic therapy.
OBJECTIVE
Photodynamic therapy (PDT) is a local antineoplastic treatment with the potential for tumor cell specificity. PDT using either hematoporphyrin derivatives or 5-aminolevulinic acid (ALA) has been reported to induce brain edema indicating disruption of the blood-brain barrier (BBB). We have evaluated the ability of ALA-mediated PDT to open the BBB in rats. This will permit access of chemotherapeutic agents to brain tumor cells remaining in the resection cavity wall, but limit their penetration into normal brain remote from the site of illumination.


METHODS
ALA-PDT was performed on non-tumor bearing inbred Fischer rats at increasing fluence levels. Contrast T(1)-weighted high field (3 T) magnetic resonance imaging (MRI) scans were used to monitor the degree of BBB disruption which could be inferred from the intensity and volume of the contrast agent visualized.


RESULTS
PDT at increasing fluence levels between 9 and 26 J demonstrated an increasing contrast flow rate. A similar increased contrast volume was observed with increasing fluence rates. The BBB was found to be disrupted 2 hours following PDT and 80-100% restored 72 hours later at the lowest fluence level. No effect on the BBB was observed if 26 J of light was given in the absence of ALA.


CONCLUSIONS
ALA-PDT was highly effective in opening the BBB in a localized region of the brain. The degradation of the BBB was temporary in nature at fluence levels of 9 J, opening rapidly following treatment and significantly restored during the next 72 hours. No signs of tissue damage were seen on histological sections at this fluence level. However, higher fluences did demonstrate permanent tissue changes localized in the immediate vicinity of the light source.
Hirschberg
Henry
H
Beckman Laser Institute, University of California, Irvine, California 92612, USA. hhirschb@uci.edu
Uzal
Francisco A
FA
Chighvinadze
David
D
Zhang
Michelle J
MJ
Peng
Qian
Q
Madsen
Steen J
SJ
D000622:Aminolevulinic Acid / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000473:pathology*; D008279:Magnetic Resonance Imaging; D008297:Male; D010778:Photochemotherapy; D017319:Photosensitizing Agents / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D011916:Rats, Inbred F344
D017319:Photosensitizing Agents; D000622:Aminolevulinic Acid
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