Targeted delivery of bleomycin to the brain using photo-chemical internalization of Clostridium perfringens epsilon prototoxin.
Cells infiltrating into normal brain from malignant brain tumors are protected by the blood brain barrier (BBB) which prevents the delivery and limits the effects of anti-tumor agents. We have evaluated the ability of photochemical internalization (PCI) to limit the effects of an agent known to broadly open the BBB to a target region of the brain. The PCI-based relocation and activation of macromolecules into the cell cytosol has the advantage of minimal side effects since the effect is localized to the area exposed to light, allowing the access of chemotherapeutic agents only to these regions. Non tumor bearing inbred Fisher rats were treated with photosensitizer, and a nontoxic intraperitoneal dose of Clostridium perfringens epsilon prototoxin (ETXp) followed by light exposure. Post-contrast T(1) MRI scans were used to monitor the degree BBB disruption. F98 tumor cells were implanted into the brains of other animals that were subsequently treated 24 h later with ETXp-PCI BBB opening followed by the i.p. administration of bleomycin (BLM). PCI delivery of ETXp at low fluence levels demonstrated significant MRI enhancement. No effect on the BBB was observed if photosensitizer and light was given in the absence ETXp. The survival of animals implanted with F98 tumor cells was significantly extended following ETXp-PCI BBB opening and BLM therapy compared to controls. PCI delivered ETXp was effective in opening the BBB in a limited region of the brain. ETXp-PCI mediated BBB opening clearly increased the efficacy of BLM therapy.
Hirschberg
Henry
H
Beckman Laser Institute, University of California, Irvine, CA, USA. hhirschb@uci.edu.|Department of Health Physics and Diagnostic Sciences, University of Nevada, Las Vegas, NV, USA. hhirschb@uci.edu.
Zhang
Michelle J
MJ
Department of Health Physics and Diagnostic Sciences, University of Nevada, Las Vegas, NV, USA.
Gach
H Michael
HM
Nevada Cancer Institute, Las Vegas, NV, USA.
Uzal
Francisco A
FA
School of Veterinary Medicine, University of California, Davis, San Bernardino, CA, USA.
Peng
Qian
Q
Department of Pathology, The Norwegian Radium Hospital, Oslo, Norway.
Sun
Chung-Ho
CH
Beckman Laser Institute, University of California, Irvine, CA, USA.
Chighvinadze
David
D
Department of Health Physics and Diagnostic Sciences, University of Nevada, Las Vegas, NV, USA.
Madsen
Steen J
SJ
Department of Health Physics and Diagnostic Sciences, University of Nevada, Las Vegas, NV, USA.
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000493:pharmacokinetics*; D001427:Bacterial Toxins / Q000493:pharmacokinetics*; D001761:Bleomycin / Q000493:pharmacokinetics*; D001812:Blood-Brain Barrier / Q000187:drug effects; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D016503:Drug Delivery Systems / Q000379:methods*; D005910:Glioma / Q000188:drug therapy* / Q000473:pathology; D053208:Kaplan-Meier Estimate; D008279:Magnetic Resonance Imaging; D008297:Male; D009368:Neoplasm Transplantation; D010778:Photochemotherapy / Q000379:methods; D017319:Photosensitizing Agents / Q000494:pharmacology; D051381:Rats; D011916:Rats, Inbred F344
D000903:Antibiotics, Antineoplastic; D001427:Bacterial Toxins; C039811:Clostridium perfringens epsilon-toxin; D017319:Photosensitizing Agents; D001761:Bleomycin