Alpha Particle Enhanced Blood Brain/Tumor Barrier Permeabilization in Glioblastomas Using Integrin Alpha-v Beta-3-Targeted Liposomes

• Published in: Molecular cancer therapeutics Vol. 16; no. 10; pp. 2191 - 2200
• Main Authors: Sattiraju, Anirudh, Xiong, Xiaobing, Pandya, Darpan N, Wadas, Thaddeus J, Xuan, Ang, Sun, Yao, Jung, Youngkyoo, Sai, Kiran Kumar Solingapuram, Dorsey, Jay F, Li, King C, Mintz, Akiva
• Format: Journal Article
• Language: English
• Published: United States American Association for Cancer Research Inc 01.10.2017
• Subjects: Actinium; Alpha rays; Angiogenesis; Anticancer properties; Antitumor activity; Astrocytoma; Barriers; Blood vessels; Blood-brain barrier; Brain; Brain tumors; Cancer; Central nervous system; Complications; Deoxyribonucleic acid; DNA; DNA damage; Glioblastoma; Hypoxia; Liposomes; Membrane permeability; Permeability; Radiation therapy; Radioisotopes; Tumors
• ISSN: 1535-7163; 1538-8514
• DOI: 10.1158/1535-7163.MCT-16-0907

Glioblastoma (GBM) is the most common primary malignant astrocytoma characterized by extensive invasion, angiogenesis, hypoxia, and micrometastasis. Despite the relatively leaky nature of GBM blood vessels, effective delivery of antitumor therapeutics has been a major challenge due to the complications caused by the blood-brain barrier (BBB) and the highly torturous nature of newly formed tumor vasculature (blood tumor barrier-BTB). External beam radiotherapy was previously shown to be an effective means of permeabilizing central nervous system (CNS) barriers. By using targeted short-ranged radionuclides, we show for the first time that our targeted actinium-225-labeled α β -specific liposomes ( Ac-IA-TLs) caused catastrophic double stranded DNA breaks and significantly enhanced the permeability of BBB and BTB in mice bearing orthotopic GBMs. Histologic studies revealed characteristic α-particle induced double strand breaks within tumors but was not significantly present in normal brain regions away from the tumor where BBB permeability was observed. These findings indicate that the enhanced vascular permeability in these distal regions did not result from direct α-particle-induced DNA damage. On the basis of these results, in addition to their direct antitumor effects, Ac-IA-TLs can potentially be used to enhance the permeability of BBB and BTB for effective delivery of systemically administered antitumor therapeutics. .