Alpha particle enhanced Blood Brain/Tumor Barrier permeabilization in glioblastomas using integrin alpha-v beta-3 targeted liposomes

摘要

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 anti-tumor 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 radiation therapy 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 αvβ3-specific liposomes (²²⁵Ac-IA-TLs) caused catastrophic double stranded DNA breaks and significantly enhanced the permeability of BBB and BTB in mice bearing orthotopic GBMs. Histological 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. Based on these results, in addition to their direct anti-tumor effects, ²²⁵Ac-IA-TLs can potentially be used to enhance the permeability of BBB and BTB for effective delivery of systemically administered anti-tumor therapeutics.