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

Abstract

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.

Blood Interactions, Pharmacokinetics, and Depth-Dependent Ablation of Rat Mammary Tumors with Photoactivatable, Liposomal Doxorubicin

“…This lack of greater efficacy, despite enhanced delivery to the tumor, is attributed to poor bioavailability of liposome-encapsulated drugs due to their slow release (9,20). Numerous molecular-targeting strategies have been explored for liposomes (21)(22)(23)(24). Alternatively, several stimulus controlled systems have been developed to address this problem, including systems that use heat, light, and pH to trigger drug release (25)(26)(27)(28)(29)(30)(31).…”

Nanoparticles for targeted cancer radiotherapy

“…225 Ac was also formulated in liposome-based nanoparticles, which were capable of crossing the blood-brain barrier and delivering a therapeutic dose to glioblastoma cells through integrin alpha-v-beta-3-targeting ( Fig. 7) [136,143]. Although not explored for cancer yet, other radionuclides, such as 166 Ho, have been used for different radiotherapies, including using radiolabeled iron oxide nanoparticles for synovectomy (arthritis treatment) of knee joints in mice [144].…”

Injectable Biomaterials for Treatment of Glioblastoma

“…Liposomes loaded with 225 Ac (an α‐emitting isotope) targeted the αvβ3 integrins expressed on angiogenic endothelial cells and invading GBM cells to effectively increase the permeability of the BBB with the aim of increasing the uptake of circulating chemotherapeutics. [ 49 ] In addition to micro‐ or nanomaterial carriers, radionuclides can also be delivered using radioimmunotherapy which relies on monoclonal antibodies to effectively target the tumor. [ 50 ] Radioimmunotherapies must be delivered intracranially because the BBB prevents antibodies from accessing the tumor.…”