Selectivity and Efficacy of CD90-targeted Phase Shift Microbubbles for HIFU-mediated Non-Thermal Ablation of Brain Tumors. - ABSTRACT Focused Ultrasound (FUS) is a promising non or minimally invasive treatment modality that can permanently destroy tissue deep within the body using thermal necrosis or mechanical effects and is currently FDA approved to treat essential and Parkinsonian tremor with small thermal ablations. While thermal ablation of tumors with FUS has been attempted, several critical challenges, including long treatment times and small treatment envelopes, have limited these investigations. Combining FUS with acoustically active materials such microbubble (MB) ultrasound contrast agents, amplifies the FUS energy locally. This combination allows for non-thermal ablation (NTA) of tissues by creating ischemic lesions through inertial cavitation of the MBs. The relatively large MB size (1-3 µm) can limit access to the interior of tumors. However, smaller acoustically active materials, such as phase shift microbubbles (PSMB, ~200-300 nm), can more easily penetrate tumors and increase NTA efficiency, potentially overcoming both treatment time and treatment envelope limitations. Microvascular Therapeutics (MVT) has, via the 505(b)(2) pathway, developed a safe and more stable lipid-based MB (MVT- 100) less likely to induce anaphylactoid reactions as compared to Definity®. MVT has subsequently made PSMB from MVT-100 (Patent, US 9,427,410B2) and conjugated MB with a peptide ligand with high affinity for CD90 (CD90-MB). CD90 is a stem cell marker of glioblastoma, and MVT has identified a CD90-binding peptide that recognizes the protein's extracellular domain. Preliminary studies performed by MVT and collaborators at the University of Utah have shown that FUS-NTA performed on a syngeneic rat glioma model allowed for substantially better tumor penetration of non-targeted PSMB compared to MB. In this Phase I SBIR, we will characterize targeted CD90-PSMB and evaluate their selectivity and effectiveness in vivo by performing NTA of brain tumors in a biologically relevant animal model. We hypothesize that CD90-PSMB will improve tumor penetration resulting in improved tumor ablation compared to untargeted PSMB. Our main objective is to evaluate the ability of acoustically activated CD90-PSMB to preferentially conjugate in tumor tissue, and when combined with FUS, safely and efficiently ablate the tumor while sparing surrounding tissues. The overall objectives of this application are to build on the existing collaboration between MVT and University of Utah with the ultimate goal to develop this technology to provide a safe, precise, non-invasive and non-ionizing treatment of brain tumors for the tens of thousands of patients succumbing to brain tumors every year. This project is poised to succeed based on the MVT-100 platform, and to lead to the rapid development of a theranostic agent for treatment of brain tumors in humans in combination with the ExAblate Neuro system by InSightec.
