TY - JOUR T1 - HIFU with microbubbles opens up BBB for loco-regional topotecan delivery into brain JF - Journal of Nuclear Medicine JO - J Nucl Med SP - 1222 LP - 1222 VL - 62 IS - supplement 1 AU - Andrei Molotkov AU - Patrick Carberry AU - Martin Dolan AU - Simon Joseph AU - Sidney Idumonyi AU - Shunichi Oya AU - John Castrillon AU - Mikhail Doubrovin AU - Francesca Zanderigo AU - Akiva Mintz Y1 - 2021/05/01 UR - http://jnm.snmjournals.org/content/62/supplement_1/1222.abstract N2 - 1222Introduction: Glioblastoma (GBM) is the most common primary adult brain malignancy with an extremely poor prognosis and a median survival of fewer than 2 years. A key reason for this high mortality is that the blood brain barrier (BBB) significantly restricts the delivery of systemic therapeutics to brain tumors. High intensity focused ultrasound (HIFU) with microbubbles is a methodology being used in clinical trials to noninvasively permeabilize the BBB for systemic therapeutic delivery to GBM. Topotecan is a topoisomerase inhibitor used as chemotherapeutic agent to treat ovarian and small cell lung cancer. Studies have suggested that topotecan can cross BBB and can be used to treat brain metastasis. However, pharmacokinetic data demonstrated that topotecan peak concentration in the brain extracellular fluid after systemic injection was 10 times lower than in the blood, suggesting less than optimal BBB penetration by topotecan. We hypothesize that HIFU with microbubbles treatment can open the BBB and significantly increase topotecan concentration in the brain. We radiolabeled topotecan with [11C] and acquired static and dynamic PET scans to quantify [11C] topotecan uptake in the brains of normal mice and mice after HIFU treatment. We found that HIFU treatments significantly increased [11C] topotecan brain uptake. Moreover, kinetic analysis of the [11C] topotecan dynamic PET data demonstrated a substantial increase of [11C] topotecan volume of distribution in the brain. Furthermore, we found a decrease in [11C] topotecan brain clearance, confirming the potential of HIFU to aid in the delivery of topotecan through the BBB. This opens the potential clinical application of [11C] topotecan as a tool to predict topotecan locoregional brain concentration in patients with GBMs undergoing experimental HIFU treatments. ER -