PT  - JOURNAL ARTICLE
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
TI  - HIFU with microbubbles opens up BBB for loco-regional topotecan delivery into brain
DP  - 2021 May 01
TA  - Journal of Nuclear Medicine
PG  - 1222--1222
VI  - 62
IP  - supplement 1
4099  - http://jnm.snmjournals.org/content/62/supplement_1/1222.short
4100  - http://jnm.snmjournals.org/content/62/supplement_1/1222.full
SO  - J Nucl Med2021 May 01; 62
AB  - 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.