Dataset Information

Pharmacoimaging of Blood-Brain Barrier Permeable (FDG) and Impermeable (FLT) Substrates After Intranasal (IN) Administration.

ABSTRACT: To illustrate the use of imaging to quantify the transfer of materials from the nasal cavity to other anatomical compartments, specifically, transfer to the brain using the thymidine analogue, [18F]fluorothymidine (FLT), and the glucose analogue, [18F]fluorodeoxyglucose (FDG). Anesthetized rats were administered FLT or FDG by intranasal instillation (IN) or tail-vein injection (IV). PET/CT imaging was performed for up to 60 min. Volumes-of-interest (VOIs) for the olfactory bulb (OB) and the remaining brain were created on the CT and transferred to the co-registered dynamic PET. Time-activity curves (TACs) were generated and compared. The disposition patterns were successfully visualized and quantified and differences in brain distribution patterns were observed. For FDG, the concentration was substantially higher in the OB than the brain only after IN administration. For FLT, the concentration was higher in the OB than the brain after both IN and IV and higher after IN than after IV administration at all times, whereas the concentration in the brain was higher after IN than after IV administration at early times only. Approximately 50 and 9% of the IN FDG and FLT doses, respectively, remained in the nasal cavity at 20 min post-administration. The initial phase of clearance was similar for both agents (t1/2?=?2.53 and 3.36 min) but the slow clearance phase was more rapid for FLT than FDG (t1/2?=?32.1 and 85.2 min, respectively). Pharmacoimaging techniques employing PET/CT can be successfully implemented to quantitatively investigate and compare the disposition of radiolabeled agents administered by a variety of routes.

SUBMITTER: Ponto LLB

PROVIDER: S-EPMC5798226 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature

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Pharmacoimaging of Blood-Brain Barrier Permeable (FDG) and Impermeable (FLT) Substrates After Intranasal (IN) Administration.

Ponto Laura L Boles LLB Walsh Susan S Huang Jiangeng J Mundt Christine C Thede-Reynolds Katherine K Leonard Watkins G G Sunderland John J Acevedo Michael M Donovan Maureen M

The AAPS journal 20171207 1

To illustrate the use of imaging to quantify the transfer of materials from the nasal cavity to other anatomical compartments, specifically, transfer to the brain using the thymidine analogue, [<sup>18</sup>F]fluorothymidine (FLT), and the glucose analogue, [<sup>18</sup>F]fluorodeoxyglucose (FDG). Anesthetized rats were administered FLT or FDG by intranasal instillation (IN) or tail-vein injection (IV). PET/CT imaging was performed for up to 60 min. Volumes-of-interest (VOIs) for the olfactory ...[more]

PMID: 29218424

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Project description:Introduction The standard treatment for glioblastoma (GBM) patients is surgical tumor resection, followed by radiation and chemotherapy with temozolomide (TMZ). Unfortunately, 60% of newly diagnosed GBM patients express high levels of the DNA repair enzyme O6-methylguanine-DNA methyltransferase (MGMT) and are TMZ-resistant, and all patients eventually become refractory to treatment. The blood-brain barrier (BBB) is an obstacle to the delivery of chemotherapeutic agents to GBM, and BBB-permeable agents that are efficacious in TMZ-resistant and refractory patients are needed. The large amino acid transporter 1 (LAT1) is expressed on the BBB and in GBM and is detected at much lower levels in normal brain tissue. A LAT1-selective therapeutic would potentially target brain tumors while avoiding uptake by healthy tissue. Methods We report a novel chemical entity (QBS10072S) that combines a potent cytotoxic chemotherapeutic domain (tertiary N-bis(2-chloroethyl)amine) with the structural features of a selective LAT1 substrate and tested it against GBM models in vitro and in vivo. For in vitro studies, DNA damage was assessed with a gamma H2A.X antibody and cell viability was assessed by WST-1 assay and/or CellTiter-Glo assay. For in vivo studies, QBS10072S (with or without radiation) was tested in orthotopic glioblastoma xenograft models, using overall survival and tumor size (as measured by bioluminescence), as endpoints. Results QBS10072S is 50-fold more selective for LAT1 vs. LAT2 in transport assays and demonstrates significant growth suppression in vitro of LAT1-expressing GBM cell lines. Unlike TMZ, QBS10072S is cytotoxic to cells with both high and low levels of MGMT expression. In orthotopic GBM xenografts, QBS10072S treatment significantly delayed tumorigenesis and prolonged animal survival compared to the vehicle without adverse effects. Conclusion QBS10072S is a novel BBB-permeable chemotherapeutic agent with the potential to treat TMZ-resistant and recurrent GBM as monotherapy or in combination with radiation treatment.

Dataset Information

Pharmacoimaging of Blood-Brain Barrier Permeable (FDG) and Impermeable (FLT) Substrates After Intranasal (IN) Administration.

Publications

Pharmacoimaging of Blood-Brain Barrier Permeable (FDG) and Impermeable (FLT) Substrates After Intranasal (IN) Administration.

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