Real-Time, in Vivo Correlation of Molecular Structure with Drug Distribution in the Brain Striatum Following Convection Enhanced Delivery

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ABSTRACT
The blood-brain barrier (BBB) represents a major obstacle in delivering therapeutics to brain lesions. Convection-enhanced delivery (CED), a method that bypasses the BBB through direct, cannula-mediated drug delivery, is one solution to maintaining increased, effective drug concentration at these lesions. CED was recently proven safe in a phase I clinical trial against diffuse intrinsic pontine glioma (DIPG), a childhood cancer. Unfortunately, the exact relationship between drug size, charge, and pharmacokinetic behavior in the brain parenchyma are difficult to observe 
in vivo. PET imaging of CED-delivered agents allows us to determine these relationships. In this study, we label different modifications of the PDGFRA inhibitor dasatinib with fluorine-18 or via a nanofiber-zirconium-89 system so that the effect of drug structure on post-CED behavior can accurately be tracked in vivo, via PET. Relatively unchanged bioactivity is confirmed in patient- and animal-model-derived cell lines of DIPG. In naïve mice, significant individual variability in CED drug clearance is observed, highlighting a need to accurately understand drug behavior during clinical translation. Generally, the half-life for a drug to clear from a CED site is short for low molecular weight dasatinib analogs that bare different charge; 13 (1, 32.2 min (95% CI: 27.7–37.8), 2, 44.8 min (27.3–80.8), and 3, 71.7 min (48.6–127.6) minutes) and is much longer for a dasatinib-nanofiber conjugate, 5, (42.8–57.0 days). Positron emission tomography allows us to accurately measure the effect of drug size and charge in monitoring real-time drug behavior in the brain parenchyma of live specimens.

Publication Name: 
ACS Chemical Neuroscience
Authors: 
Umberto Tosi, Harikrishna Kommidi, Vanessa Bellat, Christopher S. Marnell, Hua Guo, Oluwaseyi Adeuyan, Melanie E. Schweitzer, Nandi Chen, Taojunfeng Su, Guoan Zhang, Uday B. Maachani, David J. Pisapia, Benedict Law, Mark M. Souweidane, and Richard Ting

 

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