Abstract 1367: Intra-cerebral pharmacokinetic monitoring of a tyrosine kinase inhibitor (theranostic 18[F]-PET/NIRF labeled dasatinib) delivered via convection-enhanced delivery

• Published in: Cancer research (Chicago, Ill.) Ill.), 2016-07, Vol.76 (14_Supplement), p.1367-1367
• Main Authors: Wang, Melinda, Zhou, Zhiping, Kommidi, Hari Krishna, Schweitzer, Melanie, Chan, Mark, Wu, Yue Linda, Singh, Ranjodh, Ting, Richard, Souweidane, Mark M.
• Format: Article
• Language: English
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/1538-7445.AM2016-1367

Introduction: Convection enhanced delivery (CED) has been recently explored as an advantageous therapeutic strategy for central nervous system (CNS) tumors. One current limitation is the inability to quantitatively monitor distribution of chemotherapeutic agents. The use of surrogate tracers probably underestimates differences in distribution and clearance owing to discordant features between contrast molecules and therapeutic agents, including bioactivity, degradation, conductivity, and diffusivity. Ideally, direct labelling of a therapeutic compound would eliminate these concerns and afford a noninvasive method to monitor critical pharmacokinetic information. This ability would pave the way for designing infusion parameters and drug schedules that are expected to be unique for CED-based therapy. Methods: The small molecule kinase inhibitor dasatinib was modified with a dual-probe technology that utilizes a boronate trap to conjugate 18[F] with a near-infrared fluorophore into a single molecule, 1, allowing for visualization by positron emission tomography (PET) and near-infrared fluorescence (NIRF). The novel boronate trap allows for direct conjugation of 18[F] with minimal disruption of dasatinib's mechanism of action, resulting in a small, versatile probe with potential for other clinically relevant targets. Results: The modified drug was first tested in vitro in a PDGF-B driven p53 deficient DIPG tumor line from Nestin tv-a; p53 floxed mouse. 1 was shown to enter cells on fluorescence microscopy and inhibit cell proliferation. Antagonist drug potency of 1 as evaluated on pontine glioma in ATP-dependent luminescent cell viability, cell-permeant calcein AM, and an MTS cell proliferation assays show that the IC50, of 1 is ∼10nM. In addition, infusions of 1 were performed via CED and intravenous systemic delivery in a RCAS/tv-a PDGF-B driven with p53 deficiency Ntv-a mouse model of high-grade glioma. Compared to systemic delivery, CED was shown to be roughly 230 times more effective in delivery of the infusion to the tumor site. Maximal glioma delivery occurred at 115 min post a 20 min infusion, with clearance occurring with a half-life of 45 min after maximum delivery. Conclusion: Dasatinib was modified to give 1, an agent that can be imaged non-invasively by fluorescence and positron emission tomography (PET). The modified dasatinib showed little modification in biologic activity when compared to unmodified dasatinib and exhibited cytotoxic effects in v