The Use of 18[F]-labeled PET/NIRF Molecular Dual-Probes in Assessing in Vivo Distribution and Clearance of Small Molecule Kinase Inhibitors

Background:

Most brain tumors are uniformly incurable and difficult to treat, in particular because currently existing drugs and therapies have limited ability to cross the blood brain barrier which separates circulating blood from the cerebrospinal fluid. Recently, a new neurosurgical technique, convection-enhanced delivery (CED), has been pioneered as a way to bypass the blood brain barrier and deliver chemotherapy directly to the target site. However, there exists no reliable method to monitor the distribution of chemotherapeutic drugs at the site of infusion. Although previous studies have used a contrast agent, gadolinium(III), as a surrogate tracer to mimic the distribution of larger therapeutic agents delivered by CED, there is no direct model for understanding distribution and concentration profiles of small molecule chemotherapeutic drugs delivered via CED.

Project Goal:

The two small molecule kinase inhibitors, dasatinib and everolimus, are potential chemotherapeutic agents in the treatment of diffuse infiltrative pontine glioma (DIPG), a fatal cancer that affects the pons in the brainstem. DIPG is most prevalent in children and young adults under the age of 20, and it has a 0% survival rate. The two drugs will be modified with a dual-probe technology that allows for visualization by two different imaging modalities, positron emission tomography (PET) and near-infrared fluorescence (NIRF), providing an accurate real-time image of the infusion of small molecule drugs via CED. Insight into the distributive properties of small molecule therapeutic agents will improve CED therapeutic planning and dose monitoring, which may significantly improve treatment for patients with otherwise incurable brain tumors.