New targeted BDNF nanoparticles for treatment of METH addiction and neurotoxicity

Methamphetamine use disorder (MUD) represents a major chronic health problem in the US and abroad. Magnetic Resonance Imaging (MRI) studies have consistently shown striatal structural and functional abnormalities and cognitive deficits in patients with MUD. Long-term methamphetamine (METH) use is associated with neurodegeneration of dopaminergic system and new pharmaceuticals are required for treatment of both METH addiction and toxicity. In SBIR Phase 1, ExQor developed a nanotechnology platform that provides an innovative approach for dual treatment of METH addiction and neurotoxicity and consists of 3 components: a clathrin carrier nanoparticle (CNP) with attached Dopamine Transporter (DAT) targeting ligand (Methylphenidate or GBR12909 or anti-DAT antibody), and brain-derived neurotrophic factor (BDNF). CNPs successfully bypassed the blood-brain barrier (BBB) and delivered adequate concentrations of BDNF to neurons expressing DAT in mouse brain. The striatal BDNF concentrations were over 100 fold higher than reported in previous BDNF systemic and nasal delivery studies. CNPs also rescued striatal tyrosine hydroxylase-positive fibers from HIV/Tat, METH and combined Tat/METH neurotoxicity in iTat mouse model of HIV/neuroAIDS. The goal of this Phase-2 effort is to demonstrate safety and feasibility of our novel bispecific CNP with attached Methylphenidate and BDNF to suppress METH seeking, reverse METH-induced neurotoxicity and successfully treat motor and memory deficits in rats exposed to METH. First, we plan to more thoroughly test our hypothesis that CNPs deliver BDNF to the affected brain regions, reverse neurotoxic effects of METH in these regions, and improve motor and memory functions in rats exposed to toxic doses of METH. Second, we also plan to test if CNPs suppress context-, cue- and METH-induced reinstatement of drug seeking in rats during 3 weeks of abstinence from METH self-administration. To accomplish our Phase-2 goals, we will execute a series of studies that will ascertain NP stability, brain and body distribution, safety and functionality. Rats will be tested with standard behavioral tests. Further, immunohistochemistry and molecular assays will be used to evaluate density of dopaminergic fibers, number of dopaminergic neurons and levels of dopamine and its metabolites, and toxicity of new CNPs. This research project will provide new noninvasive nanotechnology tools for treatment of METH addiction and neurotoxicity. The new nanotechnology may be able to target and regenerate dopaminergic neurons; block METH-induced DA release; and suppress context, cue and METH-induced reinstatement of drug seeking. It may prevent relapse, protect and restore brain functions more quickly and completely than existing treatment methods, while using much lower therapeutic drug doses, and causing fewer side effects. The development of a stable, nontoxic nanoparticle may also provide a major new tool for research of biomarkers in MUD. This nanotechnology may serve as the basis for a next generation neurotheranostic that can specifically target relevant brain systems, and also may have utility as an imaging agent to enhance diagnosis and monitor progression of the disease.