New Targeted BDNF Nanoparticles for Treatment of Dopaminergic Neurodegeneration in METH Addiction and HAND

ABSTRACT Methamphetamine METH addiction and Human immunodeficiency virus HIV associated neurocognitive disorder HAND represent major chronic health problems in the US and abroad Magnetic Resonance Imaging MRI studies have consistently shown structural and functional abnormalities in the dopaminergic system while Positron Emission Tomography PET studies reported dopamine transporter DAT density reductions in patients with HIV and METH Advances in treatment of METH toxicity and HAND have been made by administering brain derived neurotrophic factor BDNF directly to the CNS or by using drugs that can increase BDNF indirectly BDNF promotes neuronal survival plasticity and restores brain functions However BDNF cannot cross an intact blood brain barrier BBB and is unstable in the blood or when delivered orally The goal of this effort is to produce nontoxic BDNF nanoparticles NPs and test the hypothesis that a these NPs bypass the BBB intranasally b target dopaminergic brain regions and c prevent or reverse neurotoxic effects of METH and HIV transactivator of transcription tat protein in a mouse model relevant to HAND the GT tg bi genic mouse induced with doxycycline to overexpress tat protein To accomplish these goals we will design a three part nanoparticle andlt nanometers A nanocarrier will be constructed out of clathrin a naturally occurring protein the body uses for transporting molecules into cells The second component will be a BDNF protein drug The third part will be a targeting DAT ligand e g GBR BDNF and DAT ligands will be attached to clathrin via polyethylene glycol PEG molecules A series of studies will ascertain specificity and functionality of the NP in vivo We plan to demonstrate the feasibility of this novel nanotechnology to treat METH and tat induced neurotoxicity If this research project is successful it will provide new noninvasive nanotechnology tools for treatment of neurotoxicity in METH addiction and HAND The new nanotechnology may be able to enhance neuronal survival and plasticity 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 targeted molecular NP may also provide a major new tool for research of molecular abnormalities in HAND and drug addiction This novel nanotechnology may serve as the basis for a next generation drug delivery system that can specifically target relevant brain systems and release drugs on demand and may also have utility as an imaging agent to enhance diagnosis and monitor progression of the disease NARRATIVE The development of new targeted and noninvasive nontoxic nanotechnologies for treatment of METH addiction and HAND will provide a major new tool which would be able to enhance neuronal survival and plasticity and restore brain functions quicker and better than existing treatment methods and with less side effects This new nanotechnology may serve as a new drug delivery system that can specifically target relevant brain systems and also may have utility as an imaging agent to enhance diagnosis