Polydrug Nanocarrier to Treat Opiate Addiction and HIV Disease Grant

abstract

  • Drug of abuse such as opiates have been shown to exert immunomodulatory effects and thereby serve as a cofactor in the progression of HIV-1 infection. Opiate and HIV target areas in brain such as basal ganglia and cortex that are enriched in 5 opioid receptors. Previous studies have shown that opiates act synergistically with HIV proteins (Tat and gp120) to potentiate HIV- related neurotoxicity, which ultimately leads to progression of NeuroAIDS. Currently, there is no treatment available to alleviate the synergistic effects of opiates and HIV, especially due to impenetrability of therapeutic molecules across the blood brain barrier (BBB). Therefore development of a drug delivery system containing an 5 opioid antagonist, a neuroprotective agent and ART that can cross BBB may have significant therapeutic advantage for treatment of opiate addiction and NeuroAIDS. In recent years, nanoparticle based delivery systems have shown promising approach for drug targeting to the brain. In the present proposal, we will develop a unique magnetically guided nanocarrier bound to CTOP (BBB impenetrable < opioid antagonist), BDNF (Brain Derived Neurotrophic Factor) and 5'-triphosphate-AZT (AZTTP) for drug targeting to the brain. The surface of this nanocarrier will be tagged with RGD peptide to facilitate its uptake by monocytes/macrophages. The nanocarrier will deliver the drug across BBB by external magnetic force and/or via monocyte/macrophage mediated transport. Accordingly, in the Specific Aim 1(a) we will develop a magnetoliposome based multifunctional nanocarrier bound to CTOP, BDNF and AZTTP. In Specific Aim 1(b) the developed formulation will be tested in vitro for its ability to transmigrate across BBB. Finally, in Specific Aim 2 we will evaluate the in vivo efficacy of the developed nanocarrier in an HIVE SCID morphine mouse model. The efficacy parameters will be antiretroviral efficacy, neuropathology, neuroprotection and morphine related behaviors in mouse. Based on our preliminary study which shows that AZTTP binds significantly to nanoparticles and it inhibits viral replication in PBMCs, we propose that the developed nanocarrier will provide a potential therapeutic approach to treat opiate addiction and NeuroAIDS. PUBLIC HEALTH RELEVANCE: This application has significant relevance to the purpose of the PAS-08-186, drug of abuse such as opiates have been shown to exert immunomodulatory effects and thereby serve as a cofactor in the progression of HIV-1 infection. Currently, there is no treatment available to alleviate the synergistic neurotoxicity of opiates and HIV, especially due to impenetrability of therapeutic molecules across the BBB. This project will evaluate a novel magnetically guided nanocarrier drug delivery system for simultaneous targeting of CTOP, BDNF and AZTTP across the BBB, thereby reduce opiate addiction and also NeuroAIDS in HIV infected subjects who are opiate users.

date/time interval

  • August 1, 2009 - May 31, 2016

sponsor award ID

  • 1R01DA027049-01

local award ID

  • AWD000000000864

contributor

keywords

  • AIDS neuropathy
  • Abbreviations
  • Acquired Immunodeficiency Syndrome
  • Animals
  • Anti-Retroviral Agents
  • Antiviral Agents
  • Apoptotic
  • Area
  • Atomic Force Microscopy
  • Award
  • Basal Ganglia
  • Behavior
  • Binding
  • Biocompatible Materials
  • Blood
  • Blood - brain barrier anatomy
  • Blood Circulation
  • Brain
  • Brain-Derived Neurotrophic Factor
  • CCR5 gene
  • CTOP
  • Cancer Model
  • Carbodiimides
  • Cell Death
  • Cells
  • Central Nervous System Diseases
  • Cerebrospinal Fluid
  • Cerebrovascular Circulation
  • Clinical
  • Cocaine
  • Complex
  • Dementia
  • Development
  • Disease
  • Doxorubicin
  • Drug Delivery Systems
  • Drug Formulations
  • Drug Transport
  • Drug abuse
  • Drug usage
  • Electrical Resistance
  • Elements
  • Endothelial Cells
  • Evaluation
  • Fluorescein-5-isothiocyanate
  • Funding
  • Government
  • Growth
  • HIV
  • HIV Envelope Protein gp120
  • HIV Infections
  • HIV tat Protein
  • HIV-1
  • In Vitro
  • Incidence
  • Individual
  • Infection
  • Inflammation
  • Insulin
  • Interview
  • Isothiocyanates
  • Lead
  • Leukocytes
  • Ligands
  • Lipids
  • Liposomes
  • Magnetism
  • Mediating
  • Methamphetamine
  • Minor
  • Modeling
  • Morphine
  • Morphology
  • Mus
  • Nanotechnology
  • Narcotic Antagonists
  • Neuraxis
  • Neurons
  • Neuroprotective Agents
  • Opiate Addiction
  • Opiates
  • Opioid
  • Opioid Receptor
  • Permeability
  • Persons
  • Pharmaceutical Preparations
  • Physiological
  • Polyethylene Glycols
  • Population
  • Property
  • Proteins
  • RGD (sequence)
  • Reporting
  • Research Personnel
  • Spectroscopy, Fourier Transform Infrared
  • Surface
  • System
  • Therapeutic
  • Tight Junctions
  • Toxic effect
  • Transferrin
  • Transmission Electron Microscopy
  • Urticaria
  • Viral
  • Viral Load result
  • Virus
  • Virus Replication
  • Zidovudine
  • addiction
  • antiretroviral therapy
  • base
  • carrier mediated transport
  • chemokine receptor
  • clinical application
  • cofactor
  • combat
  • cysteinyltyrosine
  • drug of abuse
  • functional group
  • in vitro testing
  • in vivo
  • interest
  • macromolecule
  • macrophage
  • magnetic field
  • magnetite ferrosoferric oxide
  • monocyte
  • mouse model
  • nanocarrier
  • nanodrug
  • nanoparticle
  • neuropathology
  • neuroprotection
  • neurotoxicity
  • neurotrophic factor
  • novel
  • prevent
  • public health relevance
  • receptor
  • response
  • transmission process
  • tripolyphosphate
  • uptake
  • viral DNA
  • zidovudine triphosphate