The hypothesis for this proposal is as follows: "a pH responsive novel nano-lipid complex delivery system targeted to lymphoid tissues and HIV host cells will greatly improve cell and tissue selectivity, and thus overcome drug insufficiency of anti-HIV drugs in lymphoid tissues, leading to maximum viral suppression." We will test this hypothesis with a well-established HIV-infected primate model to determine the effects of this novel drug delivery strategy targeted to lymphoid tissue and cells on disease progression. To do so, we will (in aim 1) design pH-responsive lipid-nanoparticles composed of anti-HIV drug combination for enhanced activity in virus host cells.
The second aim i s designed to compare the most potent anti-HIV nanoparticles containing inhibitors of HIV protease and reverse transcriptase with respect to target tissue and cell selectivity and resident time. The data collected from time-course and dose-dependent pharmacokinetic and tissue localization studies will be used to define a safe and effective dosing schedule for the proof-of-principle study in HIV-infected primates. Finally, we will evaluate the impact of the optimized, pH-responsive anti-HIV nanoparticles on HIV infection and disease progression. The proposed targeted novel drug delivery strategy will accelerate clearance of residual virus in lymphoid tissues and cells, which received limited exposure to orally administered drugs. A primate model is used to probe questions that could not be addressed in humans. The results obtained from these studies hold promise for making a profound advance in anti-HIV drug therapy and providing a proof-of-principle for "first-in-human" clinical testing. Successful completion of this study will have significant impact on treatment paradigms and outcome of HIV infections. With an established investigative team, we could proceed with first-in-human studies when a positive outcome is achieved.

Public Health Relevance

While combination antiviral drug therapies have extended the life of individuals infected with HIV, the residual virus in tissues and virus reactivation leads to disease progression. The proposed novel strategies are designed to address this unmet medical need and may eventually lead to a cure for HIV/AIDS.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI077390-05
Application #
8417745
Study Section
AIDS Discovery and Development of Therapeutics Study Section (ADDT)
Program Officer
Petrakova, Eva
Project Start
2008-12-01
Project End
2014-11-30
Budget Start
2012-12-01
Budget End
2014-11-30
Support Year
5
Fiscal Year
2013
Total Cost
$1,074,963
Indirect Cost
$383,485
Name
University of Washington
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
Koehn, Josefin; Ho, Rodney J Y (2014) Novel liquid chromatography-tandem mass spectrometry method for simultaneous detection of anti-HIV drugs Lopinavir, Ritonavir, and Tenofovir in plasma. Antimicrob Agents Chemother 58:2675-80
Duan, Jinghua; Freeling, Jennifer P; Koehn, Josefin et al. (2014) Evaluation of atazanavir and darunavir interactions with lipids for developing pH-responsive anti-HIV drug combination nanoparticles. J Pharm Sci 103:2520-9
Kraft, John C; Freeling, Jennifer P; Wang, Ziyao et al. (2014) Emerging research and clinical development trends of liposome and lipid nanoparticle drug delivery systems. J Pharm Sci 103:29-52
Kraft, John C; Ho, Rodney J Y (2014) Interactions of indocyanine green and lipid in enhancing near-infrared fluorescence properties: the basis for near-infrared imaging in vivo. Biochemistry 53:1275-83
Ho, Rodney J Y; Chien, Jenny (2014) Trends in translational medicine and drug targeting and delivery: new insights on an old concept-targeted drug delivery with antibody-drug conjugates for cancers. J Pharm Sci 103:71-7
Hoekman, John D; Srivastava, Pramod; Ho, Rodney J Y (2014) Aerosol-stable peptide-coated liposome nanoparticles: a proof-of-concept study with opioid fentanyl in enhancing analgesic effects and reducing plasma drug exposure. J Pharm Sci 103:2231-9
Endsley, Aaron N; Ho, Rodney J Y (2012) Design and characterization of novel peptide-coated lipid nanoparticles for targeting anti-HIV drug to CD4 expressing cells. AAPS J 14:225-35
Endsley, Aaron N; Ho, Rodney J Y (2012) Elucidation of the time course of adenosine deaminase APOBEC3G and viral infectivity factor vif in HIV-2(287) -infected infant macaques. J Med Primatol 41:52-9
Crouthamel, Matthew H; Kelly, Edward J; Ho, Rodney J Y (2012) Development and characterization of transgenic mouse models for conditional gene knockout in the blood-brain and blood-CSF barriers. Transgenic Res 21:113-30
Ho, Martin T; Kelly, Edward J; Bodor, Miklos et al. (2011) Novel cytochrome P450-2D6 promoter sequence variations in hepatitis C positive and negative subjects. Ann Hepatol 10:327-32

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