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 #
5R01AI077390-04
Application #
8196973
Study Section
AIDS Discovery and Development of Therapeutics Study Section (ADDT)
Program Officer
Petrakova, Eva
Project Start
2008-12-01
Project End
2013-11-30
Budget Start
2011-12-01
Budget End
2012-11-30
Support Year
4
Fiscal Year
2012
Total Cost
$799,505
Indirect Cost
$274,181
Name
University of Washington
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
Shao, Jingwei; Kraft, John C; Li, Bowen et al. (2016) Nanodrug formulations to enhance HIV drug exposure in lymphoid tissues and cells: clinical significance and potential impact on treatment and eradication of HIV/AIDS. Nanomedicine (Lond) 11:545-64
Freeling, Jennifer P; Koehn, Josefin; Shu, Cuiling et al. (2015) Anti-HIV drug-combination nanoparticles enhance plasma drug exposure duration as well as triple-drug combination levels in cells within lymph nodes and blood in primates. AIDS Res Hum Retroviruses 31:107-14
Ho, Rodney J Y; Yu, Jesse; Li, Bowen et al. (2015) Systems Approach to targeted and long-acting HIV/AIDS therapy. Drug Deliv Transl Res 5:531-9
Koehn, Josefin; Ding, Yue; Freeling, Jennifer et al. (2015) A simple, efficient, and sensitive method for simultaneous detection of anti-HIV drugs atazanavir, ritonavir, and tenofovir by use of liquid chromatography-tandem mass spectrometry. Antimicrob Agents Chemother 59:6682-8
Volkin, David B; Hershenson, Susan; Ho, Rodney J Y et al. (2015) Two decades of publishing excellence in pharmaceutical biotechnology. J Pharm Sci 104:290-300
Zhang, Yitong J; Zhan, Xi; Wang, Liguo et al. (2015) pH-responsive artemisinin dimer in lipid nanoparticles are effective against human breast cancer in a xenograft model. J Pharm Sci 104:1815-24
Freeling, Jennifer P; Ho, Rodney J Y (2015) Antiretroviral nanoparticles: the future is now: authors' response to editorial comments. AIDS 29:863-4
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
Freeling, Jennifer P; Ho, Rodney J Y (2014) Anti-HIV drug particles may overcome lymphatic drug insufficiency and associated HIV persistence. Proc Natl Acad Sci U S A 111:E2512-3
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

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