Program Director/Principal Investigator (Last, First, Middle): SinkO, Patrick J. PROJECT SUMMARY (See instmctlons): The long-term objective of this MERIT renewal remains to design, synthesize, characterize and evaluate novel polymeric drug nanocarriers that enhance anti-AIDS drug bioefficacy by improving delivery, pharmacokinetics, and pharmacodynamics. Our strategy utilizes polymeric bioconjugate-type nanocarriers comprising a novel peptide-polymer scaffold with component agents that: (a) target HIV-infected cells through specific cell-surface receptors, (b) control cellular and body disposition &retention, (c) alter cell uptake pathways, and (d) selectively release drug inside cells.
Specific aims : (1) To evaluate nanocarriers for macrophage targeting and anti-HIV activity using multiplex affinity ligands for the formyl peptide receptor, mannose receptor, CCR5 and CXCR4 using protease inhibitors in cells chronically infected with HIV-1;(2) To determine the effect of peptide-polymer scaffold topology, effectors and physical form on cell/organ retention and pharmacokinetics of nanocarriers (polymer-bioconjugate and nanoparticle-types) in major sites of HIV infection;(3) To assess HIV-entry inhibition using nanocarriers with single and /or dual-receptor multiplex ligand binding;(4) To identify transferrin receptor (brain) and CD4 receptor (T-cell, macrophage) binding peptides using a state ofthe art T7 random peptide phage display library and an endocytosis-based selection screening method and evaluate binding in vitro. In addition to delivering a drug payload, a significant advantage of designing nanocarrier bioconjugates that bind to target cell surface receptors is that it is possible to block HIV entry into cells offering a second pathway for reducing/eradicating HIV infection. The proposed MERIT renewal focuses on continuing mechanistic active targeting approaches utilizing novel nanocarriers and peptidic targeting ligands as well as translationai studies that will enable the clinical development of these promising therapeutics. The multiplicity of activities resulting from drug delivery and targeting approaches complements pharmacological approaches and should result in improved potency, bioefficacy and patient outcomes.

Public Health Relevance

(See Instructions): The relatively poor potency of existing anti-AIDS drugs requires that frequent and high doses be administered. Utilizing a nanotechnology approach, the proposed research will develop novel anti-HIV therapeutics that will dramatically increase potency resulting in reduced doses, less frequent administration, reduced side effects, higher patient compliance rates and better therapeutic outcomes.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37AI051214-13
Application #
8616018
Study Section
Special Emphasis Panel (NSS)
Program Officer
Zhang, Hao
Project Start
2001-12-01
Project End
2016-02-29
Budget Start
2014-03-01
Budget End
2015-02-28
Support Year
13
Fiscal Year
2014
Total Cost
$509,440
Indirect Cost
$180,769
Name
Rutgers University
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
001912864
City
New Brunswick
State
NJ
Country
United States
Zip Code
08901
Liu, Donglin; Zhang, Xiaoping; Gao, Jieming et al. (2014) Core functional sequence of C-terminal GAG-binding domain directs cellular uptake of IGFBP-3-derived peptides. Protein Pept Lett 21:124-31
Palombo, Matthew; Deshmukh, Manjeet; Myers, Daniel et al. (2014) Pharmaceutical and toxicological properties of engineered nanomaterials for drug delivery. Annu Rev Pharmacol Toxicol 54:581-98
Gao, Jieming; Chen, Peiming; Singh, Yashveer et al. (2013) Novel Monodisperse PEGtide Dendrons: Design, Fabrication, and Evaluation of Mannose Receptor-Mediated Macrophage Targeting. Bioconjug Chem :
D'Addio, Suzanne M; Baldassano, Steven; Shi, Lei et al. (2013) Optimization of cell receptor-specific targeting through multivalent surface decoration of polymeric nanocarriers. J Control Release 168:41-9
Weinberger, Barry; Laskin, Jeffrey D; Sunil, Vasanthi R et al. (2011) Sulfur mustard-induced pulmonary injury: therapeutic approaches to mitigating toxicity. Pulm Pharmacol Ther 24:92-9
Cai, Catherine Yi; Zhang, Xiaoping; Sinko, Patrick J et al. (2011) Two sorting motifs, a ubiquitination motif and a tyrosine motif, are involved in HIV-1 and simian immunodeficiency virus Nef-mediated receptor endocytosis. J Immunol 186:5807-14
Black, Adrienne T; Hayden, Patrick J; Casillas, Robert P et al. (2011) Regulation of Hsp27 and Hsp70 expression in human and mouse skin construct models by caveolae following exposure to the model sulfur mustard vesicant, 2-chloroethyl ethyl sulfide. Toxicol Appl Pharmacol 253:112-20
Black, Adrienne T; Gordon, Marion K; Heck, Diane E et al. (2011) UVB light regulates expression of antioxidants and inflammatory mediators in human corneal epithelial cells. Biochem Pharmacol 81:873-80
Gunaseelan, Simi; Gunaseelan, Krishnan; Deshmukh, Manjeet et al. (2010) Surface modifications of nanocarriers for effective intracellular delivery of anti-HIV drugs. Adv Drug Deliv Rev 62:518-31
Laskin, Jeffrey D; Black, Adrienne T; Jan, Yi-Hua et al. (2010) Oxidants and antioxidants in sulfur mustard-induced injury. Ann N Y Acad Sci 1203:92-100

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