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.
(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.
|Samizadeh, Mahta; Zhang, Xiaoping; Gunaseelan, Simi et al. (2016) Colorectal delivery and retention of PEG-Amprenavir-Bac7 nanoconjugates--proof of concept for HIV mucosal pre-exposure prophylaxis. Drug Deliv Transl Res 6:1-16|
|Gao, Yu; Jin, Biyu; Shen, Weiyu et al. (2016) China and the United States--Global partners, competitors and collaborators in nanotechnology development. Nanomedicine 12:13-9|
|Nelson, Antoinette G; Zhang, Xiaoping; Ganapathi, Usha et al. (2015) Drug delivery strategies and systems for HIV/AIDS pre-exposure prophylaxis and treatment. J Control Release 219:669-680|
|Chen, Peiming; Zhang, Xiaoping; Jia, Lee et al. (2014) Optimal structural design of mannosylated nanocarriers for macrophage targeting. J Control Release 194:341-9|
|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|
|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|
|Pinkerton, Nathalie M; Zhang, Stacey W; Youngblood, Richard L et al. (2014) Gelation chemistries for the encapsulation of nanoparticles in composite gel microparticles for lung imaging and drug delivery. Biomacromolecules 15:252-61|
|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|
|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 24:1332-44|
|Wan, Jiandi; Shi, Lei; Benson, Bryan et al. (2012) Microfluidic generation of droplets with a high loading of nanoparticles. Langmuir 28:13143-8|
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