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 evaluatenovel polymeric drug nanocarriers that enhance anti-AIDS drug bioefficacy by improving delivery,pharmacokinetics, and pharmacodynamics. Our strategy utilizes polymeric bioconjugate-type nanocarrierscomprising a novel peptide-polymer scaffold with component agents that: (a) target HIV-infected cellsthrough specific cell-surface receptors, (b) control cellular and body disposition & retention, (c) alter celluptake pathways, and (d) selectively release drug inside cells.
Specific aims : (1) To evaluate nanocarriersfor 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/organretention and pharmacokinetics of nanocarriers (polymer-bioconjugate and nanoparticle-types) in majorsites of HIV infection; (3) To assess HIV-entry inhibition using nanocarriers with single and /or dual-receptormultiplex 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-basedselection screening method and evaluate binding in vitro. In addition to delivering a drug payload, asignificant advantage of designing nanocarrier bioconjugates that bind to target cell surface receptors is thatit 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 novelnanocarriers and peptidic targeting ligands as well as translationai studies that will enable the clinicaldevelopment of these promising therapeutics. The multiplicity of activities resulting from drug delivery andtargeting 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 beadministered. Utilizing a nanotechnology approach, the proposed research will develop novel anti-HIVtherapeutics that will dramatically increase potency resulting in reduced doses, less frequent administration,reduced side effects, higher patient compliance rates and better therapeutic outcomes.
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