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Cell-Targeted Antiretroviral Nanoformulations: Translational Studies in Mice
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Dissertation
Cell-Targeted Antiretroviral Nanoformulations: Translational Studies in Mice
2015
Overview
Previous efforts from our laboratory were successful in harnessing mononuclear phagocytes (MP; monocytes, dendritic cells and macrophages) for nanoformulated drug transport, delivery and distribution. This is particularly noteworthy for nanoformulated antiretroviral therapy (nanoART) as the paths traveled by MP parallel the virus itself. Thus, using MP as Trojan horses for drug delivery could facilitate virus elimination in its target tissues. Prior works showed that ritonavir (RTV), atazanavir (ATV) and efavirenz (EFV) nanoparticles facilitated entry, release and antiretroviral activities into and from infected cells. However, the major share of the administered drug was metabolized within 24 hours after parenteral administration. Thus, improving bioavailability and the therapeutic index of the drug formulations is urgently needed. We believe this can be achieved through cell-targeted nanoART that would speed MP uptake and achieve sustained cell and tissue drug depots. To this end, we posit that nanoART coated with folic acid (FA), N-formyl methionine leucine phenylalanine (fMLP) or a mannose-decorated monomer polymer can engage MP receptors to enhance particle entry in subcellular MP compartments during both steady state conditions and following immune activation. Laboratory results were tested in normal (Balb/cJ), Hu-PBL reconstituted NOD/scid-gcnull (NSG) and CD34+ hematopoietic stem cell transplanted humanized mice. The drug biodistribution, pharmacokinetics (PK) and bioavailability were determined in formulation optimization. Improvements in cell uptake, intracellular compartmentalization, release and antiretroviral responses correlated to the physicochemical particle characteristics, ligand coating, biologic properties and cell receptor expression. We believe that finding an appropriate targeting ligand of the newly developed nanoformulations will facilitate clinical translation of antiretroviral nanoformulations.
Publisher
ProQuest Dissertations & Theses
Subject
ISBN
1321774990, 9781321774993
