Microvascular Targeting Drug (ARV)-Loaded Multifunctional Nanoparticles to M Cells Overlaying GALT (HIV-1 Reservoir)

The goal of HIV therapy is the eradication of human immunodeficiency virus-1 (HIV-1), but cellular reservoirs (latently infected CD4+ T cells and macrophages, and the anatomical reservoirs (gut-associated lymphoid tissue (GALT) and the brain) make it difficult. The ongoing low level of HIV-1 replication in the GALT replenishes the latent reservoir. The long term objective of this work is to couple a targeting ligand to the surface of ARV-drugs-Ioaded nanoparticles to facilitate their uptake by the 131 integrin receptor expressed uniquely on the apical surface of M cells overlaying the GALT, to eradicate the low levels of ongoing viral replication in GALT (efficacy), to make ARV drugs reach the lymphatic system, to decrease the toxicity of ARV drugs, and to prevent P-glycoprotein efflux pump, gut wall metabolism and first pass effect. This project has two inter-related aims. First, we will synthesize blank and zidovudine, lamivudine, nevirapine, and raltegravir-Ioaded biodegradable nanoparticles and characterize them for drug delivery properties, in vitro verification of inhibition of HIV-1 transcription in CEM T cells and 293T cells and productive HIV-1 replication in primary CD4+ T cells and primary human macrophages infected with dualtropic HIV-1 89.6, and transport across an in vitro model of human gastrointestinal follicle-associated epithelium. Second, we will conjugate M cell 131 integrin receptor ligands (invasin or peptide with RGD motif) to the surface of promising blank and ARV-Ioaded nanoparticles synthesized in Aim 1 and characterize them for drug delivery properties. Biodistribution studies of 131 integrin receptor ligand modified nanoparticles and unmodified nanoparticles in BL T mice (humanized mice model that will facilitate clinical translation) will be investigated. Once completed, our pilot studies will identify suitable nanoparticles for oral targeted delivery to GALT via M cells and identify the better of the two 131 integrin receptor ligands in terms of nanoparticle transepithelia transport and tissue localization in BL T mice.