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Chu, YenJu (2023) Mesenteric Lymphatic Targeting of Antiretroviral agents for Improved Treatment of HIV/AIDS. PhD thesis, University of Nottingham.

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Abstract

Human immunodeficiency virus (HIV) is a worldwide pandemic that causes irreversible and unstoppable disease progression. Antiretroviral therapy (ART) can efficiently suppress viral replication and control the pace of HIV infection. However, discontinuing ART usually leads to rebound viremia and drug resistance when resuming ART. This is primarily due to establishment of latent HIV reservoirs in cellular and anatomical sites. Suboptimal levels of ART in viral reservoirs might allow the persistence of latent infection. Gut-associated lymphoid tissue (GALT), in particular mesenteric lymph nodes (MLNs), is the largest immune system in the body and an important HIV reservoir. This study selects two antiretroviral agents (ARVs), tipranavir (TPV) and dolutegravir (DTG), as candidate drugs for targeted delivery to the mesenteric lymphatic system. In view of the different physicochemical properties between TPV and DTG, this study was conducted by two different approaches: (1) Targeting of lipophilic drug TPV to mesenteric lymphatics by means of intestinal lymphatic transport using a long-chain triglyceride (LCT)-based formulation approach; (2) Developing a lipophilic ester prodrug system of hydrophilic drug DTG, combined with LCT-based formulation to target DTG to mesenteric lymph and MLNs.

The introduction of combination antiretroviral therapy (cART) led to substantial improvement in mortality and morbidity of HIV-1 infection. However, the poor penetration of ARVs to HIV-1 reservoirs limits the ability of the ARVs to eliminate the virus. MLNs are one of the main HIV1 reservoirs in patients under suppressive ART. The intestinal lymphatic absorption pathway substantially increases the concentration of lipophilic drugs in mesenteric lymph and MLNs when they are co-administered with LCT. Chylomicrons (CM) play a crucial role in intestinal lymphatic absorption as they transport drugs to the lymph lacteals rather than blood capillary by forming drug-CM complexes in the enterocytes. Thus, lipophilic antiretroviral drugs could potentially be delivered to HIV-1 reservoirs in MLNs by an LCT-based formulation approach. In this study, protease inhibitors (PIs) were initially screened for their potential for intestinal lymphatic targeting using a computational model. The candidates were further assessed for their experimental affinity to CM. TPV was the only-candidate with substantial affinity to both artificial and natural CM in vitro and ex vivo. Pharmacokinetics and biodistribution studies were then performed to evaluate the oral bioavailability and intestinal lymphatic targeting of TPV in rats. The results showed similar oral bioavailability of TPV with and without co-administration of LCT vehicle. Although LCT-based formulation led to 3-fold higher concentrations of TPV in mesenteric lymph compared to plasma, the levels of the drug in MLNs were similar to plasma in both LCT-based and lipid-free formulation groups. Thus, LCT-based formulation approach alone was not sufficient for effective delivery of TPV to MLNs. Future efforts should be directed to a combined highly lipophilic prodrugs/lipidbased formulation approach to target TPV, other PIs and potentially other classes of antiretroviral agents to viral reservoirs within the mesenteric lymphatic system.

Item Type:	Thesis (University of Nottingham only) (PhD)
Supervisors:	Gershkovich, Pavel Stocks, Michael
Keywords:	mesenteric lymphatic targeting, antiretroviral agents, lipoproteins, HIV
Subjects:	R Medicine > RS Pharmacy and materia medica
Faculties/Schools:	UK Campuses > Faculty of Science > School of Pharmacy
Item ID:	74663
Depositing User:	Chu, YenJu
Date Deposited:	12 Dec 2023 04:40
Last Modified:	12 Dec 2023 04:40
URI:	https://eprints.nottingham.ac.uk/id/eprint/74663

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