Development and In Vitro and In Vivo Evaluation of Lamivudin-Loaded Lipid-Coated Particulate Formulations for Nasal-to-Brain Targeting in NeuroAIDS Treatment

Project no. 23983 · Status: Kapanmış · 2022

Summary

AIDS (Acquired Immune Deficiency Syndrome) is a viral disease characterized by severe immune suppression caused by the Human Immunodeficiency Virus (HIV), which targets and destroys critical cells of the immune system. As a result of this immunosuppression, patients become susceptible to severe infections and malignancies. HIV invades the central nervous system (CNS) during the early stages of infection, and inadequate antiretroviral (ARV) drug levels within the CNS contribute to the development of NeuroAIDS in long-term seropositive individuals. Lamivudine, a nucleoside reverse transcriptase inhibitor (NRTI), was approved by the FDA in 2001 for oral use in HIV therapy and is widely employed in current treatment regimens. However, the oral form of lamivudine exhibits limited penetration across the blood–brain barrier (BBB) and undergoes extensive first-pass metabolism, resulting in low bioavailability and insufficient suppression of viral reservoirs within the CNS. Therefore, intranasal drug delivery—capable of bypassing the BBB and providing direct access to the CNS—has gained increasing attention in recent years for NeuroAIDS management. The intranasal route offers several advantages, including rapid absorption, avoidance of first-pass metabolism, high bioavailability, reduced dose requirements, improved patient compliance, and rapid therapeutic onset.In this project, the aim was to develop a lamivudine-loaded nano-carrier formulation suitable for intranasal administration and to evaluate its performance through in vitro, ex vivo, and in vivo studies. Lamivudine-loaded lipid-coated nanoparticles were first prepared and characterized. These nanoparticles were then incorporated into an in situ gelling semi-solid formulation to enable intranasal application. The permeability and cellular efficacy of the formulation were assessed in vitro, and finally, the in vivo therapeutic potential was investigated in a rat model. This study enabled the development of a novel intranasal nano-carrier–hydrogel platform designed to enhance CNS targeting of lamivudine for the treatment of NeuroAIDS.

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