Enhancing the Delivery of Anti Retroviral Drug “Saquinavir” Across the Blood Brain Barrier Using Nanoparticles

Supriya      D. Mahajan; Indrajit      Roy; GaiXia      Xu; Ken-Tye      Yong; Hong      Ding; Ravikumar      Aalinkeel; Jessica      L. Reynolds; Donald      E. Sykes; Bindukumar      B. Nair; Elaine      Y. Lin; Paras      N. Prasad; Stanley      A. Schwartz

Abstract

Antiretroviral drugs are ineffective at treating viral infection in the brain because they cannot freely diffuse across the blood-brain barrier (BBB). Therefore, HIV-1 viral replication persists in the central nervous system (CNS) and continues to augment the neuropathogenesis process. Nanotechnology can play a pivotal role in HIV-1 therapeutics as it can increase drug solubility, enhance systemic bioavailability, and at the same time offer multifunctionality. Moreover, following conjugation with transferrin (Tf), these drug-loaded nanoformulations can permeate across biological barriers such as the blood brain barrier (BBB) via a receptor mediated transport mechanism. In the current study, we have stably incorporated the antiviral drug, Saquinavir, within Tf-conjugated quantum rods (QRs), which are novel nanoparticles with unique optical properties. We have evaluated the transversing ability of the QR-Tf-Saquinavir nanoformulation across an in vitro model of BBB. In addition, we have analyzed the subsequent antiviral efficacy of this targeted nanoformulation in HIV-1 infected peripheral blood mononuclear cells (PBMCs), which are cultured on the basolateral end of the in vitro BBB model. Our results show a significant uptake of QR-Tf-Saquinavir by brain microvascular endothelial cells (BMVECs), which constitute the BBB. In addition, we observed a significant enhancement in the transversing capability of QR-Tf-Saquinavir across the BBB, along with a marked decrease in HIV-1 viral replication in the PBMCs. These observations indicate that drug-loaded nanoparticles can deliver therapeutics across the BBB. These results highlight the potential of this nanoformulation in the treatment of Neuro-AIDS and other neurological disorders.

Keywords: HIV-1, antiretroviral drugs, saquinavir, protease inhibitor, quantum rods (QR), blood brain barrier, transferrin receptor, multimodal nanoparticles, bioconjugation