Development of HIV Reservoir Targeted Long Acting Nanoformulated Antiretroviral Therapies

Abstract

Human immunodeficiency virus (HIV) infection commonly results in a myriad of comorbid conditions secondary to immune deficiency. Infection also affects broad organ system function. Although current antiretroviral therapy (ART) reduces disease morbidity and mortality through effective control of peripheral viral load, restricted infection in HIV reservoirs including gut, lymphoid and central nervous system tissues, is not eliminated. What underlies these events is, in part, poor ART penetrance into each organ across tissue barriers, viral mutation and the longevity of infected cells. We posit that one means to improve these disease outcomes is through nanotechnology. To this end, this review discusses a broad range of cutting-edge nanomedicines and nanomedicine platforms that are or can be used to improve ART delivery. Discussion points include how polymer-drug conjugates, dendrimers, micelles, liposomes, solid lipid nanoparticles and polymeric nanoparticles can be harnessed to best yield cell-based delivery systems. When completely developed, such nanomedicine platforms have the potential to clear reservoirs of viral infection.

Autophagy facilitates macrophage depots of sustained-release nanoformulated antiretroviral drugs

“…However, the production of more hydrophobic and protein-bound ARVs provides only a partial solution. Controlling the dynamics of particle trafficking inside the cell and within early, recycling, and late endosomes is necessary to sustain intracellular drug particle depots and limit hepatic and renal metabolism and drug excretion (4,6,11,14,15).…”

Why Novel Nanoparticle-based Delivery Platforms Hold Key for HIV/AIDS Treatment and Prevention?

“…4 The nanocarriers have properties that improve drug delivery: increased drug stability, enhance intestinal absorption and bioavailability, prolonged pharmacokinetics, optimized drug bio-distribution, improved toxicity profiles, and selective drug delivery. 5,[8][9][10] In what follows, I describe the recent nanotechnologybased novel platforms for systemic delivery of antiretroviral drugs. Drug polymer conjugates have been used to deliver ART because: they increase stability, reduce toxicity and enhance long circulation duration and can permeate across physiological barriers due to their small size.…”

“…Drug polymer conjugates have been used to deliver ART because: they increase stability, reduce toxicity and enhance long circulation duration and can permeate across physiological barriers due to their small size. 8 Drug polymer conjugates are used to deliver nucleoside reverse transcriptase inhibitor. Nanosized monophosphate-polymer conjugate delivery system investigated by Yang, et al was made using stavudine (d4T).…”

“…This conjugate was found to enhance the activity of ART and had low toxicity compared to native nucleoside d4T. 8 Another nanocarrier used to deliver ART is Poloxamer 407-coated nanocrystals, a nanoformulated ART (nanoART). A nanoART facilitates drug delivery within intracellular compartments and within the sites of viral replication cycle as investigated by Dongwei Guo, et al Poloxamer 407-coated nanocrystals containing a protease inhibitor Atazanavir (ATV) easily accumulated in macrophages.…”

Antiretroviral Therapy through Barriers: A Prominent Role for Nanotechnology in HIV-1 Eradication from Sanctuaries

“…Since that study, a significant part of the nano-research has focused on improving the bioavailability of ART (antiretroviral therapy). Since 2009, Gendelman and colleagues have developed the so-called "nanoART", a polymer excipient-coated drug nanosuspension with high drug loading capacity, controllable size and charge, and tunable surface conjugation [5,6]. NanoART demonstrated a high efficacy in controlling HIV-1 infection, with more than 1000-fold reduction in viral load upon weekly injections in murine models [7].…”