Nano-NRTIs: Efficient Inhibitors of HIV Type-1 in Macrophages with a Reduced Mitochondrial Toxicity

Vinogradov, Serguei V.; Poluektova, Larisa Y.; Makarov, Edward; Gerson, Trevor; Senanayake, Madapathage T.

doi:10.3851/imp1680

Cited by 51 publications

(46 citation statements)

References 41 publications

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“…An efficient intracellular release of nucleoside analogs has been demonstrated, which encourages applications of nanogel carriers for targeted drug delivery [14]. Nanogel-PEG carriers have been tested for brain delivery of activated nucleoside reverse transcriptase inhibitors for HIV-1 into monocyte-derived macrophages, which act as reservoirs for the virus [15]. Antiviral efficacy and a reduction of neurotoxicity due to mitochondrial DNA depletion were demonstrated.…”

Section: Nanogelsmentioning

confidence: 98%

Nanobiotechnology-Based Strategies for Crossing The Blood–Brain Barrier

2012

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The blood-brain barrier (BBB) is meant to protect the brain from noxious agents; however, it also significantly hinders the delivery of therapeutics to the brain. Several strategies have been employed to deliver drugs across this barrier and some of these may do structural damage to the BBB by forcibly opening it to allow the uncontrolled passage of drugs. The ideal method for transporting drugs across the BBB should be controlled and should not damage the barrier. Among the various approaches that are available, nanobiotechnology-based delivery methods provide the best prospects for achieving this ideal. This review describes various nanoparticle (NP)-based methods used for drug delivery to the brain and the known underlying mechanisms. Some strategies require multifunctional NPs combining controlled passage across the BBB with targeted delivery of the therapeutic cargo to the intended site of action in the brain. An important application of nanobiotechnology is to facilitate the delivery of drugs and biological therapeutics for brain tumors across the BBB. Although there are currently some limitations and concerns for the potential neurotoxicity of NPs, the future prospects for NP-based therapeutic delivery to the brain are excellent.

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Section: Nanogelsmentioning

confidence: 98%

Nanobiotechnology-Based Strategies for Crossing The Blood–Brain Barrier

2012

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“…Other investigators that have fabricated nucleoside reverse transcriptase inhibitor-based nanoformulations containing zidovudine or didanosine triphosphate (at 15 g/ml) have demonstrated reduced mitochondrial toxicity similar to these results (31). We carried out ex vivo cytotoxicity studies using three-dimensional human vaginal endocervical tissue (EpiVaginal; MatTek Corp).…”

Section: Figmentioning

confidence: 63%

Topical Tenofovir Disoproxil Fumarate Nanoparticles Prevent HIV-1 Vaginal Transmission in a Humanized Mouse Model

Destache

Mandal

Yuan

et al. 2016

Antimicrob Agents Chemother

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e Preexposure prophylaxis (PrEP) with 1% tenofovir (TFV) vaginal gel has failed in clinical trials. To improve TFV efficacy in vaginal gel, we formulated tenofovir disoproxil fumarate nanoparticles in a thermosensitive (TMS) gel (TDF-NP-TMS gel). TDF-NPs were fabricated using poly(lactic-co-glycolic acid) (PLGA) polymer and an ion-pairing agent by oil-in-water emulsification. The efficacy of TDF-NP-TMS gel was tested in humanized bone marrow-liver-thymus (hu-BLT) mice. Hu-BLT mice in the treatment group (Rx; n ‫؍‬ 15) were administered TDF-NP-TMS gel intravaginally, having TDF at 0.1%, 0.5%, and 1% (wt/vol) concentrations, whereas the control (Ctr; n ‫؍‬ 8) group received a blank TMS gel. All Rx mice ( Presently, a total of 36.9 million people worldwide are living with HIV-1 (1). Topical preexposure prophylaxis (PrEP) currently is a promising preventative strategy (2). The basic idea is to protect the vagina (and/or rectum) from HIV-1 infection by applying gel containing antiretroviral drug(s) around the time of sexual intercourse. This topical preparation is considered a microbicide, inhibiting infection by blocking viral transmission at the mucosal surface. To date, tenofovir (TFV) is the only drug administered locally as a 1% vaginal gel shown to be effective at preventing heterosexual contraction of HIV-1 (3). TFV tissue concentrations indicate a direct relationship between levels of TFV in genitals and protection (4-7). The minimum amount of TFV in cervicovaginal fluid levels when associated with gel that shows protection against HIV-1 infection has been reported to be Ͼ1,000 ng/ml (4). This level is greater than 10 times that seen in patients receiving oral TDF and emtricitabine (4). In female macaques given 1% TFV gel, the intracellular half-life for the active metabolite, tenofovir diphosphate, is significantly shorter (averaging 25 h) in vaginal lymphocytes than peripheral PBMCs (averaging 49 h) (7). A coitally independent strategy using 1% TFV gel has not shown efficacy in several clinical trials (8,9). Based on the dramatic negative results of the Vaginal and Oral Interventions to Control the Epidemic (VOICE) trial, it is important to consider female attitudes and opinions for a vaginal gel-based prevention delivery system. A safe and effective female-controlled, discrete gel-based delivery system has the potential to prevent millions of HIV-1 infections worldwide annually.When designing female-controlled preventative delivery systems, the gel-based system should have features important for the female user. Namely, the delivery system should be (i) easy to administer; (ii) adherent to the mucosal surface once applied vaginally; (iii) low seepage; and (iv) free of side effects or cytotoxicity to the mucosal surfaces of the female genital tract (10). All of these factors, if not optimized, could diminish gel effectiveness or lead to gel aversion. Finally, a long-acting preparation would be highly desirable if it offered long-term protection from HIV-1 (11).Our laboratory has been developing a nanotechn...

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“…[68], nanogel carriers consisting of dendritic networks decorated with apolipoprotien E (ApOE) peptide molecules were synthesized for delivery of nucleoside reverse transcriptase inhibitors. Antiviral efficacy of the nanocarriers was evaluated in HIV-1 infected monocyte derived macrophages (MDM).…”

Section: Art Nanomedicinesmentioning

confidence: 99%

Development of HIV Reservoir Targeted Long Acting Nanoformulated Antiretroviral Therapies

Edagwa¹,

Zhou²,

McMillan³

et al. 2014

CMC

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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.

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Nano-NRTIs: Efficient Inhibitors of HIV Type-1 in Macrophages with a Reduced Mitochondrial Toxicity

Cited by 51 publications

References 41 publications

Nanobiotechnology-Based Strategies for Crossing The Blood–Brain Barrier

Nanobiotechnology-Based Strategies for Crossing The Blood–Brain Barrier

Topical Tenofovir Disoproxil Fumarate Nanoparticles Prevent HIV-1 Vaginal Transmission in a Humanized Mouse Model

Development of HIV Reservoir Targeted Long Acting Nanoformulated Antiretroviral Therapies

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