anti-HIV Drug Delivery Research Articles

Construction and characterization of a novel Tenofovir-loaded PEGylated niosome conjugated with TAT peptide for evaluation of its cytotoxicity and anti-HIV effects

In recent years, nanocarriers have become potent drug delivery system candidates, especially in anti-HIV therapies. Meanwhile, using cell-penetrating peptides such as TAT for improvement of cellular transportation has been widely noticed. In the current study, a novel PEGylated niosomal formulation (PEG-NI) loaded with an anti-HIV drug (Tenofovir) has been prepared by using thin-film hydration method based on cholesterol and Span 60 surfactant. Then, the TAT peptide was incorporated into optimized PEGylated niosome. Further morphological and in vitro studies were performed by TAT conjugated (TAT-NI1) and PEGylated niosomes. The average size, polydispersity index and encapsulation efficiency of Tenofovir-loaded TAT-NI1 were 208 ± 9.004 nm, 0.39 ± 0.008 and 75 ± 2.516%, respectively. The cytotoxicity effects of TAT-NI1 and PEG-NI niosomes were analyzed by MTT assay in comparison with Tenofovir. The IC50 of PEG-NI, empty PEG-NI, TAT-NI1, free Tenofovir and TAT peptide were 65.41, 37.04, 41.02, 43.07, and 37.12, respectively. Furthermore, the inhibitory effects of samples against the HIV infected HeLa cells were evaluated. The results displayed a higher cytotoxicity, lower anti-Scr HIV effect and improved Tenofovir release profile for TAT-NI1 in comparison with PEG-NI. Overall, this study revealed that PEGylation is a superior alternative rather than TAT conjugation in anti-HIV drug delivery systems.

Statement of Retraction

This article refers to:RETRACTED ARTICLE: LDH hybrid thermosensitive hydrogel for intravaginal delivery of anti-HIV drugs

RETRACTED ARTICLE: LDH hybrid thermosensitive hydrogel for intravaginal delivery of anti-HIV drugs

We, the Editors and Publisher of the journal Artificial Cells, Nanomedicine, and Biotechnology, have retracted the following article: Wenxue Tian, Shangcong Han, Xia Huang, Mei Han, Jie Cao, Yan Liang & Yong Sun (2019) LDH hybrid thermosensitive hydrogel for intravaginal delivery of anti-HIV drugs. Artificial Cells, Nanomedicine, and Biotechnology, 47:1, 1234–1240, DOI: 10.1080/21691401.2019.1596935 Since publication, concerns were raised about Figure 3. When approached for an explanation, the authors have been unable to provide a satisfactory response. We are therefore retracting this article and the corresponding author listed in this publication has been informed. We have been informed in our decision-making by our policy on publishing ethics and integrity and the COPE guidelines on retractions. The retracted article will remain online to maintain the scholarly record, but it will be digitally watermarked on each page as ‘Retracted’.

Study on the Release of Quinine Sulfate from Polylactic Acid/Chitosan/Quinine Sulfate Composite Materials

Recently, the polylactic acid /chitosan composite has been used as a drug carrier to regulate the drug release aim to increase effective and decrease drug dosage. Polylactic acid/chitosan composite materials carry 10-50% quinine sulfate was prepared by the water/oil water method to study the release of quinine sulfate. Effects of quinine sulfate content, pH and kinetics of quinine sulphate release were investigated. The results showed that polyacid/chitosan composite materials with high quinine sulfate content for slow speed of release quinine sulfate. The polylactic acid/chitosan composite materials carry 50% quinine sulfate is smallest speed of release quinine sulfate. In pH = 7.4 the release rate of quinine sulfate is greater than the pH = 2.0. The process of releasing quinine sulfate from polylactic acid/chitosan/quinine sulfate composites materials follows the Korsmeyer-Peppas kinetics model and diffuses following the Fick law.
 Keyword
 Release, composite materials, polyaxit lactic, chitosan, quinin sulfat
 References
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Platelet microparticles: An effective delivery system for anti-viral drugs

Platelet microparticles are the most frequent bloodstream microparticles (∼70–90%) which act as a vector for delivery of mRNA, miRNA and signaling proteins under physiological conditions. A variety of platelet microparticles were produced during the storage of platelet concentrates. In this study, platelet microparticles were isolated from platelet concentrates at day 3 of storage and used to deliver anti-HIV drugs including Lamivudine and Tenofovir. At first, encapsulation efficiency and release of anti-HIV drugs were evaluated by spectrophotometry at different wavelengths. Then, cellular uptake, cytotoxicity and HIV-1 inhibitory effects of drugs and drugs-platelet microparticles were assessed using flow cytometry, MTT and P24 assay kit in vitro. Our data showed that the platelet microparticles (300–1000 nm) have high ability for entrapment of Lamivudine and Tenofovir drugs up to 60% and 40%, respectively. Moreover, the release of drugs from the microparticles slowly occurred. HIV-1 inhibitory effects of Lamivudine- and Tenofovir-platelet microparticles were increased in comparison with drugs alone at different concentrations. Also, the toxicity of drugs loaded in the microparticles was decreased at various doses due to their slow release compared to drugs. Generally, platelet microparticles could be considered as a safe, inexpensive and natural vehicle for anti-HIV drug delivery compared to other synthetic nanoparticles.

Lipid Based Nanocarriers for Delivery of Anti-HIV Drugs: A Mini Review

Lipid Based Nanocarriers for Delivery of Anti-HIV Drugs: A Mini Review

Characterization of Nanodiamond-based anti-HIV drug Delivery to the Brain

Human Immunodeficiency Virus Type 1 (HIV-1) remains one of the leading causes of death worldwide. Present combination antiretroviral therapy has substantially improved HIV-1 related pathology. However, delivery of therapeutic agents to the HIV reservoir organ like Central nervous system (CNS) remains a major challenge primarily due to the ineffective transmigration of drugs through Blood Brain Barrier (BBB). The recent advent of nanomedicine-based drug delivery has stimulated the development of innovative systems for drug delivery. In this regard, particular focus has been given to nanodiamond due to its natural biocompatibility and non-toxic nature–making it a more efficient drug carrier than other carbon-based materials. Considering its potential and importance, we have characterized unmodified and surface-modified (-COOH and -NH2) nanodiamond for its capacity to load the anti-HIV-1 drug efavirenz and cytotoxicity, in vitro. Overall, our study has established that unmodified nanodiamond conjugated drug formulation has significantly higher drug loading capacity than surface-modified nanodiamond with minimum toxicity. Further, this nanodrug formulation was characterized by its drug dissolution profile, transmigration through the BBB, and its therapeutic efficacy. The present biological characterizations provide a foundation for further study of in-vivo pharmacokinetics and pharmacodynamics of nanodiamond-based anti-HIV drugs.

Encapsulation of zidovudine in PF-68 coated alginate conjugate nanoparticles for anti-HIV drug delivery

Retroviral drug delivery faces many challenges due to its low bioavailability, short half life and hydrophobicity. In this study, the anti viral drug zidovudine (AZT) was encapsulated inside the amide functionalised alginate nanoparticles (AZT-GAAD NPs) using emulsion solvent evaporation method. The amide derivative of alginate was prepared by coupling reaction with d,l glutamic acid using carbodiimide activation chemistry. The stabilizer, PF-68 was integrated during the preparation of nanoparticles. The alginate nanoparticles were prepared via chemical cross linking. The novelty of this work imparts the absence of chemical cross-linking for the preparation of nanoparticles.The resulting nanoparticles had spherical shape with an average size of 432±11.9nm as confirmed by TEM images. The nanoparticles had a loading efficacy of 29.5±3.2% obtained by dialysis method. The release of AZT in PBS(pH-7.4) was studied and a slow and sustained release of AZT was observed. The nanoparticles were found to be biocompatible and in vitro cellular internalization studies indicated significantly higher internalization efficiency. All these results suggested that (AZT-GAAD NPs) can function as a promising delivery vectors for efficient antiviral drug delivery.

Designing and developing suppository formulations for anti-HIV drug delivery.

Despite a long history of use for rectal and vaginal drug delivery, the current worldwide market for suppositories is limited primarily due to a lack of user acceptability. Therefore, virtually no rational pharmaceutical development of antiviral suppositories has been performed. However, suppositories offer several advantages over other antiviral dosage forms. Current suppository designs have integrated active pharmaceutical ingredients into existing formulation designs without optimization. As such, emerging suppository development has been focused on improving upon the existing classical design to enhance drug delivery and is poised to open suppository drug delivery to a broader range of drugs, including antiretroviral products. Thus, with continuing research into rational suppository design and development, there is significant potential for antiretroviral suppository drug delivery.

Development of engineered nanocarrier for controlled delivery of a protease inhibitor

Background: AIDS is a chronic, progressive syndrome, characterized by intense viral replication and profound immunosuppression, resulting in the development of life threatening opportunistic infections. HIV infection leads to deterioration of immune functions. The objective of the present study was to develop, optimize and characterize engineered nanocarriers for controlled delivery of a protease inhibitor. Lopinavir was the drug of choice as it is an effective antiretroviral drug having specific and prominent anti-HIV action. In the present study, it is envisaged to develop and characterize a controlled delivery system wherein the drug lopinavir (LPV) will be entrapped in engineered nanocarrier. Engineered nanocarriers targeted towards the prespecified target tissues by coupling with mannose delivers the drug in a controlled manner to the site of action. Thus it results in increased bioavailability and avoids the adverse effects associated with the drug. Overall the approach leads to a safe, economical and effective Anti-HIV formulation. Methods & Materials: The uncoupled Solid Lipid Nanoparticles (SLN) were prepared by Solvent diffusion method and then coupled with mannose. Characterization studies were done by Scanning & Transmission Electron Microscopy (SEM & TEM). X-ray diffraction (XRD) and Differential scanning calorimetry (DSC) studies were performed along with the in-vitro studies followed by in-vivo studies on albino rats. Results: In-vitro & in-vivo studies results shows Mannose coated SLNs (MSLN) deliver their contents to macrophage rich organs and tissues, which are the reservoir of HIV. Low elimination and better distribution profile can be achieved by MSLNs. The dose of the antiviral agent can be reduced due to the site-specific delivery from this carrier.View Large Image Figure ViewerDownload Hi-res image Download (PPT) Conclusion: Conclusively, ligand-mediated bio-disposition and cellular interaction of MSLNs, especially at the target sites, would be a focal paradigm for upcoming research in the field of anti-HIV drug delivery. MSLNs have paved the way for the bio-stable, site-specific and ligand-mediated delivery systems with desired therapeutics.

RTG-loaded nanomicelles (CS–VES–NAC) for oral anti-HIV drug delivery

An acetylcysteine–chitosan–vitamin E succinate copolymer (CVN) was synthesized from chitosan (CS), vitamin E succinate (VES) and N-acetyl-l-cysteine (NAC) as self-assembled nanomicelles for multifunctional delivery of anti-HIV drug Raltegravir (RTG).

Colorectal delivery and retention of PEG-Amprenavir-Bac7 nanoconjugates--proof of concept for HIV mucosal pre-exposure prophylaxis.

Local delivery of anti-HIV drugs to the colorectal mucosa, a major site of HIV replication, and their retention within mucosal tissue would allow for a reduction in dose administered, reduced dosing frequency and minimal systemic exposure. The current report describes a mucosal pre-exposure prophylaxis (mPrEP) strategy that utilizes nanocarrier conjugates (NC) consisting of poly(ethylene glycol) (PEG), amprenavir (APV), and a cell-penetrating peptide (CPP; namely Bac7, a fragment derived from bactenecin 7). APV-PEG NCs with linear PEGs (2, 5, 10, and 30 kDa) exhibited reduced (52-21%) anti-HIV-1 protease (PR) activity as compared to free APV in an enzyme-based FRET assay. In MT-2 T cells, APV-PEG3.4 kDa-FITC (APF) anti-HIV-1 activity was significantly reduced (160-fold, IC50 = 8064 nM) due to poor cell uptake, whereas it was restored (IC50 = 78.29 nM) and similar to APV (IC50 = 50.29 nM) with the addition of Bac7 to the NC (i.e., APV-PEG3.4 kDa-Bac7, APB). Flow cytometry and confocal microscopy demonstrated Bac7-PEG3.4 kDa-FITC (BPF) uptake was two- and fourfold higher than APF in MT-2 T cells and Caco-2 intestinal epithelial cells, respectively. There was no detectable punctate fluorescence in either cell line suggesting that BPF directly enters the cytosol thus avoiding endosomal entrapment. After colorectal administration in mice, BPF mucosal concentrations were 21-fold higher than APF concentrations. BPF concentrations also remained constant for the 5 days of the study suggesting that (1) the NC's structural characteristics (i.e., the size of the PEG carrier and the presence of a CPP) significantly influenced tissue persistence, and (2) the NCs were probably lodged in the lamina propria since the average rodent colon mucosal cell turnover time is 2-3 days. These encouraging results suggest that Bac7 functionalized NCs delivered locally to the colorectal mucosa may form drug delivery depots that are capable of sustaining colorectal drug concentrations. Although the exact mechanisms for tissue persistence are unclear and will require further study, these results provide proof-of-concept feasibility for mPrEP.

Drug delivery strategies and systems for HIV/AIDS pre-exposure prophylaxis and treatment

The year 2016 will mark an important milestone — the 35th anniversary of the first reported cases of HIV/AIDS. Antiretroviral Therapy (ART) including Highly Active Antiretroviral Therapy (HAART) drug regimens is widely considered to be one of the greatest achievements in therapeutic drug research having transformed HIV infection into a chronically managed disease. Unfortunately, the lack of widespread preventive measures and the inability to eradicate HIV from infected cells highlight the significant challenges remaining today. Moving forward there are at least three high priority goals for anti-HIV drug delivery (DD) research: (1) to prevent new HIV infections from occurring, (2) to facilitate a functional cure, i.e., when HIV is present but the body controls it without drugs and (3) to eradicate established infection. Pre-exposure Prophylaxis (PrEP) represents a significant step forward in preventing the establishment of chronic HIV infection. However, the ultimate success of PrEP will depend on achieving sustained antiretroviral (ARV) tissue concentrations and will require strict patient adherence to the regimen. While first generation long acting/extended release (LA/ER) DD Systems (DDS) currently in development show considerable promise, significant DD treatment and prevention challenges persist. First, there is a critical need to improve cell specificity through targeting in order to selectively achieve efficacious drug concentrations in HIV reservoir sites to control/eradicate HIV as well as mitigate systemic side effects. In addition, approaches for reducing cellular efflux and metabolism of ARV drugs to prolong effective concentrations in target cells need to be developed. Finally, given the current understanding of HIV pathogenesis, next generation anti-HIV DDS need to address selective DD to the gut mucosa and lymph nodes. The current review focuses on the DDS technologies, critical challenges, opportunities, strategies, and approaches by which novel delivery systems will help iterate towards prevention, functional cure and eventually the eradication of HIV infection.

Progress in Brain Delivery of Anti-HIV Drugs

Article history: Received on: 17/01/2015 Revised on: 22/04/2015 Accepted on: 17/06/2015 Available online: 27/07/2015 The HIV/AIDS pandemic is an increasing global burden with devastating health-related and socioeconomic effects. The widespread use of antiretroviral therapy has dramatically improved life quality and expectancy of infected individuals. But currently available drug regimens and dosage forms are not good enough to eradicate HIV. Suboptimal adherence, toxicity, drug resistance and viral reservoirs make the lifelong treatment of HIV infection challenging. Along with some other organs, highly vascularized and secured with blood-brain barrier (BBB), brain acts as a great reservoir for the HIV virus. But all the available drug delivery techniques are not capable of bypassing the BBB and deliver anti-HIV drugs to the brain. In this review, all the brain delivery techniques available till date has been reviewed and recent noble ideas for delivering anti-HIV drugs to brain has been discussed.

Cyclic peptide-capped gold nanoparticles for enhanced siRNA delivery.

Previously, we have reported the synthesis of a homochiral l-cyclic peptide [WR]5 and its use for delivery of anti-HIV drugs and biomolecules. A physical mixture of HAuCl4 and the peptide generated peptide-capped gold nanoparticles. Here, [WR]5 and [WR]5-AuNPs were tested for their efficiency to deliver a small interfering RNA molecule (siRNA) in human cervix adenocarcinoma (HeLa) cells. Flow cytometry investigation revealed that the intracellular uptake of a fluorescence-labeled non-targeting siRNA (200 nM) was enhanced in the presence of [WR]5 and [WR]5-AuNPs by 2- and 3.8-fold when compared with that of siRNA alone after 24 h incubation. Comparative toxicity results showed that [WR]5 and [WR]5-AuNPs were less toxic in cells compared to other available carrier systems, such as Lipofectamine.

Targeting strategies for delivery of anti-HIV drugs.

Human Immunodeficiency Virus (HIV) infection remains a significant cause of mortality globally. Though antiretroviral therapy has significantly reduced AIDS-related morbidity and mortality, there are several drawbacks in the current therapy, including toxicity, drug–drug interactions, development of drug resistance, necessity for long-term drug therapy, poor bio-availability and lack of access to tissues and reservoirs. To circumvent these problems, recent anti-HIV therapeutic research has focused on improving drug delivery systems through drug delivery targeted specifically to host cells infected with HIV or could potentially get infected with HIV. In this regard, several surface molecules of both viral and host cell origin have been described in recent years, that would enable targeted drug delivery in HIV infection. In the present review, we provide a comprehensive overview of the need for novel drug delivery systems, and the successes and challenges in the identification of novel viral and host-cell molecules for the targeted drug delivery of anti-HIV drugs. Such targeted anti-retroviral drug delivery approaches could pave the way for effective treatment and eradication of HIV from the body.

Analysis of vaginal microbicide film hydration kinetics by quantitative imaging refractometry.

We have developed a quantitative imaging refractometry technique, based on holographic phase microscopy, as a tool for investigating microscopic structural changes in water-soluble polymeric materials. Here we apply the approach to analyze the structural degradation of vaginal topical microbicide films due to water uptake. We implemented transmission imaging of 1-mm diameter film samples loaded into a flow chamber with a 1.5×2 mm field of view. After water was flooded into the chamber, interference images were captured and analyzed to obtain high resolution maps of the local refractive index and subsequently the volume fraction and mass density of film material at each spatial location. Here, we compare the hydration dynamics of a panel of films with varying thicknesses and polymer compositions, demonstrating that quantitative imaging refractometry can be an effective tool for evaluating and characterizing the performance of candidate microbicide film designs for anti-HIV drug delivery.

Nanoemulsion-based intranasal drug delivery system of saquinavir mesylate for brain targeting

The central nervous system (CNS) is an immunological privileged sanctuary site-providing reservoir for HIV-1 virus. Current anti-HIV drugs, although effective in reducing plasma viral levels, cannot eradicate the virus completely from the body. The low permeability of anti-HIV drugs across the blood–brain barrier (BBB) leads to insufficient delivery. Therefore, developing a novel approaches enhancing the CNS delivery of anti-HIV drugs are required for the treatment of neuro-AIDS. The aim of this study was to develop intranasal nanoemulsion (NE) for enhanced bioavailability and CNS targeting of saquinavir mesylate (SQVM). SQVM is a protease inhibitor which is a poorly soluble drug widely used as antiretroviral drug, with oral bioavailability is about 4%. The spontaneous emulsification method was used to prepare drug-loaded o/w nanoemulsion, which was characterized by droplet size, zeta potential, pH, drug content. Moreover, ex-vivo permeation studies were performed using sheep nasal mucosa. The optimized NE showed a significant increase in drug permeation rate compared to the plain drug suspension (PDS). Cilia toxicity study on sheep nasal mucosa showed no significant adverse effect of SQVM-loaded NE. Results of in vivo biodistribution studies show higher drug concentration in brain after intranasal administration of NE than intravenous delivered PDS. The higher percentage of drug targeting efficiency (% DTE) and nose-to-brain drug direct transport percentage (% DTP) for optimized NE indicated effective CNS targeting of SQVM via intranasal route. Gamma scintigraphy imaging of the rat brain conclusively demonstrated transport of drug in the CNS at larger extent after intranasal administration as NE.

Specific Increase in MDR1 Mediated Drug-Efflux in Human Brain Endothelial Cells following Co-Exposure to HIV-1 and Saquinavir

Persistence of HIV-1 reservoirs within the Central Nervous System (CNS) remains a significant challenge to the efficacy of potent anti-HIV-1 drugs. The primary human Brain Microvascular Endothelial Cells (HBMVEC) constitutes the Blood Brain Barrier (BBB) which interferes with anti-HIV drug delivery into the CNS. The ATP binding cassette (ABC) transporters expressed on HBMVEC can efflux HIV-1 protease inhibitors (HPI), enabling the persistence of HIV-1 in CNS. Constitutive low level expression of several ABC-transporters, such as MDR1 (a.k.a. P-gp) and MRPs are documented in HBMVEC. Although it is recognized that inflammatory cytokines and exposure to xenobiotic drug substrates (e.g HPI) can augment the expression of these transporters, it is not known whether concomitant exposure to virus and anti-retroviral drugs can increase drug-efflux functions in HBMVEC. Our in vitro studies showed that exposure of HBMVEC to HIV-1 significantly up-regulates both MDR1 gene expression and protein levels; however, no significant increases in either MRP-1 or MRP-2 were observed. Furthermore, calcein-AM dye-efflux assays using HBMVEC showed that, compared to virus exposure alone, the MDR1 mediated drug-efflux function was significantly induced following concomitant exposure to both HIV-1 and saquinavir (SQV). This increase in MDR1 mediated drug-efflux was further substantiated via increased intracellular retention of radiolabeled [3H-] SQV. The crucial role of MDR1 in 3H-SQV efflux from HBMVEC was further confirmed by using both a MDR1 specific blocker (PSC-833) and MDR1 specific siRNAs. Therefore, MDR1 specific drug-efflux function increases in HBMVEC following co-exposure to HIV-1 and SQV which can reduce the penetration of HPIs into the infected brain reservoirs of HIV-1. A targeted suppression of MDR1 in the BBB may thus provide a novel strategy to suppress residual viral replication in the CNS, by augmenting the therapeutic efficacy of HAART drugs.

Enzymatic triggered release of an HIV-1 entry inhibitor from prostate specific antigen degradable microparticles

This paper describes the design, construction and characterization of the first anti-HIV drug delivery system that is triggered to release its contents in the presence of human semen. Microgel particles were synthesized with a crosslinker containing a peptide substrate for the seminal serine protease prostate specific antigen (PSA) and were loaded with the HIV-1 entry inhibitor sodium poly(styrene-4-sulfonate) (pSS). The particles were composed of N-2-hydroxyproplymethacrylamide and bis-methacrylamide functionalized peptides based on the PSA substrates GISSFYSSK and GISSQYSSK. Exposure to human seminal plasma (HSP) degraded the microgel network and triggered the release of the entrapped antiviral polymer. Particles with the crosslinker composed of the substrate GISSFYSSK showed 17 times faster degradation in seminal plasma than that of the crosslinker composed of GISSQYSSK. The microgel particles containing 1 mol% GISSFYSSK peptide crosslinker showed complete degradation in 30 h in the presence of HSP at 37 °C and pSS released from the microgels within 30 min reached a concentration of 10 μg/mL, equivalent to the published IC 90 for pSS. The released pSS inactivated HIV-1 in the presence of HSP. The solid phase synthesis of the crosslinkers, preparation of the particles by inverse microemulsion polymerization, HSP-triggered release of pSS and inactivation of HIV-1 studies are described.