Mannose-Anchored Nano-Selenium Loaded Nanostructured Lipid Carriers of Etravirine for Delivery to HIV Reservoirs.

The present investigation aims to develop and explore mannosylated lipid-based carriers to deliver an anti-HIV drug, Etravirine (TMC) and Selenium nanoparticles (SeNPs), to the HIV reservoirs via the mannose receptor. The successful mannosylation was evaluated by the change in zeta potential and lectin binding assay using fluorescence microscopy. Electron microscopy and scattering studies were employed to study the structure and surface of the nanocarrier system. The presence of selenium at the core-shell of the nanocarrier system was confirmed by X-ray photoelectron spectroscopy and energy dispersive X-ray analysis. Further, the in vitro anti-HIV1 efficacy was assessed using HIV1 infected TZM-bl cells followed by in vivo biodistribution studies to evaluate distribution to various reservoirs of HIV. The results exhibited higher effectiveness and a significant increase in the therapeutic index as against the plain drug. The confocal microscopy and flow cytometry studies exhibited the efficient uptake of the coumarin-6 tagged respective formulations. The protective effect of nano selenium toward oxidative stress was evaluated in rats, demonstrating the potential of the lipidic nanoparticle-containing selenium in mitigating oxidative stress in all the major organs. The in vivo biodistribution assessment in rats showed a 12.44, 8.05 and 9.83-fold improvement in the brain, ovary, and lymph node biodistribution, respectively as compared with plain TMC. Delivery of such a combination via mannosylated nanostructured lipid carriers could be an efficient approach for delivering drugs to reservoirs of HIV while simultaneously reducing the oxidative stress induced by such long-term therapies by co-loading Nano-Selenium.

Nanostructured Lipid Carrier of Propofol: a Promising Alternative to Marketed Soybean Oil-Based Nanoemulsion.

Nanostructured lipid carrier (NLC) of propofol was formulated using hot emulsification-probe sonication method for improvising its parenteral delivery by reducing pain on injection and risk of microbial contamination. The formulated NLC was optimized using central composite design and evaluated for particle size, zeta potential, morphology, free propofol concentration, hemocompatibility, stability, pain on injection, in vivo anesthetic activity, pharmacokinetics, and antimicrobial effectiveness in comparison to the marketed formulation. Optimized NLCs exhibited globule size, less than 200 nm, and zeta potential - 24.1 mV, indicating its stability. TEM images confirmed the spherical shape and nanosize (200 nm) of optimized NLCs. Free propofol concentration was also found to be 40% lesser than marketed formulation. Optimized NLC was found to be non-hemolytic. Rat paw-lick study showed that propofol NLC was significantly less painful compared to the marketed formulation. Anesthetic potential and pharmacokinetics of optimized NLCs were found to be similar to that of the marketed formulation. NLC was found stable in long-term storage under room temperature. Antimicrobial effectiveness study showed that propofol NLC suppressed microbial growth to a greater extent as compared to the marketed formulation. Hence, the developed propofol NLCs appeared to be clinically useful as a potential carrier for propofol delivery.

Modified rankin scale is a reliable tool for the rapid assessment of stroke severity and predicting disability outcomes.

Background: 'Time is brain' goes the adage. Rapid and precise management of stroke is of the utmost essence. The modified National Institutes of Health Stroke Scale (mNIHSS) and the modified Rankin Scale (mRS) predict stroke severity and functional disability outcomes. However, the mRS can be administered more rapidly than the mNIHSS and therefore might be better to assess patient outcomes. Hence, the aim of this study was to assess the correlation of stroke severity on admission and functional disability outcomes on the day of discharge or on the 8th day of hospitalization. Materials and Methods: This was an observational, cross-sectional study with a sample size of 61 participants. The mNIHSS score was calculated on admission for patients with clinical features suggestive of stroke and mRS was calculated on the 8th day of hospitalization or on discharge. Evaluation of the association between continuous variables was done using Spearman's correlation analysis. Results: Correlation between mNIHSS and mRS was positive and statistically significant (rho = 0.866, 95% CI [0.751, 0.925]. For each point increase in the mNIHSS, the odds of having higher mRS scores are 153% more than the odds of having lower mRS scores (aOR = 2.534, 95% CI [1.904, 3.560]). Conclusion: Our study concluded that mRS can be reliably used to predict the functional outcomes for patients with stroke in circumstances where the mNIHSS may prove to be lengthy. Thus, where 'time is brain', the mRS can be used with a similar power to predict the outcome.

Amalgamation of Nanoparticles within Drug Carriers: A Synergistic Approach or a Futile Attempt?

In recent years, nanotechnology has gained much attention from scientists and significant advances in therapeutic potential. Nano-delivery systems have emerged as an effective way in order to improve the therapeutic properties of drugs including solubility, stability, prolongation of half-life as well as promoting the accumulation of drug at the target site. The nanoparticles have also been incorporated into various conventional drug delivery systems. This review study aims to introduce the amalgamation of nanoparticles into drug carriers. To overcome the limitations of single nanoparticles such as toxicity, high instability, rapid drug release as well as limited drug loading capacity, a multi-component system is developed. Liposomes, microparticles, nanofibers, dendrimers etc., are promising drug carriers, having some limitations that can be minimized, and the compilation of nanoparticles synergizes the properties. The amalgamated nanocarriers are used for the diagnostic purpose as well as treatment of various chronic diseases. It also increases the solubility of hydrophobic drugs. However, each system has its advantages and disadvantages based on its physicochemical properties, efficacy, and other parameters. This review details the past and present state of development for the fusion of nanoparticles within drug carriers and from which we identify future research works needed for the same.

Novel Nanotechnology-Based Approaches for Targeting HIV Reservoirs.

Highly active anti-retroviral therapy (HAART) is prescribed for HIV infection and, to a certain extent, limits the infection's spread. However, it cannot completely eradicate the latent virus in remote and cellular reservoir areas, and due to the complex nature of the infection, the total eradication of HIV is difficult to achieve. Furthermore, monotherapy and multiple therapies are not of much help. Hence, there is a dire need for novel drug delivery strategies that may improve efficacy, decrease side effects, reduce dosing frequency, and improve patient adherence to therapy. Such a novel strategy could help to target the reservoir sites and eradicate HIV from different biological sanctuaries. In the current review, we have described HIV pathogenesis, the mechanism of HIV replication, and different biological reservoir sites to better understand the underlying mechanisms of HIV spread. Further, the review deliberates on the challenges faced by the current conventional drug delivery systems and introduces some novel drug delivery strategies that have been explored to overcome conventional drug delivery limitations. In addition, the review also summarizes several nanotechnology-based approaches that are being explored to resolve the challenges of HIV treatment by the virtue of delivering a variety of anti-HIV agents, either as combination therapies or by actively targeting HIV reservoir sites.

Multi-organ targeting of HIV-1 viral reservoirs with etravirine loaded nanostructured lipid carrier: An in-vivo proof of concept.

The inadequate bioavailability and toxicity potential of antiretroviral therapy limit their effectiveness in the complete eradication of HIV from viral reservoirs. The penetration of these drugs into the brain is challenging because of the unfavorable physicochemical properties required to cross the membranes, limiting the transport of the drugs. Thus, in the current study, the authors report a nanocarrier-based drug delivery of a highly hydrophobic drug to overcome the existing limitations of the conventional therapies. An explicitly simple approach was used to overcome the limitations of existing anti-HIV therapies. The monophasic hot homogenized solution of lipid, drug, and solubilizer was diluted with the predetermined hot surfactant solution followed by the ultrasonication to generate the polydisperse nanoparticles with the size range of 50-1000 nm. The anti-HIV1 potential of nanostructured lipid carriers of Etravirine on HIV-infected cell lines showed efficacy with an appreciable increase in the therapeutic index as compared with the plain drug. Further, the results obtained from confocal microscopy along with flow cytometry exhibited efficient uptake of the nanocarrier loaded with coumarin-6 in cells. The pharmacokinetics of Etravirine nanostructured carriers was significantly better in all aspects compared to the plain drug solution, which could be attributed to molecular dispersion in the lipid matrix of the nanocarrier. A significant enhancement of Etravirine concentration of several-fold was also observed in the liver, ovary, lymph node, and brain, respectively, as compared to plain drug solution when assessed by biodistribution studies in rats. In conclusion, ETR-NLC systems could serve as a promising approach for simultaneous multi-site targeting and could provide therapeutic benefits for the efficient eradication of HIV/AIDS infections.

Dual loaded nanostructured lipid carrier of nano-selenium and Etravirine as a potential anti-HIV therapy.

There is a dire need for dual-long-acting therapy that could simultaneously target different stages of the HIV life cycle and providing a dual-prolonged strategy for improved anti-HIV therapy while reducing oxidative stress associated with the prolonged treatment. Thus, in the present work, nanostructured lipid carriers of Etravirine were developed and modified with nano-selenium. The dual-loaded nanocarrier system was fabricated using the double emulsion solvent evaporation method, further screened and optimized using the design of experiments methodology. The spherical core-shell type of a system was confirmed with an electron microscope and small-angle neutron scattering, while XPS confirmed the presence of selenium at the core-shell of the nanocarrier. In vitro assessment against HIV1 (R5 and X4 strains) infected TZM-bl cells exhibited higher efficacy for the dual-loaded nanocarrier system than the plain drug, which could be attributed to the synergistic effect of the nano-selenium. Confocal microscopy and flow cytometry results exhibited enhanced uptake in TZM-bl cells compared to plain drug. A significant increase of GSH, SOD, CAT was observed in animals administered with the dual-loaded nanocarrier system containing nano-selenium, suggesting the protective potential of the lipidic nanoparticle containing the nano-selenium. Improvement in the in vivo pharmacokinetic parameters was also observed, along with a higher accumulation of the dual-loaded nanocarrier in remote HIV reservoir organs like the brain, ovary, and lymph node. The results suggest the potential of a dual-loaded formulation for synergistically targeting the HIV1 infection while simultaneously improving the intracellular anti-oxidant balance for improving a prolonged anti-HIV therapy.

Chitosan oligosaccharide enhances binding of nanostructured lipid carriers to ocular mucins: Effect on ocular disposition.

The objective of the study was to assess the effect of enhanced mucoadhesion of a cationic mucoadhesive nanostructured lipid carrier (NLC) on its ocular disposition after topical administration. The NLC was made mucoadhesive by surface coating with chitosan oligosaccharide (COS), a low molecular weight derivate of chitosan which is more suitable for drug delivery applications as compared to the native chitosan. The NLC was characterised by surface evaluating techniques like SANS and XPS for confirming coating of COS over the surface of NLC. In order to assess the effect of COS coating on in vivo ocular mucoadhesion, coumarin loaded NLC were topically administered to rats and the sagittal sections of the eyes were imaged using confocal microscopy. The COS coated NLC were seen to adhere more around the ocular surface than the uncoated NLC during the 4-h study. The improved ocular retention for COS-NLC reflected on the content of Etoposide within the eye, which showed a higher concentration of Etoposide, as compared to the uncoated NLC. The NLC was also assessed for any ocular irritancy in rabbits and repeat dose toxicity in rats and found to be relatively non-irritant and non-toxic as compared to appropriate controls. Thus, the study asserts that to achieve higher concentration of therapeutics within the eye, the formulations like NLC are not just required to be permeating but also retentive on the surface of the eye to achieve appreciable concentrations.

Exploring molecular dynamics simulation to predict binding with ocular mucin: An in silico approach for screening mucoadhesive materials for ocular retentive delivery systems.

In recent times, molecular dynamic (MD) simulations have been applied in the area of drug delivery, as an in silico tool to predict the behaviour of nanoparticles with respect to their interaction with larger biological entities like bilayer membranes, DNA and dermal surface. However, the predictions must be systematically evaluated by extensive studies with actual biological entities in order to deem the in silico models accurate. Thus, in the present study, MD simulation was used to screen ligands with respect to ocular mucoadhesion. Mucin-4, a cell surface-associated mucin was selected as the substrate for the in silico study due to its abundance across the ocular surface. The ligands were then incorporated into a delivery system like nanostructured lipid carriers (NLC) and assessed for mucoadhesion by relevant in vitro and in vivo techniques. The in silico study suggested chitosan oligosaccharide (COS) to have an extensive mucoadhesive potential towards ocular mucin followed by stearylamine (STA) and cetrimonium bromide (CTAB) which showed intermediate and low mucoadhesion respectively. The corresponding in vitro assessment by spectrophotometry and nanoparticle tracking analysis showed a similar outcome wherein COS was found to be extensively mucoadhesive, followed by both STA and CTAB, which showed mucoadhesion to a nearly equal extent. The findings of in vivo confocal imaging following topical administration to rats showed that while COS and STA adhered extensively to the ocular surface, CTAB showed negligible adhesion. MD simulation was thus found to accurately predict interactions critical to mucoadhesion and the same could be fairly correlated well by relevant mucoadhesion studies both in vitro and in vivo.

Liposils: An effective strategy for stabilizing Paclitaxel loaded liposomes by surface coating with silica.

The present work aims at improving stability of paclitaxel (PTX) loaded liposomes by its coating with silica on the surface by a modified sol-gel method. Effect of various components of liposomes such as phosphatidylcholine to cholesterol ratio (PC:CH), PTX and stearylamine on entrapment efficiency (% EE) and particle size were systematically investigated and optimized using central composite design on Design-Expert®. The optimized liposomes were utilized as a template for silica coating to prepare surface coated PTX liposils. Physical stability of liposomes and liposils was evaluated with Triton X-100 and the results indicated that liposils were much more stable as compared to liposomes and the same has been reiterated in stability study performed over 6 months. In vitro cytotoxicity study on B16F10 tumor cells showed cytotoxicity of PTX liposils was not significantly different than PTX liposomes, whereas both were less cytotoxic as compared to the commercial Taxol®. In vivo pharmacokinetics on rats, exhibited increased T1/2 of liposils when compared to liposomes and Taxol®, thus releasing the drug over a longer duration. The enhanced physicochemical stability as well as controlled release of PTX in liposils developed in this study could be an effective alternative to Taxol® and PTX liposomes.

Nose to Brain Delivery of Rivastigmine by In Situ Gelling Cationic Nanostructured Lipid Carriers: Enhanced Brain Distribution and Pharmacodynamics.

Present investigation explores the potential of nanostructured lipid carriers (NLCs) for nose to brain delivery of rivastigmine (RV), which is further enhanced by incorporating into an in situ gelling system, increasing retention in nasal cavity. NLCs having particle size of 123.2 ± 2.3 nm, entrapment efficiency of 68.3 ± 3.4%, and zeta potential of 32 ± 1.2 mV was fabricated by a scalable method. Pharmacokinetics showed sustained release of intranasal (IN) and intravenous (IV) NLCs compared with RV solution by same route, with significantly higher AUC and Thalf. Biodistribution indicated blood brain barrier penetrating potential of IV NLCs (457.24 ± 38.41.12 ng/mL) and IN NLCs (736.42 ± 34.54 ng/mL) with 4.6 and 5.3-fold enhancement in brain concentrations compared with IV and IN solution of RV. Similar results reflected in pharmacodynamics, indicating faster regain of memory loss in amnesic mice with 5-fold decrease in escape latency with NLCs compared with plain RV solution by IV and IN routes respectively. Sub-acute toxicity studies demonstrated safety of developed formulations to vital organs without any hematological and biochemical changes compared with control group. Moreover, nasal toxicity studies of NLCs showed no signs of inflammation, maintaining the integrity of ciliary epithelial cells, thus confirming safety of the formulation for its intended nasal application.

Development and Evaluation of Chitosan Microparticles Based Dry Powder Inhalation Formulations of Rifampicin and Rifabutin.

BACKGROUND: The lung is the primary entry site and target for Mycobacterium tuberculosis; more than 80% of the cases reported worldwide are of pulmonary tuberculosis. Hence, direct delivery of anti-tubercular drugs to the lung would be beneficial in reducing both, the dose required, as well as the duration of therapy for pulmonary tuberculosis. In the present study, microsphere-based dry powder inhalation systems of the anti-tubercular drugs, rifampicin and rifabutin, were developed and evaluated, with a view to achieve localized and targeted delivery of these drugs to the lung. METHODS: The drug-loaded chitosan microparticles were prepared by an ionic gelation method, followed by spray-drying to obtain respirable particles. The microparticles were evaluated for particle size and drug release. The drug-loaded microparticles were then adsorbed onto an inhalable lactose carrier and characterized for in vitro lung deposition on an Andersen Cascade Impactor (ACI) followed by in vitro uptake study in U937 human macrophage cell lines. In vivo toxicity of the developed formulations was evaluated using Sprague Dawley rats. RESULTS: Both rifampicin and rifabutin-loaded microparticles had MMAD close to 5 µm and FPF values of 21.46% and 29.97%, respectively. In vitro release study in simulated lung fluid pH 7.4 showed sustained release for 12 hours for rifampicin microparticles and up to 96 hours for rifabutin microparticles, the release being dependent on both swelling of the polymer and solubility of the drugs in the dissolution medium. In vitro uptake studies in U937 human macrophage cell line suggested that microparticles were internalized within the macrophages. In vivo acute toxicity study of the microparticles in Sprague Dawley rats revealed no significant evidence for local adverse effects. CONCLUSION: Thus, spray-dried microparticles of the anti-tubercular drugs, rifampicin and rifabutin, could prove to be an improved, targeted, and efficient system for treatment of tuberculosis.