Damping and Interfacial Dzyaloshinskii-Moriya Interaction in Thulium Iron Garnet/Bismuth-Substituted Yttrium Iron Garnet Bilayers.

Thin films of ferrimagnetic iron garnets can exhibit useful magnetic properties, including perpendicular magnetic anisotropy (PMA) and high domain wall velocities. In particular, bismuth-substituted yttrium iron garnet (BiYIG) films grown on garnet substrates have a low Gilbert damping but zero Dzyaloshinskii-Moriya interaction (DMI), whereas thulium iron garnet (TmIG) films have higher damping but a nonzero DMI. We report the damping and DMI of thulium-substituted BiYIG (BiYTmIG) and TmIG|BiYIG bilayer thin films deposited on (111) substituted gadolinium gallium garnet and neodymium gallium garnet (NGG) substrates. The films are epitaxial and exhibit PMA. BiYIG|TmIG bilayers have a damping value that is an order of magnitude lower than that of TmIG, and BiYIG|TmIG|NGG have DMI of 0.0145 ± 0.0011 mJ/m2, similar to that of TmIG|NGG. The bilayer therefore provides a combination of DMI and moderate damping, useful for the development of high-speed spin orbit torque-driven devices.

Nose-to-brain drug delivery for the treatment of glioblastoma multiforme: nanotechnological interventions.

Glioblastoma multiforme (GBM) is the most aggressive malignant brain tumor with a short survival rate. Extensive research is underway for the last two decades to find an effective treatment for GBM but the tortuous pathophysiology, development of chemoresistance, and presence of BBB are the major challenges, prompting scientists to look for alternative targets and delivery strategies. Therefore, the nose to brain delivery emerged as an unorthodox and non-invasive route, which delivers the drug directly to the brain via the olfactory and trigeminal pathways and also bypasses the BBB and hepatic metabolism of the drug. However, mucociliary clearance, low administration volume, and less permeability of nasal mucosa are the obstacles retrenching the brain drug concentration. Thus, nanocarrier delivery through this route may conquer these limitations because of their unique surface characteristics and smaller size. In this review, we have emphasized the advantages and limitations of nanocarrier technologies such as polymeric, lipidic, inorganic, and miscellaneous nanoparticles used for nose-to-brain drug delivery against GBM in the past 10 years. Furthermore, recent advances, patents, and clinical trials are highlighted. However, most of these studies are in the early stages, so translating their outcomes into a marketed formulation would be a milestone in the better progression and survival of glioma patients.

Withdrawal Notice: Recent Advancements in Lung Cancer Treatment us-ing Receptor Targeting

The article for the journal Current Molecular Pharmacology has been removed by the Publisher due to acute language inconsistencies and grammatical errors.The Bentham Editorial Policy on Article Withdrawal can be found at https://benthamscience.com/editorial-policiesmain.php Bentham Science Disclaimer: It is a condition of publication that manuscripts submitted to this journal have not been published and will not be simultaneously submitted or published elsewhere. Furthermore, any data, illustration, structure or table that has been published elsewhere must be reported, and copyright permission for reproduction must be obtained. Plagiarism is strictly forbidden, and by submit-ting the article for publication the authors agree that the publishers have the legal right to take appropriate action against the authors, if plagiarism or fabricated information is discovered. By submitting a manuscript, the authors agree that the copyright of their article is transferred to the publishers if and when the article is accepted for publication.

DoE Based Optimization and Development of Spray-Dried Chitosan-Coated Alginate Microparticles Loaded with Cisplatin for the Treatment of Cervical Cancer.

BACKGROUND: The existing parenteral treatment of cervical cancer has high toxicity and poor distribution of drugs at the targeted site. PURPOSE: To formulate localized mucoadhesive cisplatin loaded microparticles based formulation to treat cervical cancer so that enhanced therapeutics benefits with low toxicity could be achieved. METHODS: Cisplatin loaded chitosan coated spray-dried microparticles were prepared by ionotropic gelation technique and optimized by Central Composite Design. The spray-dried uncoated and chitosan- coated microparticles were characterized for various parameters (Particle size, Morphology, Drug entrapment efficiency). In vitro drug release study was carried out in simulated vaginal fluids by dialysis membrane method. Ex vivo studies were carried out to evaluate the cytotoxic potential of the developed formulation by the MTT assay. A drug permeability study was performed by Franz diffusion cell using the vaginal tissue of Swiss Albino Mice. RESULTS: All in vitro characterization parameters were found to be optimum. The in vitro release studies indicated a controlled release following the Higuchi model. The chitosan-coated microparticles were found to be more cytotoxic than uncoated microparticles and plain cisplatin solution. The chitosan-coated microparticles were found to be more permeable than uncoated microparticles. Finally, in vivo tumor regression and histopathological studies confirmed the significant decrease in tumor volume at different time intervals. CONCLUSION: Thus, it can be concluded that mucoadhesive spray-dried microparticles could provide a favorable approach for localized delivery of the anticancer drug via vaginal route against cervical cancer with its enhanced effectiveness.

Formulation, Optimization and In vitro / In vivo Characterization of Spray Dried Doxorubicin Loaded Folic Acid Conjugated Gelatin Nanoparticles.

AIM: Formulation, optimization and anticancer activity of spray-dried Doxorubicin loaded folic acid conjugated Gelatin nanoparticles (DOX-FA-GN). METHODS: Doxorubicin loaded gelatin nanoparticles (DOX-GN) were prepared by the Coacervation phase separation method, optimized using DoE and then conjugated with folic acid by covalent coupling to formulate Doxorubicin loaded folic acid conjugated nanoparticles (DOX-FA-GN). The formulated nanoparticles were characterized to evaluate its physicochemical properties. Cellular uptake and cell viability studies were carried out using MTT assay and biodistribution studies were carried out in Wistar rats. RESULTS: Particle size, PDI and entrapment efficiency for optimized DOX-GN were found to be 152.3 ± 9.3 nm 0.294 ± 0.1 and 86.9± 3.4% while for DOX-FA-GN, 193.9 ± 12.3 nm 0.247 ± 0.2 and 84 ± 3.6%. The cytotoxic studies showed a cell viability of 75.1% for DOX-GN and 29.5% DOX-FA-GN. Biodistribution studies were found to be statistically insignificant for conjugated nanoparticles with excellent flow properties. Significantly higher DOX distribution in the lungs was observed in the case of DOX-FA-GN. CONCLUSION: There was a higher uptake of DOX on HeLa cells with DOX-FA-GN compared to DOX-GN. Also, the biodistribution of Dox in the lungs of Wistar rats was higher in conjugated nanoparticles as compared to unconjugated nanoparticles.

Statistical development and in vivo evaluation of resveratrol-loaded topical gel containing deformable vesicles for a significant reduction in photo-induced skin aging and oxidative stress.

OBJECTIVE: The present study aims to formulate and evaluate a novel vesicular formulation of resveratrol to achieve its dermatological benefits in terms of antiphotoaging and antioxidant. METHOD: In this study, resveratrol-loaded deformable vesicular gel was prepared and optimized using Box-Behnken design. Selected critical material attributes were amount of phospholipid (X1), concentration of ethanol (X2), and amount of sodium cholate (X3). The prepared transethosomal vesicles were incorporated into carbopol gel base and evaluated. Ultraviolet radiation-induced skin aging and oxidative stress model in Swiss Albino mice was used to evaluate the clinical potential of the developed formulation and compared with conventional gel. Levels of Super Oxide Dismutase (SOD), catalase, glutathione peroxidase, protein content, and malondialdehyde were measured to assess the extent of lipid peroxidation and reactive oxygen species inhibition in different groups. RESULT: DoE was successfully employed to optimize the vesicular formulation. Vesicle size was found to be 158.9 ± 7.65 nm, while values of entrapment efficiency and skin deposition were found to be 77.83 ± 2.87% and 371.84 ± 5.12 µg cm-2, respectively. Visual skin grading and histopathological studies confirmed the higher efficacy of transethosomal resveratrol against oxidative stress. Significant enhancement in the levels of antioxidant enzymes and protein content confirmed the ameliorated potential of flexible transethosomal resveratrol as compared to the plain gel of resveratrol. CONCLUSION: Restoration of first-line defense mechanism in chronic UV-exposed animal model has proved that transethosomal resveratrol can be developed as an innovative cosmetic product for significant improvement and repair of photo-aged skin.

A Comprehensive Review on Nanotechnology-Based Innovations in Topical Drug Delivery for the Treatment of Skin Cancer.

BACKGROUND: Skin is the largest organ of the body and helps to regulate several physiological functions. It acts as a barrier that protects the body against UV-radiation, toxic substances, infections, etc. The abnormal growth of the skin cells is called skin cancer. Different types of skin cancer can be classified as Basal Cell Carcinoma (BCC) and Squamous Cell Carcinoma (SCC); which mainly occur due to chronic exposure to UV- sunlight and pollution. METHODS: The conventional topical treatments of skin cancer such as cream, gel, ointment, etc., are more occlusive and thus they do not penetrate deep into the skin (dermal layer) and remain at the upper part of the skin (epidermal layer). The stratum corneum acts as a physiological barrier for the drug-loaded in the conventional formulation. The novel carrier systems have the potential to facilitate the penetration of the drug deep into the skin (dermal layer) because these have less size and higher flexibility than conventional treatment. CONCLUSION: In the present review, we have discussed various novel carrier systems being investigated for the topical application of chemotherapeutic agents for efficient skin targeting and better dermatological as well as therapeutic benefits with minimal systemic exposure and toxicity.

FbD Supported Development and In Vitro Evaluation of Carbomer based Resveratrol Loaded Topical Antipsoriatic Nanoemulgel for its Targeted Skin Delivery.

BACKGROUND: Resveratrol is a wonder therapy for the treatment of several skin disorders, including psoriasis, but its skin permeation limits its applications. OBJECTIVE: The present work dealt with optimizing and formulating resveratrol loaded vitamin E based nanoemulsion and carbomer based nanoemulgel intended for topical application in the treatment of plaque psoriasis. The major objective of this study was to achieve the quality target product profile with respect to enhanced skin permeation and superior skin deposition of the formulated nanoemulgel to achieve the superlative therapeutic advantages. METHODS: Formulation by design (FbD) approach was employed to optimize varied critical material attributes such as the concentration of oil and Smix to achieve the desired quality characteristics. Carbomer based nanoemulgel was formulated and evaluated. RESULTS: Optimized formulation was having globule size (168.3 ± 4.98 nm), percentage cumulative permeation (4.81 ± 0.65%), permeation flux (7.62 ± 0.39 µg hr-1cm-2), and skin deposition (668.65 ± 11.98 µg cm-2). Nanoemulgel was found to have optimum physical properties in terms of viscosity, spreadability, pH and physical stability. The extent of skin deposition was approximately 6.682 times higher while the permeation enhancement ratio was around 2.872 as compared to conventional formulation indicating its higher skin targeting abilities, which was further ratified by Confocal Laser Scanning Microscopy results. CONCLUSION: Nanoemulgel formulated by the current FbD approach has enhanced skin permeation and skin deposition properties as compared to conventional carbomer gel. Thus, it could augment the therapeutic benefits of encapsulated bioactive in the treatment of several skin disorders like psoriasis.

DoE directed optimization, development and evaluation of resveratrol loaded ultradeformable vesicular cream for topical antioxidant benefits.

Objective: Aim of the present work was to optimize and formulate resveratrol loaded vesicular cream intended for dermal delivery of resveratrol with high skin deposition potential.Methods: Formulation was developed and optimized using Central Composite Design. Amount of phospholipid and sodium cholate were selected as critical material attributes and vesicle size and entrapment efficiency of resveratrol were taken as critical quality attributes. To increase the skin applicability and patient compliance, vesicles were further developed as vesicular cream which was then thoroughly characterized for physicochemical parameters, ex vivo skin permeation/deposition profile and antioxidant potential.Results: Vesicle size and entrapment efficiency of the optimized batch were found to be 178.9 ± 12.87 nm with 72.32 ± 3.45% respectively. Physicochemical properties and viscosity of cream formulation were also found to be favorable for skin applicability. Permeation flux at the end of 24 h was found to be 2.70 ± 0.73, 4.45 ± 0.56 and 4.95 ± 0.69 µg cm-2 h-1 for conventional cream, vesicular dispersion, and vesicular cream formulation respectively. Higher drug deposition in the skin via vesicular cream formulation was observed i.e. 335.2 ± 4.12 µg cm-2 (70.16 ± 0.87%) as compared to conventional cream i.e. 67.12 ± 19.63 µg cm-2 (14.05 ± 4.11%). Resveratrol encapsulated in vesicular cream has retained its inherent antioxidant activity suggesting the stability of resveratrol in vesicular cream.Conclusion: Thus, it can be concluded that deformable vesicular cream is capable of delivering encapsulated bioactive in deeper layers of skin, where it can be retained for achieving higher dermatological benefits.

Recent Advances in Nanosuspension Technology for Drug Delivery.

BACKGROUND: Discovery and development of BCS class 1 drugs through high throughput screening is one of the biggest challenge faced by formulation scientist. METHODS: There are a number of approaches that have been exploited to enhance the solubility and permeability of drugs. Among them, development of nanosuspension has offered several benefits. These techniques may increase effective surface area due to nanonization of drug particles and further increases saturation solubility and dissolution properties for improved bioavailability. Various development methods are patented which are cost effective and easy to scale up. CONCLUSION: Several unique features of nanosuspension make it a versatile delivery system for different routes of administration including oral, dermal, ocular, parenteral and pulmonary. The present review is focused on preparatory techniques and formulation considerations of nanosuspension. Brief information about evaluation parameters, applications of nanosuspension in drug delivery and patented and marketed products available is also discussed.

Lipoplexes versus nanoparticles: pDNA/siRNA delivery.

Small interfering RNA (siRNA) has been widely used as potential therapeutic for treatment of various genetic disorders. However, rapid degradation, poor cellular uptake and limited stability in blood limit the effectiveness of the systemic delivery of siRNA. Therefore, an efficient delivery system is required to enhance its transfection and duration of therapeutics. In the present study, plasmid DNA (pEGFPN3) expressing green fluorescent protein (GFP) was used as a reporter gene. Chitosan nanoparticles/polyplexes and cationic liposomes/lipoplexes were developed and compared for their transfectivity and therapeutic activity in mammalian cell line (HEK 293). The nanoparticulates were first characterized by assessing the surface charge (zeta potential), size (dynamic light scattering) and morphology (transmission electron microscope) followed by evaluation for their DNA retardation ability, transfection efficiency and cytotoxicity on HEK 293 cell line. The chitosan nanoparticles/plasmid DNA (pDNA) complex and liposomes/pDNA complex were co-transfected with GFP-specific siRNA into HEK 293 cells and it was found that both are efficient delivery vehicles for siRNA transfection, resulting in ~57% and ~70% suppression of the targeted gene (GFP), respectively, as compared with the mock control (cells transfected with nanocarrier/pDNA complexes alone). This strong inhibition of GFP expression indicated that cationic liposomes are better than chitosan nanoparticles and can be used as an effective carrier of siRNA in mammalian cells.

Human TOP1 residues implicated in species specificity of HIV-1 infection are required for interaction with BTBD2, and RNAi of BTBD2 in old world monkey and human cells increases permissiveness to HIV-1 infection.

BACKGROUND: Host determinants of HIV-1 viral tropism include factors from producer cells that affect the efficiency of productive infection and factors in target cells that block infection after viral entry. TRIM5α restricts HIV-1 infection at an early post-entry step through a mechanism associated with rapid disassembly of the retroviral capsid. Topoisomerase I (TOP1) appears to play a role in HIV-1 viral tropism by incorporating into or otherwise modulating virions affecting the efficiency of a post-entry step, as the expression of human TOP1 in African Green Monkey (AGM) virion-producing cells increased the infectivity of progeny virions by five-fold. This infectivity enhancement required human TOP1 residues 236 and 237 as their replacement with the AGM counterpart residues abolished the infectivity enhancement. Our previous studies showed that TOP1 interacts with BTBD1 and BTBD2, two proteins which co-localize with the TRIM5α splice variant TRIM5δ in cytoplasmic bodies. Because BTBD1 and BTBD2 interact with one HIV-1 viral tropism factor, TOP1, and co-localize with a splice variant of another, we investigated the potential involvement of BTBD1 and BTBD2 in HIV-1 restriction. RESULTS: We show that the interaction of BTBD1 and BTBD2 with TOP1 requires hu-TOP1 residues 236 and 237, the same residues required to enhance the infectivity of progeny virions when hu-TOP1 is expressed in AGM producer cells. Additionally, interference with the expression of BTBD2 in AGM and human 293T target cells increased their permissiveness to HIV-1 infection two- to three-fold. CONCLUSIONS: These results do not exclude the possibility that BTBD2 may modestly restrict HIV-1 infection via colocation with TRIM5 variants in cytoplasmic bodies.

siRNA delivery using nanocarriers - an efficient tool for gene silencing.

Small interfering RNAs (siRNA) are one of the most recent additions used to silence gene expression. At present siRNA is the most extensively used gene-silencing technique over other nucleic-acid based approaches to treat disease including cancer, hepatitis, respiratory disease, cardiovascular diseases, neuronal disease and autoimmune disease. However, systemic delivery of siRNA in vivo, remains to be the biggest challenge to be overcome. Various strategies have been developed to deliver siRNA efficiently into target cell such as chemical modification of siRNA, physical strategies, viral and non viral-vectors mediated delivery. Among all the approaches non viral vectors including lipoplexes and polyplexes were found to be most successful which have been reviewed in this article. Further therapeutic applications of RNAi have also been briefly reviewed.

Evaluation of immune response to bovine rotavirus following oral and intraperitoneal inoculation in mice.

With a view to use mice as an experimental model for studying immune response to bovine rotavirus (BRV), the kinetics of humoral and cellular immune responses to BRV in mice were evaluated by immunizing through intraperitoneal and oral route with UK strain of BRV. Following immunization with BRV, anti-rotavirus antibodies was developed in mice. The mean log antibody titres as measured by ELISA in mice immunized by intraperitoneal route were significantly higher than those immunized by oral route. Significant cellular immune response was observed in BRV-immunized mice on stimulation with BRV antigen, as measured by lymphocyte proliferation assay. The thymidine uptake by splenic and mesenteric lymph-node cells of intraperitoneally immunized mice on stimulation with BRV was 21328 +/- 1225 and 739 +/- 55 CPM, respectively. The splenic cells showed significantly higher stimulation (stimulation index 12.98) as compared to those of mesenteric cells (stimulation index 1.57). Foot pad inoculation test showed maximum virus-specific delayed type hypersensitivity reaction at 24 hr post-challenge following primary immunization and at 18 hr post-challenge following secondary immunization. The results indicate that BRV immunization by intraperitoneal route generates more efficient immune response in mice than by oral route and this route may be used for immune response studies involving BRV infection.

A protein sequestering system reveals control of cellular programs by the transcriptional coactivator HCF-1.

The mammalian transcriptional coactivator HCF-1 is a critical component of the multiprotein herpes simplex virus immediate early gene enhancer core complex. The protein has also been implicated in basic cellular processes such as cell-cycle progression, transcriptional coactivation, and mRNA processing. Functions have been attributed to HCF-1 primarily from analyses of protein-protein interactions and from the cell-cycle-arrested phenotype of an HCF-1 temperature-sensitive mutant. However, neither the mechanisms involved nor specific cellular transcriptional targets have been identified. As the protein is essential for cell viability and proliferation, a genetic system was developed to specifically sequester the nuclear factor in the cell cytoplasm in a regulated manner. This approach exhibits no significant cell toxicity yet clearly demonstrates the requirement of available nuclear HCF-1 for herpes simplex virus immediate early gene expression during productive infection. Additionally, cellular transcriptional events were identified that contribute to understanding the functions ascribed to the protein and implicate the protein in events that impact the regulation of critical cellular processes.

Functions of LIM proteins in cell polarity and chemotactic motility.

LimC and LimD are two novel LIM proteins of Dictyostelium, which are comprised of double and single LIM domains, respectively. Green fluorescent protein-fused LimC and LimD proteins preferentially accumulate at areas of the cell cortex where they co-localize with actin and associate transiently with cytoskeleton-dependent dynamic structures like phagosomes, macropinosomes and pseudopods. Furthermore, both LimC and LimD interact directly with F-actin in vitro. Mutant cells that lack either LimC or LimD, or both, exhibit normal growth. They are, however, significantly impaired in growth under stress conditions and are highly sensitive to osmotic shock, suggesting that LimC and LimD contribute towards the maintenance of cortical strength. Moreover, we noted an altered morphology and F-actin distribution in LimD(-) and LimC(-)/D(-) mutants, and changes in chemotactic motility associated with an increased pseudopod formation. Our results reveal both unique and overlapping roles for LimC and LimD, and suggest that both act directly on the actin cytoskeleton and provide rigidity to the cortex.