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.

Design and Evaluation of SLNs Encapsulated Curcumin-based Topical Formulation for the Management of Cervical Cancer.

OBJECTIVE: Curcumin has the propensity to inhibit cancer growth, slow cancer development, increase chemotherapy effectiveness, and shield healthy cells from radiation treatment harm. As a result of curcumin's ability to block several signaling pathways, cervical cancer cells can once again proliferate normally. To optimize topically applied curcumin-loaded solid lipid nanoparticles (SLNPs) for the treatment of cervical cancer, this study set out to establish the relationship between design variables and experimental data. It also performed in vitro characterizations to determine the formulation's efficacy and safety. METHODS: Curcumin-loaded SLNPs were constructed and optimized using a systematic design of experiment (DoE) technique. SLNPs that were loaded with curcumin were produced utilizing a cold emulsification ultrasonication process. Using the Box Behnken Design, it was determined how independent variables (factors) like the quantity of lipid (A), the quantity of phospholipid (B), and the concentration of surfactant (C) affected the responses of the dependent variables (responses), such as particle size (Y1), polydispersity index (PDI) (Y2), and entrapment efficiency (EE) (Y3) (BBD). RESULTS: The ideal formulation (SLN9) was chosen using the desirability technique based on 3-D surface response graphs. Using polynomial equations and three-dimensional surface plots, the influence of independent factors on the dependent variables was evaluated. The observed responses were almost equal to the levels that the optimal formulation expected. The improved SLNP gel's shape and other physicochemical characteristics were also assessed, and they were determined to be ideal. The sustained release profile of the produced formulations was validated by in vitro release tests. Studies on hemolysis, immunogenic response, and in vitro cell cytotoxicity demonstrate the efficacy and safety of the formulations. CONCLUSION: To improve the treatment effect, chitosan-coated SLNPs may carry encapsulated curcumin to the desired location and facilitate its localization and deposition in the desired vaginal tissue.

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.

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.

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.

Quality by design driven development of resveratrol loaded ethosomal hydrogel for improved dermatological benefits via enhanced skin permeation and retention.

Resveratrol is a potent anti-oxidant agent and can be used for the effective management of different skin conditions like extrinsic skin ageing, psoriasis, etc. The objective of this research was to develop a dermal delivery system of resveratrol for its improved dermatological benefits for achieving its enhanced skin deposition profile with limited systemic exposure. Resveratrol loaded ethosomal hydrogel was developed and optimized using systematic Quality by Design approach. Firstly, the quality target product profile (QTPP) of ethosomal formulation was defined and critical quality attributes (CQAs) and critical material attributes (CMAs) were screened through risk assessment studies based on fish bone diagram. 32 full factorial design using Design Expert software was employed to optimize the selected CMAs. Concentration of phospholipid (X1) and concentration of ethanol (X2) were selected as independent CMAs. Vesicle size (Y1), entrapment efficiency (Y2), permeation flux (Y3) and drug deposition in dermal layer (Y4) were evaluated as dependant CQAs. Optimized formulation was then evaluated for physicochemical and skin permeation properties. Ethosomal hydrogel was able to significantly enhance the skin permeation parameters and skin deposition of resveratrol in comparison to the conventional cream. The results were highly ratified by CLSM studies in which ethosomal hydrogel was found to be vastly scattered in the deeper skin layers. Thus, there is evidence that systemically developed ethosomal gel can deliver enhanced amounts of bioactives into the skin and it is expected that a number of products for dermal/transdermal applications will be developed in the future based on it.

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.

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.

Role of TOPS (a simplified assessment of neonatal acute physiology) in predicting mortality in transported neonates.

AIM: To evaluate role of TOPS (a simplified assessment of neonatal acute physiology) in predicting mortality in transported neonates and to compare it with SNAP II. DESIGN: Prospective study. SETTING: Referral Neonatal Unit of a teaching hospital. SUBJECTS: 175 neonates > 1000 g admitted to referral nursery. METHODS: Temperature, oxygenation, capillary refill time (proxy for perfusion) and blood sugar (given the acronym of TOPS) were recorded at admission. SNAP II was also recorded for first 12 hours following admission. RESULTS: All the TOPS variables had significant correlation with fatality on univariate analysis. Fatality was 100% when all the four TOPS variables were deranged. The sensitivity, specificity, positive and negative predictive values of derangements of two or more TOPS parameters in predicting mortality were 81.6%, 77.39%, 65.3% and 89%, respectively All the variables of SNAP II significantly correlated with mortality. A cut-off score of 24 was derived from the ROC curve. The sensitivity, specificity, positive and negative predictive values of SNAP II score > 24 in predicting mortality were 78.3%, 86.1%, 74.6% and 88.4%, respectively. The area under ROC curve for derangements of 2 or more TOPS parameters was 0.89 while that for SNAP II was 0.88. Both models were well calibrated (p value for Hosmer Lemeshow goodness of fit for TOPS was 0.75 while that for SNAP II was 0.80). The total correct classification rate for TOPS was 81.7%, while that for SNAP II was 83.4%. CONCLUSION: TOPS has an equally good prediction for mortality as SNAP II and can be used as a simple and useful method of assessment of risk of fatality that can be assessed immediately, at admission.