Recent advancements on in vitro blood-brain barrier model: A reliable and efficient screening approach for preclinical and clinical investigation.

INTRODUCTION: The efficiency of brain therapeutics is greatly hindered by the blood-brain barrier (BBB). BBB's protective function, selective permeability, and dynamic functionality maintain the harmony between the brain and peripheral region. Thus, the design of any novel drug carrier system requires the complete study and investigation of BBB permeability, efflux transport, and the effect of associated cellular and non-vascular unit trafficking on BBB penetrability. The in vitro BBB models offer a most promising, and reliable mode of initial investigation of BBB permeability and associated factors as strong evidence for further preclinical and clinical investigation. AREA COVERED: This review work covers the structure and functions of BBB components and different types of in vitro BBB models along with factors affecting BBB model development and model selection criteria. EXPERT OPINION: In vivo models assume to reciprocate the physiological environment to the maximum extent. However, the interspecies variability, NVUs trafficking, dynamic behavior of BBB, etc., lead to non-reproducible results. The in vitro models are comparatively less complex, and flexible, as per the study design, could generate substantial evidence and help identify suitable in vivo animal model selection.

Application of thermoresponsive smart polymers based in situ gel as a novel carrier for tumor targeting.

The temperature-triggered in situ gelling system has been revolutionized by introducing an intelligent polymeric system. Temperature-triggered polymer solutions are initially in a sol state and then undergo a phase transition to form a gel at body temperature due to various parameters like pH, temperature, and so on. These smart polymers offer a number of advantages, including ease of administration, long duration of release of the drug, low administration frequency with good patient compliance, and targeted drug delivery with fewer adverse effects. Polymers such as poly(N-isopropylacrylamide) (PNIPAAm), polyethylene glycol (PEG), poly (N, N'-diethyl acrylamide), and polyoxypropylene (PPO) have been briefly discussed. In addition to various novel Drug Delivery Systems (DDS), the smart temperature-triggered polymeric system has various applications in cancer therapy and many other disease conditions. This review focuses on the principals involved in situ gelling systems using various temperature-triggered polymers for chemotherapeutic purposes, using smart DDS, and their advanced application in cancer therapy, as well as available marketed formulations and recent advances in these thermoresponsive sol-gel transforming systems.

In vitro-in vivo correlation in nanocarriers: From protein corona to therapeutic implications.

Understanding and establishing a link between the physicochemical characteristics of nanoparticles (NPs) and their biological interactions poses to be a great challenge in the field of nanotherapeutics. Recent analytical advancements concerning bio-nanointerfaces have accelerated the quest to comprehend the fate of nanocarrier systems in vivo. Scientists have discovered that protein corona, an adsorbed layer of biomolecules on the surface of NPs takes a leading part in interacting with cells and in the cellular uptake process, thereby determining the in vivo behaviour of NPs. Another useful method to assess the in vivo fate of NPs is by performing dissolution testing. This forms the basis for in vitro in vivo correlation (IVIVC), relating in vitro dissolution of NPs and their in vivo properties. Scientists are continuously directing their efforts towards establishing IVIVC for different nanocarrier systems while concurrently gaining insights into protein corona. This review primarily summarizes the importance of protein corona and its interaction with nanoparticles. It also gives an insight into the factors affecting the interaction and various in vitro dissolution media used for varied nanocarrier systems. The article concludes with a discussion of the limitations of IVIVC modelling and its position from a regulatory perspective.

Overcoming skin barriers through advanced transdermal drug delivery approaches.

Upon exhaustive research, the transdermal drug delivery system (TDDS) has appeared as a potential, well-accepted, and popular approach to a novel drug delivery system. Ease of administration, easy handling, minimum systemic exposure, least discomfort, broad flexibility and tunability, controlled release, prolonged therapeutic effect, and many more perks make it a promising approach for effective drug delivery. Although, the primary challenge associated is poor skin permeability. Skin is an intact barrier that serves as a primary defense mechanism to preclude any foreign particle's entry into the body. Owing to the unique anatomical framework, i.e., compact packing of stratum corneum with tight junction and fast anti-inflammatory responses, etc., emerged as a critical physiological barrier for TDDS. Fusion with other novel approaches like nanocarriers, specially designed transdermal delivery devices, permeation enhancers, etc., can overcome the limitations. Utilizing such strategies, some of the products are under clinical trials, and many are under investigation. This review explores all dimensions that overcome poor permeability and allows the drug to attain maximum potential. The article initially compiles fundamental features, components, and design of TDDS, followed by critical aspects and various methods, including in vitro, ex vivo, and in vivo methods of assessing skin permeability. The work primarily aimed to highlight the recent advancement in novel strategies for effective transdermal drug delivery utilizing active methods like iontophoresis, electroporation, sonophoresis, microneedle, needleless jet injection, etc., and passive methods such as the use of liposomes, SLN, NLC, micro/nanoemulsions, dendrimers, transferosomes, and many more nanocarriers. In all, this compilation will provide a recent insight on the novel updates along with basic concepts, the current status of clinical development, and challenges for the clinical translation of TDDS.

Investigation of ROS generating capacity of curcumin-loaded liposomes and its in vitro cytotoxicity on MCF-7 cell lines using photodynamic therapy.

Photodynamic therapy (PDT) is highly efficient in eradicating targetlesions by using photosensitizers (PS) triggered by external light energy. Nanotechnology may help increase the solubility and effective delivery of PS towards improving its efficacy. Curcumin (Cur) was used as a natural PS for PDT in the present work. Briefly, curcumin was encapsulated in liposomes (LPs) using the thin film hydration method and optimized using the QbD approach through the Box-Behnken Design (BBD) to optimize the responses like entrapment efficiency and drug loading with a smaller vesicle size. The in vitro release studies performed using a dialysis bag (MWCO 12 KDa) suggested a sustained release of the Cur over 72 h in pH 7.4 PBS following the Weibull drug release kinetics. In addition, the ROS generating capabilities upon application of blue light (460 nm) and resulting cytotoxicity were evaluated in MCF-7 cell lines. The Cur-loaded liposome exhibited significant ROS generation and cytotoxicity to the cancer cells than free curcumin. Thus, the Cur-loaded liposomes could be used to treat breast cancer with photodynamic therapy.

PCL-PEG copolymer based injectable thermosensitive hydrogels.

A number of stimuli-responsive-based hydrogels has been widely explored in biomedical applications in the last few decades because of their excellent biodegradability and biocompatibility. The development of synthetic chemistry and materials science leads to the emergence of in situ stimuli-responsive hydrogels. In this regard, several synthetic and natural polymers have been synthesized and utilized to prepare temperature-sensitive in situ forming hydrogels. This could be best used via injections as temperature stimulus could trigger in situ hydrogels gelation and swelling behaviors. There are many smart polymers available for the formulation of the in situ based thermoresponsive injectable hydrogel. Among these, poly (ε-caprolactone) (PCL) polymer has been recognized and approved by the FDA for numerous biomedical applications. More specifically, the PCL is coupled with polyethylene glycol (PEG) to obtain amphiphilic thermosensitive "smart" copolymers (PCL-PEG), to form rapid and reversible physical gelation behavior. However, the chemical structure of the copolymer is a critical aspect in determining water solubility, thermo-gelation behavior, drug release rate, degradation rate, and the possibility to deliver a diverse range of drugs. In this review, we have highlighted the typical PCL-PEG-based thermosensitive injectable hydrogels progress in the last decade for tissue engineering and localized drug delivery applications to treat various diseases. Additionally, the impact of molecular weight of PCL-PEG upon gelling behavior has also been critically highlighted for optimum hydrogels properties for potential pharmaceutical and biomedical applications.

Nose-to-brain drug delivery for the treatment of Alzheimer's disease: current advancements and challenges.

INTRODUCTION: The irreversible destruction of neurons, progressive loss of memory and cognitive behavior, high cost of therapy, and impact on society, desire a better, effective, and affordable treatment of AD. The nose-to-brain delivery approach holds great potential to access the brain without any hindrance of BBB and results in higher bioavailability and thus better therapeutic efficacy of anti-AD drugs. AREAS COVERED: The present review article highlights the current facts and worldwide statistics of AD and its detailed etiology. This is followed by barriers to brain delivery, nose-to-brain delivery, their limitations, and amalgamation with various novel carrier systems. We have emphasized recent advancements in nose-to-brain delivery using mucoadhesive, stimuli-responsive carriers, polymeric nanoparticles, lipid nanoparticles, and protein/peptide delivery for treatment of AD. EXPERT OPINION: The available therapies are symptomatic and mitigate the symptoms of AD at the initial stages. In lieu of this, nose-to-brain delivery has the ability to overcome these limitations and increase drug bioavailability in the brain. Various novel strategies including stimuli-responsive systems, nanoparticles, etc. enhance the nasal permeation, protect the drug, and enhance its therapeutic potency. However, successful preclinical data do not assure the clinical success of the therapy, and hence exhaustive clinical investigations are needed to make the therapy available for patients.

In-line treatments and clinical initiatives to fight against COVID-19 outbreak.

In December 2019, when the whole world is waiting for Christmas and New Year, the physicians of Wuhan, China, are astounded by clusters of patients suffering from pneumonia from unknown causes. The pathogen isolated from the respiratory epithelium of the patients is similar to previously known coronaviruses with some distinct features. The disease was initially called nCoV-2019 or SARS-nCoV-2 and later termed as COVID-19 by WHO. The infection is rapidly propagating from the day of emergence, spread throughout the globe and now became a pandemic which challenged the competencies of developed nations in terms of health care management. As per WHO report, 216 countries are affected with SARS-CoV-19 by August 5, 2020 with 18, 142, 718 confirmed cases and 691,013 deaths reports. Such huge mortality and morbidity rates are truly threatening and calls for some aggressive and effective measures to slow down the disease transmission. The scientists are constantly engaged in finding a potential solution to diagnose and treat the pandemic. Various FDA approved drugs with the previous history of antiviral potency are repurposed for COVID-19 treatment. Different drugs and vaccines are under clinical trials and some rapid and effective diagnostic tools are also under development. In this review, we have highlighted the current epidemiology through infographics, disease transmission and progression, clinical features and diagnosis and possible therapeutic approaches for COVID-19. The article mainly focused on the development and possible application of various FDA approved drugs, including chloroquine, remdesivir, favipiravir, nefamostate mesylate, penciclovir, nitazoxanide, ribavirin etc., vaccines under development and various registered clinical trials exploring different therapeutic measures for the treatment of COVID-19. This information will definitely help the researchers to understand the in-line scientific progress by various clinical agencies and regulatory bodies against COVID-19.

Application of chitosan modified nanocarriers in breast cancer.

As per the WHO, every year around 2.1 million women are detected with breast cancer. It is one of the most invasive cancer in women and second most among all, contributing around 15% of death worldwide. The available anticancer therapies including chemo, radio, and hormone therapy are associated with a high load of reversible and irreversible adverse effects, limited therapeutic efficacy, and low chances of quality survival. To minimize the side effects, improving therapeutic potency and patient compliance promising targeted therapies are highly desirable. In this sequence, various nanocarriers and target modified systems have been explored by researchers throughout the world. Among these chitosan-based nanocarriers offers one of the most interesting, flexible, and biocompatible systems. The unique characteristics of chitosan like surface flexibility, biocompatibility, hydrophilicity, non-toxic and cost-effective behavior assist to overcome the inadequacy of existing therapy. The present review throws light on the successes, failures, and current status of chitosan modified novel techniques for tumor targeting of bioactives. It also emphasizes the molecular classification of breast cancer and current clinical development of novel therapies. The review compiles most relevant works of the past 10 years focusing on the application of chitosan-based nanocarrier against breast cancer.

Effect of supplementation of vitamin D and calcium on patients suffering from chronic non-specific musculoskeletal pain: A pre-post study.

BACKGROUND AND OBJECTIVE: Despite abundant sunshine, India is a country with high prevalence of vitamin D deficiency. It has been suggested that vitamin D deficiency could be a potential cause of chronic non-specific musculoskeletal pain. The study was conducted to evaluate the effect of supplementation of vitamin D and calcium on patients suffering with chronic non-specific musculoskeletal pain. METHODOLOGY: The experimental trial was a pre-post study conducted on 50 hypovitaminosis D patients aged 30-60 years visiting a local orthopedician or physician with complain of chronic non-specific musculoskeletal pain. Oral supplementation with vitamin D and calcium was given for 3 months. Before the intervention trial, pain, physical activity, serum vitamin D, serum calcium, body mass index and waist to hip ratio (WHR) of the respondents were assessed, which was statistically compared with post-intervention data of the same parameters. Assessment of pain was carried out using visual analog scale. Physical activity levels were compared pre and post the intervention. Also, fatigue, mood alteration, and sleep were compared. RESULTS: Ninety percent of the subjects had vitamin D deficiency. Thirty-six percent of the subjects had severe chronic non-specific musculoskeletal pain, whereas 56% had moderate chronic non-specific musculoskeletal pain. The mean pain score prior to intervention was 6.22 which significantly decreased to 3.52. Mean vitamin D levels significantly rose from 17.38 ng/ml to 39.40 ng/ml. Serum vitamin D, serum calcium, and physical activity levels increased, whereas pain, weight, BMI, and WHR decreased significantly post-intervention. CONCLUSIONS: Supplementation with vitamin D and calcium decreases chronic non-specific musculoskeletal pain.

Design and optimization of curcumin loaded nano lipid carrier system using Box-Behnken design.

Herbal antioxidant like curcumin holds great potential to treat neurodegenerative disease like Alzheimer's disease. However, its therapeutic potency is obstructed due to rapid metabolism, poor solubility, GI susceptibility, enzymatic degradation and lower bioavailability. Thus, the present work aimed to design and optimize curcumin-loaded NLC (CNL) with higher drug entrapment, prolonged release and better stability. CNL was prepared by modified melt emulsification method followed by ultrasonication. The formulation was optimized by 3 factor 3 level Box-Behnken design using solid: liquid lipid, surfactant concentration and ultrasonication time as independent variable while particle size, entrapment efficiency and % drug release as dependant variable. The design suggested 3.092 solid:liquid lipid, 2.131% surfactant and 4.757 min ultrasonication fit best to get the optimized formulation. The size of the optimized CNL was noted 124.37 ± 55.81 nm, which is in the acceptable range for brain delivery. SEM results also comply with this size range (near 150 nm) and demonstrated almost spherical and uniform particles with porous and uneven surface structures. PDI, zeta potential, entrapment efficiency and % drug release were observed as 0.201 ± 0.00, - 17.2 ± 2.35 mV, 93.62 ± 0.68% and 92.73 ± 0.06%, respectively. The NLC demonstrated initial burst release with subsequent prolonged release of drug for 48 h. Weibull kinetic equation with 0.9958 R2, minimum AIC and maximum MSC value was found best fit to explain the release behavior. The ß exponent and diffusional coefficient (n) indicated combined release mechanism with Fickian diffusion as drug release mechanism. Formulation was also found stable at different storage condition.

Biomaterials in treatment of Alzheimer's disease.

Alzheimer's disease (AD) is a non-recoverable progressive neurodegenerative disorder most prevalent but not limited to the old age population. After all the scientific efforts, there are still many unmet criteria and loopholes in available treatment and diagnostic strategies, limiting their efficacy. The poor drug efficacy is attributed to various biological hurdles, including blood-brain barrier (BBB) and peripheral side effects as most prominent ones and the lack of promising carriers to precisely deliver the drug to the brain by conserving its therapeutic potency. The increasing disease prevalence and unavailability of effective therapy calls for developing a more innovative, convenient and affordable way to treat AD. To fulfill such need, researchers explored various biomaterials to develop potential vectors or other forms to target the bioactives in the brain by preserving their inherent properties, improving the existing lacuna like poor solubility, permeability and bioavailability etc. and minimize the side effect. The unique characteristic properties of biomaterials are used to develop different drug carriers, surface modifying target active ligands, functional carriers, drug conjugate, biosensing probe, diagnostic tool and many more. The nanoparticulate system and other colloidal carriers like hydrogel and biodegradable scaffold can effectively target the drug moieties to the brain. Also, the use of different target-acting ligands and stimuli-responsive carriers assures the site-specificity and controlled release at the desired site by interaction with receptors and various exo- and endogenous stimuli. This review article has highlighted the application of biomaterials for targeting the drug to the brain and as promising diagnostic tools to detect the markers for better AD management. The work particularly focuses on the use of biomaterials as smart drug carriers including pH, thermo, photo, electro and magnetically triggered system; novel drug carriers for brain targeting including polymeric carriers (polymeric nanoparticle, dendrimer and polymeric micelle); lipid carrier (liposome, nanoemulsion, NLC and SLN); inorganic nanoparticles (quantum dots, gold nanoparticles etc.); and other drug vectors (hydrogel, biodegradable scaffold, and carbon nanotube) in treatment of AD. It also highlighted the application of some novel carrier systems and biomaterials as biosensor and other diagnostic tools for early and precise AD diagnosis.

Oral peptide delivery: challenges and the way ahead.

Peptides and proteins have emerged as potential therapeutic agents and, in the search for the best treatment regimen, the oral route has been extensively evaluated because of its non-invasive and safe nature. The physicochemical properties of peptides and proteins along with the hurdles in the gastrointestinal tract (GIT), such as degrading enzymes and permeation barriers, are challenges to their delivery. To address these challenges, several conventional and novel approaches, such as nanocarriers, site-specific and stimuli specific delivery, are being used. In this review, we discuss the challenges to the oral delivery of peptides and the approaches used to tackle these challenges.

Recent advances in targeted nanomedicine as promising antitumor therapeutics.

A tumor serves as a major avenue in drug development owing to its complexity. Conventional therapies against tumors possess limitations such as suboptimal therapeutic efficacy and extreme side effects. These display poor pharmacokinetics and lack specific targeting, with non-specific distribution resulting in systemic toxicity. Therefore, nanocarriers targeted against cancers are increasingly being explored. Nanomedicine aids in maintaining a balance between efficacy and toxicity by specifically accumulating in tumors. Nanotherapeutics possess advantages such as increased solubility of chemotherapeutics, encapsulation of multiple drugs and improved biodistribution, and can ensure tumor-directed drug delivery and release via the approaches of passive targeting and active targeting. This review aims to offer a general overview of the current advances in tumor-targeting nanocarriers for clinical and diagnostic use.

Stimuli-responsive In situ gelling system for nose-to-brain drug delivery.

The diagnosis and treatment of neurological ailments always remain an utmost challenge for research fraternity due to the presence of BBB. The intranasal route appeared as an attractive and alternative route for brain targeting of therapeutics without the intrusion of BBB and GI exposure. This route directly and effectively delivers the therapeutics to different regions of the brain via olfactory and trigeminal nerve pathways. However, shorter drug retention time and mucociliary clearance curtail the efficiency of the intranasal route. The in situ mucoadhesive gel overthrow the limitations of direct nose-to-brain delivery by not only enhancing nasal residence time but also minimizing the mucociliary clearance and enzymatic degradation. This delivery system further improves the nasal absorption as well as bioavailability of drugs in the brain. The in situ mucoadhesive gel is a controlled and sustained release system that facilitates the absorption of various proteins, peptides and other larger lipophilic and hydrophilic moieties. Owing to multiple benefits, in situ gelling system has been widely explored to target the brain via nasal route. However, very few review works are reported which explains the application of in situ nasal gel for brain delivery of CNS acting moieties. Hence, in this piece of work, we have initially discussed the global statistics of neurological disorders reported by WHO and other reputed organizations, nasal anatomy, mechanism and challenges of nose-to-brain drug delivery. The work mainly focused on the use of different stimuli-responsive polymers, specifically thermoresponsive, pH-responsive, and ion triggered systems for the development of an effective and controlled dosage form, i.e., in situ nasal gel for brain targeting of bioactives. We have also highlighted the origin, structure, nature and phase transition behavior of the smart polymers found suitable for nasal administration, including poloxamer, chitosan, EHEC, xyloglucan, Carbopol, gellan gum and DGG along with their application in the treatment of neurological disorders. The article is aimed to gather all the information of the past 10 years related to the development and application of stimuli-responsive in situ nasal gel for brain drug delivery.

Virology, pathogenesis, diagnosis and in-line treatment of COVID-19.

SARS-CoV-2, a newly emerged pathogen in December 2019, marked as one of the highly pathogenic Coronavirus, and altogether this is the third coronavirus attack that crossed the species barrier. As of 1st July 2020, it is spreading around 216 countries, areas or territories, and a total of 10,185,374 and 503,862 confirmed cases and death reports, respectively. The SARS-CoV-2 virus entered into the target cells by binding with the hACE2 receptors. Spike glycoprotein promotes the entry of the virus into host target cells. Literature reported a significant mutation in receptor binding sites and membrane proteins of the previous SARS-CoV to turned as SARS-CoV-2 virus, responsible for most dreadful pandemic COVID-19. These modifications may be the probable reason for the extreme transmission and pathogenicity of the virus. A hasty spread of COVID-19 throughout the world is highly threatening, but still, scientists do not have a proper therapeutic measure to fight with it. Scientists are endeavoring across the world to find effective therapy to combat COVID 19. Several drugs such as Remdesivir, Hydroxychloroquine, Chloroquine, Ribavirin, Ritonavir, Lopinavir, Favipiravir, Interferons, Bevacizumab, Azithromycin, etc. are currently under clinical trials. Vaccine development from various pharmaceutical companies and research institutes is under progress, and more than ten vaccine candidates are in the various phases of clinical trials. This review work highlighted the origin, emergence, structural features, pathogenesis, and clinical features of COVID-19. We have also discussed the in-line treatment strategies, preventive measures, and vaccines to combat the emergence of COVID-19.

Insulin mediated novel therapies for the treatment of Alzheimer's disease.

Alzheimer's disease, a progressive neurodegenerative disorder, is one of the leading causes of death in the USA, along with cancer and cardiac disorders. AD is characterized by various neurological factors like amyloid plaques, tau hyperphosphorylation, mitochondrial dysfunction, acetylcholine deficiency, etc. Together, impaired insulin signaling in the brain is also observed as essential factor to be considered in AD pathophysiology. Hence, currently researchers focused on studying the effect of brain insulin metabolism and relation of diabetes with AD. Based on the investigations, AD is also considered as type 3 or brain diabetes. Besides the traditional view of correlating AD with aging, a better understanding of various pathological factors and effects of other physical ailments is necessary to develop a promising therapeutic approach. There is a vast scope of studying the relation of systemic insulin level, insulin signaling, its neuroprotective potency and effect of diabetes on AD progression. The present work describes worldwide status of AD and its relation with diabetes mellitus and insulin metabolism; pathophysiology of AD; different metabolic pathways associating insulin metabolism with AD; insulin receptor and signaling in the brain; glucose metabolism; insulin resistance; and various preclinical and clinical studies reported insulin-based therapies to treat AD via systemic route and through direct intranasal delivery to the brain.

Imaging of the aortic root on high-pitch non-gated and ECG-gated CT: awareness is the key!

The aortic pathologies are well recognized on imaging. However, conventionally cardiac and proximal aortic abnormalities were only seen on dedicated cardiac or aortic studies due to need for ECG gating. Advances in CT technology have allowed motionless imaging of the chest and abdomen, leading to an increased visualization of cardiac and aortic root diseases on non-ECG-gated imaging. The advances are mostly driven by high pitch due to faster gantry rotation and table speed. The high-pitch scans are being increasingly used for variety of clinical indications because the images are free of motion artifact (both breathing and pulsation) as well as decreased radiation dose. Recognition of aortic root pathologies may be challenging due to lack of familiarity of radiologists with disease spectrum and their imaging appearance. It is important to recognize some of these conditions as early diagnosis and intervention is key to improving prognosis. We present a comprehensive review of proximal aortic anatomy, pathologies commonly seen at the aortic root, and their imaging appearances to familiarize radiologists with the diseases of this location.

Formulation Strategies of Nano Lipid Carrier for Effective Brain Targeting of Anti-AD Drugs.

NLC is a next-generation lipid nanocarrier, which holds many advantages over other colloidal lipid carrier systems like higher drug loading, better and controlled release and enhanced stability. Owing to the unique structural composition, i.e. crystallized solid and liquid lipid blend, it offers excellent biocompatibility and higher permeation across physiological membranes like BBB. Moreover, the surface of NLC can easily be modified with target-specific ligands, proteins, peptides, etc. which makes it a potential candidate for brain targeting of CNS acting drugs. NLC has found various applications for the treatment of various CNS disorders including Alzheimer's disease, Parkinson's disease, schizophrenia, epilepsy, migraine, cerebral ischemia, etc. Among these, the application of NLC towards the treatment of AD has been well-explored in the past two decades. In this piece of work, we have discussed the types of NLC, its composition, fabrication techniques, characterization, stability profile and application in the treatment of AD.