Quality by design endorsed atorvastatin-loaded nanostructured lipid carriers embedded in pH-responsive gel for melanoma.

AIM: Our aim was to repurpose atorvastatin for melanoma by encapsulating in a nanostructured lipid carrier matrix to promote tumour cell internalisation and skin permeation. pH-responsive chitosan gel was employed to restrict At-NLCs in upper dermal layers. METHODS: We utilised a quality by design approach for encapsulating At within the NLC matrix. Further, cellular uptake and cytotoxicity was evaluated along with pH-responsive release and ex vivo skin permeation. RESULTS: Cytotoxicity assay showed 3.13-fold enhanced cytotoxicity on melanoma cells compared to plain drug with nuclear staining showing apoptotic markers. In vitro, release studies showed 5.9-fold rapid release in chitosan gel matrix at pH 5.5 compared to neutral pH. CONCLUSIONS: At-NLCs prevented precipitation, promoted skin permeation, and SK-MEL 28 cell internalisation. The localisation of NLCs on the upper dermal layer due to electrostatic interactions of skin with chitosan gel diminished the incidence of untoward systemic effects.

Tuning Mesoporous Silica Nanoparticles in Novel Avenues of Cancer Therapy.

The global menace of cancer has led to an increased death toll in recent years. The constant evolution of cancer therapeutics with novel delivery systems has paved the way for translation of innovative therapeutics from bench to bedside. This review explains the significance of mesoporous silica nanoparticles (MSNs) as delivery vehicles with particular emphasis on cancer therapy, including novel opportunities for biomimetic therapeutics and vaccine delivery. Parameters governing MSN synthesis, therapeutic agent loading characteristics, along with tuning of MSN toward cancer cell specificity have been explained. The advent of MSN in nanotheranostics and its potential in forming nanocomposites for imaging purposes have been illustrated. Additionally, various hurdles encountered during the bench to bedside translation have been explained along with potential avenues to circumvent them. This also opens up new horizons in drug delivery, which could be useful to researchers in the years to come.

Lived Experiences of Bereaved Family Members During COVID-19 Pandemic in a Tertiary Care Hospital With Special Reference to Imposed Restrictive COVID Guidelines-a Qualitative Study.

This study aimed to understand the experiences of bereaved family members in view of restrictive COVID guidelines using qualitative approach. 10 Hindu, Gujarati bereaved family members who lost their loved ones during the first wave were interviewed telephonically after a month of their loss. Findings were difficulty in proper communication during hospitalization, disrupted end-of-life and funeral rituals and accepting harsh realities related to the changes imposed by using content analysis. Most of the family members felt that there was a need of staying with the patients. Telephonic mode of communication was not sufficient for them and created doubts related to death. Most of them felt remorseful as they were not able to see or bring their loved one home during their last moments and felt deprived of the traditional rituals. Also, they had to deal with their grief by themselves.

Bridging the gap: academia, industry and FDA convergence for nanomaterials.

Nano-medicine is the fastest growing field in pharmaceutical industry today. However, there still exist several hurdles preceding its clinical translation. This review provides insights on the guidelines for nanomaterials provided by the US-FDA (United States Food and Drug Administration), various approval pathways and also addresses the lacunae between academic research, pharmaceutical industry and US-FDA through an attempt to overcome the hurdle to its clinical translation. We have also emphasized various ways to overcome the described barriers which will provide the readers a brief understanding over the critical aspects where the scope of the guidelines may need to be revisited in order to exhibit their successful clinical translation from academic research to commercial feasibility.

Quality by Design Approach for the Development of Self-Emulsifying Systems for Oral Delivery of Febuxostat: Pharmacokinetic and Pharmacodynamic Evaluation.

The goal of the present investigation is to formulate febuxostat (FXT) self-nanoemulsifying delivery systems (liquid SNEDDS, solid SNEDDS, and pellet) to ameliorate the solubility and bioavailability. To determine the self-nanoemulsifying region, ternary plot was constructed utilizing Capmul MCM C8 NF® as an oil phase, Labrasol® as principal surfactant, and Transcutol HP® being the co-surfactant. Liquid SNEDDS (L-SNEDDS) were characterized by evaluating droplet size, zeta potential, % transmission, and for thermodynamic stability. In vitro dissolution study of FXT loaded L-SNEDDS (batch F7) showed increased dissolution (about 48.54 ± 0.43% in 0.1 N HCl while 86.44 ± 0.16% in phosphate buffer pH 7.4 within 30 min) compared to plain drug (19.65 ± 2.95% in 0.1 N HCl while about 17.61 ± 2.63% in phosphate buffer pH 7.4 within 30 min). Single pass intestinal permeability studies revealed fourfold increase in the intestinal permeability of F7 compared to plain drug. So, for commercial aspects, F7 was further transformed into solid SNEDDS (S-SNEDDS) as readily nanoemulsifying powder form (SNEP) as well as pellets prepared by application of extruder spheronizer. The developed formulation was found superior to pure FXT with enhanced oral bioavailability and anti-gout activity (with reduced uric acid levels), signifying a lipidic system being an efficacious substitute for gout treatment.

Prevalence and pattern of antipsychotic induced movement disorders in a tertiary care teaching hospital in India - a cross-sectional study.

OBJECTIVES: To assess prevalence and pattern of movement disorders among patients taking antipsychotic medications. METHODS: This cross-sectional, intensive monitoring (patient interview, case record form review and clinical examination) study was conducted in patients taking antipsychotic drugs irrespective of duration for the development of movement disorders. The psychiatrist used Modified Simpson-Angus Scale score (10-item scale), Barnes' rating scale and Abnormal Involuntary Movement Scale to diagnose parkinsonism, akathisia and tardive dyskinesia, respectively. We assessed movement disorders for the preventability and seriousness. RESULTS: The overall prevalence of antipsychotic induced movement disorders was 5.67% (95% CI: 4.19-7.62). The prevalence of parkinsonism, akathisia and tardive dyskinesia was 5.10% (95% CI: 3.71-6.98), 0.85% (95% CI: 0.39-1.84) and 0.57% (95% CI: 0.22-1.45), respectively. There was a trend of high proportions of movement disorders in extreme of age group, female gender, patients treated with conventional antipsychotics, on poly therapy, patients of epilepsy with psychosis, schizophrenia and bipolar mood disorder. The movement disorder was lowest with quetiapine (2.02%). CONCLUSIONS: The higher use of atypical antipsychotics had reduced the occurrence of movement disorders in our setup.

Surface Functionalized Lipid Nanoparticles in Promoting Therapeutic Outcomes: An Insight View of the Dynamic Drug Delivery System.

Compared to the conventional approach, nanoparticles (NPs) facilitate a non-hazardous, non-toxic, non-interactive, and biocompatible system, rendering them incredibly promising for improving drug delivery to target cells. When that comes to accomplishing specific therapeutic agents like drugs, peptides, nucleotides, etc., lipidic nanoparticulate systems have emerged as even more robust. They have asserted impressive ability in bypassing physiological and cellular barriers, evading lysosomal capture and the proton sponge effect, optimizing bioavailability, and compliance, lowering doses, and boosting therapeutic efficacy. However, the lack of selectivity at the cellular level hinders its ability to accomplish its potential to the fullest. The inclusion of surface functionalization to the lipidic NPs might certainly assist them in adapting to the basic biological demands of a specific pathological condition. Several ligands, including peptides, enzymes, polymers, saccharides, antibodies, etc., can be functionalized onto the surface of lipidic NPs to achieve cellular selectivity and avoid bioactivity challenges. This review provides a comprehensive outline for functionalizing lipid-based NPs systems in prominence over target selectivity. Emphasis has been put upon the strategies for reinforcing the therapeutic performance of lipidic nano carriers' using a variety of ligands alongside instances of relevant commercial formulations.

Supramolecular self-assembled peptide-engineered nanofibers: A propitious proposition for cancer therapy.

Cancer is a devastating disease that causes a substantial number of deaths worldwide. Current therapeutic interventions for cancer include chemotherapy, radiation therapy, or surgery. These conventional therapeutic approaches are associated with disadvantages such as multidrug resistance, destruction of healthy tissues, and tissue toxicity. Therefore, there is a paradigm shift in cancer management wherein nanomedicine-based novel therapeutic interventions are being explored to overcome the aforementioned disadvantages. Supramolecular self-assembled peptide nanofibers are emerging drug delivery vehicles that have gained much attention in cancer management owing to their biocompatibility, biodegradability, biomimetic property, stimuli-responsiveness, transformability, and inherent therapeutic property. Supramolecules form well-organized structures via non-covalent linkages, the intricate molecular arrangement helps to improve tissue permeation, pharmacokinetic profile and chemical stability of therapeutic agents while enabling targeted delivery and allowing efficient tumor imaging. In this review, we present fundamental aspects of peptide-based self-assembled nanofiber fabrication their applications in monotherapy/combinatorial chemo- and/or immuno-therapy to overcome multi-drug resistance. The role of self-assembled structures in targeted/stimuli-responsive (pH, enzyme and photo-responsive) drug delivery has been discussed along with the case studies. Further, recent advancements in peptide nanofibers in cancer diagnosis, imaging, gene therapy, and immune therapy along with regulatory obstacles towards clinical translation have been deliberated.

Exploration of Abiraterone acetate loaded Nanostructured lipid carriers for bioavailability improvement and circumvention of fast-fed variability.

Abiraterone acetate (ABA), a biopharmaceutical class IV drug suffers from solubility and permeability pitfalls resulting in limited oral bioavailability and positive food effect, i.e. multi-fold enhancement in drug absorption in the presence of food. This poses difficulties to physicians towards the estimation of dose and dosage regimen required for efficacious therapy of prostate cancer (PCa). Nanostructured lipid carriers (NLC) have demonstrated tremendous outcomes in enhancing the oral bioavailability of various entities along with food effect attenuation. In this study, Quality by design and multivariate analysis was employed for optimization of ABA loaded NLC (ABA NLC). The optimal size, PDI and zeta potential obtained using QbD were 134.6 nm, 0.163 and -15.7 mV respectively. Ex vivo qualitative and quantitative intestinal permeability studies demonstrated improved traversion of NLC through the intestinal segments. In vitro dissolution profile in biorelevant fast and fed gastric and intestinal media revealed minimal differences for ABA NLC compared to ABA. In vivo pharmacokinetics was performed to decipher the efficacy of ABA NLC in mitigating the food effect of ABA. The studies demonstrated 14.51-fold and 1.94-fold improvement in oral bioavailability during fasted and fed state respectively as compared to free ABA. The absorption mechanism of ABA NLC using chylomicron flow blocking approach conveyed lymphatic uptake as the major mechanism. Cmax fast/fed ratio was 0.9758 whereas, AUC fast/fed ratio was 0.9386, which being nearly equivalent, confirmed the food effect attenuation. Therefore, the results of the study demonstrate optimal pharmacokinetics of ABA NLC and its utility in circumventing the fast fed variability.

Quality by design empowered preparation of itraconazole albumin nanoparticles for prostate cancer.

The current advent explores the potential of itraconazole (ITR) in prostate cancer (PCa), by its incorporation into albumin nanoparticles (NP). ITR as a repurposed moiety has displayed tremendous potential in various cancers. However, poor aqueous solubility poses hurdles towards its clinical translation. Amorphisation of ITR was observed post-incorporation within NP matrix which could prevent its precipitation in aqueous media. ITR NP was developed using quality by design and multivariate analysis and evaluated for cellular uptake, cell proliferation inhibition and the mechanism of PCa cell inhibition. Time and concentration-dependent serum stability and hemolytic potential revealed safety of ITR NP. Morphological changes and nuclear staining studies revealed the efficacy of ITR and ITR NP in promoting growth inhibition of PC-3 cells. Superior qualitative and quantitative uptake, reactive oxygen species (ROS) and mitochondrial impairment for ITR NP in comparison with ITR and control group was observed. Cell cycle study revealed remarkable G2/M phase inhibition in PC-3 cells. ITR NP demonstrated superior anticancer potential in 3D tumoroids mimicking the micro-metastatic lesions compared to control and ITR. Hence, ITR NP can be a favorable alternative therapeutic alternative in PCa.

Sulfo-butyl ether ß-cyclodextrin inclusion complexes of bosutinib: in silico, in vitro and in vivo evaluation in attenuating the fast-fed variability.

Bosutinib (BOS) is a BCS class IV drug that shows low oral bioavailability and high fast-fed variability. Various pharmaceutical formulations have been explored thus far in order to improve its bioavailability while avoiding fast-fed variability. In the present study, we explored cyclodextrin (CD) complexation strategy to overcome the aforementioned disadvantages associated with BOS. CD complexation is a simple, versatile and economic approach that enables formation of inclusion complexes, thereby improving aqueous solubility while nullifying pH-dependent solubility and fast-fed variability for poorly soluble drugs. Initially, we performed molecular dynamics and docking studies to select appropriate CD derivative. The results of in silico studies revealed that sulfo-butyl ether ß-cyclodextrin (SBE-CD) offered superior binding affinity with BOS. Further, Job's plot revealed that 1:1 stoichiometry of BOS and CD resulted in enhancement of BOS solubility up to ~ 132.6-folds. In vitro release studies in bio-relevant media (fasted and fed state simulated gastric and intestinal fluids) revealed higher drug release while overcoming its pH-dependent solubility. In vitro studies on K562 cells demonstrated a 1.83-fold enhancement in cytotoxicity due to enhanced ROS production and G2/M phase arrest.In vivo pharmacokinetic studies in Sprague-Dawley rats revealed insignificant fast-fed variability with AUCfast/fed 0.9493 and Cmaxfast/fed 0.8291 being closer to 1 in comparison with BOS. Hence, we conclude that SBE-CD complexation could be a promising approach in diminishing fast-fed variability of BOS.

Amelioration of breast cancer therapies through normalization of tumor vessels and microenvironment: paradigm shift to improve drug perfusion and nanocarrier permeation.

Breast cancer (BC) is the most commonly diagnosed cancer among women. Chemo-, immune- and photothermal therapies are employed to manage BC. However, the tumor microenvironment (TME) prevents free drugs and nanocarriers (NCs) from entering the tumor premises. Formulation scientists rely on enhanced permeation and retention (EPR) to extravasate NCs in the TME. However, recent research has demonstrated the inconsistent nature of EPR among different patients and tumor types. In addition, angiogenesis, high intra-tumor fluid pressure, desmoplasia, and high cell and extracellular matrix density resist the accumulation of NCs in the TME. In this review, we discuss TME normalization as an approach to improve the penetration of drugs and NCSs in the tumor premises. Strategies such as normalization of tumor vessels, reversal of hypoxia, alleviation of high intra-tumor pressure, and infiltration of lymphocytes for the reversal of therapy failure have been discussed in this manuscript. Strategies to promote the infiltration of anticancer immune cells in the TME after vascular normalization have been discussed. Studies strategizing time points to administer TME-normalizing agents are highlighted. Mechanistic pathways controlling the angiogenesis and normalization processes are discussed along with the studies. This review will provide greater tumor-targeting insights to the formulation scientists.

Unravelling the role of tumor microenvironment responsive nanobiomaterials in spatiotemporal controlled drug delivery for lung cancer therapy.

Design and development of efficient drug delivery technologies that impart site-specificity is the need of the hour for the effective treatment of lung cancer. The emergence of materials science and nanotechnology partially helped drug delivery scientists to achieve this objective. Various stimuli-responsive materials that undergo degradation at the pathological tumor microenvironment (TME) have been developed and explored for drug delivery applications using nanotechnological approaches. Nanoparticles (NPs), owing to their small size and high surface area to volume ratio, demonstrated enhanced cellular internalization, permeation, and retention at the tumor site. Such passive accumulation of stimuli-responsive materials helped to achieve spatiotemporally controlled and targeted drug delivery within the tumors. In this review, we discussed various stimuli-physical (interstitial pressure, temperature, and stiffness), chemical (pH, hypoxia, oxidative stress, and redox state), and biological (receptor expression, efflux transporters, immune cells, and their receptors or ligands)-that are characteristic to the TME. We mentioned an array of biomaterials-based nanoparticulate delivery systems that respond to these stimuli and control drug release at the TME. Further, we discussed nanoparticle-based combinatorial drug delivery strategies. Finally, we presented our perspectives on challenges related to scale-up, clinical translation, and regulatory approvals.

Quality by design fostered fabrication of cabazitaxel loaded pH-responsive Improved nanotherapeutics against prostate cancer.

Cabazitaxel has been approved for the treatment of prostate cancer since 2010. However, its poor solubility and permeability pitfalls prevent its accumulation at the target site and promote severe adverse effects. About 90% of prostate cancer (PCa) patients suffer from bone metastasis. This advent reports the development of CBZ-loaded pH-responsive polydopamine nanoparticles (CBZ NP) against metastatic PCa cells. Quality by design (QbD) and multivariate analysis tools were employed for the optimization of CBZ NP. Amorphisation of CBZ along with metastatic microenvironment responsive release was observed thereby imparting spatial release and circumventing solubility pitfalls. CBZ NP retained its cytotoxic potential, with a significant increase in quantitative cellular uptake. Apoptotic markers observed from nuclear staining with elevated reactive oxygen species (ROS) and mitochondrial damage revealed by JC-1 staining demonstrated the efficacy of CBZ NP against PC-3 cells with good serum stability and diminished hemolysis. Cell cycle analysis revealed substantial S and G2/M phase arrest with enhancement in apoptosis was observed. Western blot studies revealed an elevation in caspase-1 and suppression in Bcl-2 indicating enhanced apoptosis compared to the control group. Substantial reduction in the diameter of 3D-Tumoroid and enhanced cell proliferation inhibition indicated the efficacy of CBZ NP in PCa. Thus, we conclude that CBZ NP could be a promising Nanotherapeutic approach for PCa.

Exploration of novel drug delivery systems in topical management of osteoarthritis.

Osteoarthritis is one of the foremost disabling disorders in the world. There is no definitive treatment to prevent the progression of osteoarthritis. Hence, palliative treatment aims at minimizing pain, disability and improving function, performance and quality of life. Oral administration of nonsteroidal anti-inflammatory drug is associated with number of adverse effects and reduced therapeutic efficacy. Intra-articular injection has been the preferred route of drug administration. However, the clearance of drug from the arthritic site, risk of infections, cost and the pain associated with frequent injections make this route highly non-compliant to patients. Since osteoarthritis is a chronic condition which requires treatment for prolonged duration, there is an urgent need for another administration route which circumvents the hindrances linked with intra-articular route. Transdermal route across the skin locally at the osteoarthritis site could help in surpassing the disadvantages associated with intra-articular route. However, traversing skin barrier and reaching the chondrocytes with sufficient amount of the drug is extremely difficult. Nanocarrier-based approaches could hold an answer to the said shortcomings owing to their reduced size, targeting tunability and site specificity. In this article, we discuss the pathophysiology of osteoarthritis, molecular targets, and utilization of nanocarrier-based approaches to strategize the treatment of osteoarthritis in a new direction, i.e. topical delivery of nanocarriers in osteoarthritis.

The portrayal of macrophages as tools and targets: A paradigm shift in cancer management.

Macrophages play a major role in maintaining an organism's physiology, such as development, homeostasis, tissue repair, and immunity. These immune cells are known to be involved in tumor progression and modulation. Monocytes can be polarized to two types of macrophages (M1 macrophages and pro-tumor M2 macrophages). Through this article, we aim to emphasize the potential of targeting macrophages in order to improve current strategies for tumor management. Various strategies that target macrophages as a therapeutic target have been discussed along with ongoing clinical trials. We have discussed the role of macrophages in various stages of tumor progression epithelial-to-mesenchymal transition (EMT), invasion, maintaining the stability of circulating tumor cells (CTCs) in blood, and establishing a premetastatic niche along with the role of various cytokines and chemokines involved in these processes. Intriguingly macrophages can also serve as drug carriers due to their tumor tropism along the chemokine gradient. They surpass currently explored nanotherapeutics in tumor accumulation and circulation half-life. We have emphasized on macrophage-based biomimetic formulations and macrophage-hitchhiking as a strategy to effectively target tumors. We firmly believe that targeting macrophages or utilizing them as an indigenous carrier system could transform cancer management.

Albumin-hitchhiking: Fostering the pharmacokinetics and anticancer therapeutics.

Nanotherapeutics demonstrate poor accumulation in the tumor microenvironment due to poor extravasation and penetration into the tumor. Therapeutics such as oligonucleotides, peptides and other biologicals suffer from low systemic half-life and rapid degradation. Albumin-hitchhiking has emerged as an effective strategy to enhance tumor-specific accumulation of various therapeutics. Hitchhiking on serum albumin (SA) have shown to improve biological half-life of various therapeutics including nanocarriers (NCs), biologics, oligonucleotides, vaccines, etc. In addition, passive and active accumulation of SA-riding therapeutics in the tumor, site-specific drug release, and SA-mediated endosomal escape have improved the potential of various anticancer modalities such as chemo-, immune-, vaccine, and gene therapies. In this review, we have discussed the advantages of employing SA-hitchhiking in anticancer therapies. In addition, vaccine strategies employing inherent lymph-nodes accumulating property of albumin have been discussed. We have presented a clinical overview of SA-hitchhiked formulations along with possible bottlenecks for improved clinical outcomes. We have also discussed the role of physiologically based pharmacokinetics (PBPK) modelling for efficient characterization of anti-cancer nanotherapeutics.

Paradigm of lyotropic liquid crystals in tissue regeneration.

The liquid crystalline phase has attracted tremendous attention from researchers across the globe due to its intriguing properties. In this article, we enumerate the different classes of liquid crystals. Lyotropic liquid crystals (LLCs) exhibit their liquid crystalline nature based on the surrounding solvent media, which opens novel horizons in drug delivery and tissue regeneration. The advantages of LLCs in the said fields and the thermodynamic mechanistic insights responsible for their structural stabilization have been conveyed. Various fabrication and characterization techniques, along with factors influencing the formation of LLCs, have been discussed. Applications in novel therapeutic avenues like bone extracellular matrix, cardiac remodeling, wound management, and implants have been unveiled. Also, regulatory considerations, patent, and clinical portfolios to circumvent the hurdles of clinical translation have been discussed. LLCs could be a promising approach in diverse avenues of tissue regeneration.

Immune cell-camouflaged surface-engineered nanotherapeutics for cancer management.

Nanocarriers (NCs) have shown potential in delivering hydrophobic cytotoxic drugs and tumor-specific targeting. However, the inability to penetrate the tumor microenvironment and entrapment by macrophages has limited their clinical translation. Various cell-based drug delivery systems have been explored for their ability to improve circulation half-life and tumor accumulation capabilities. Tumors are characterized by high inflammation, which aids in tumor progression and metastasis. Immune cells show natural tumor tropism and penetration inside the tumor microenvironment (TME) and are a topic of great interest in cancer drug delivery. However, the TME is immunosuppressive and can polarize immune cells to pro-tumor. Thus, the use of immune cell membrane-coated NCs has gained popularity. Such carriers display immune cell-specific surface receptors for tumor-specific accumulation but lack cell machinery. The lack of immune cell machinery makes them unaffected by the immunosuppressive TME, meanwhile maintaining the inherent tumor tropism. In this review, we discuss the molecular mechanism behind the movement of various immune cells toward TME, the preparation and characterization of membrane-coated NCs, and the efficacy of immune cell-mimicking NCs in tumor therapy. Regulatory guidelines and the bottlenecks in clinical translation are also highlighted. STATEMENT OF SIGNIFICANCE: Nanocarriers have been explored for the site-specific delivery of chemotherapeutics. However, low systemic circulation half-life, extensive entrapment by macrophages, and poor accumulation inside the tumor microenvironment prevent the clinical translation of conventional nanotherapeutics. Immune cells possess the natural tropism towards the tumor along the chemokine gradient. Hence, coating the nanocarriers with immune cell-derived membranes can improve the accumulation of nanocarriers inside the tumor. Moreover, coating with membranes derived autologous immune cells will prevent engulfment by the macrophages.

Nanomedicine based strategies for oligonucleotide traversion across the blood-brain barrier.

Neurological disorders are considered the most prominent cause of disability worldwide. The major hurdle in the management of neurological disorders is the existence of the blood-brain barrier (BBB), which hinders the entry of several therapeutic moieties. In recent years, oligonucleotides have gained tremendous attention for their target specificity, diminished dose and adverse effects, thereby halting disease progression. However, enzymatic degradation, rapid clearance, limited circulation and availability at the bio-active site, etc., limit its clinical translation. Nanomedicine has opened up a breadth of opportunities in the delivery of oligonucleotides across the BBB. This review addresses the pitfalls associated with oligonucleotide delivery in traversing the BBB via nanotherapeutics for the management of brain disorders. Regulatory perspectives pertaining to hastening the clinical translation of oligonucleotide-loaded nanocarriers for brain delivery have been highlighted.