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.

Nanocarrier-Integrated Microneedles: Divulging the Potential of Novel Frontiers for Fostering the Management of Skin Ailments.

The various kinds of nanocarriers (NCs) have been explored for the delivery of therapeutics designed for the management of skin manifestations. The NCs are considered as one of the promising approaches for the skin delivery of therapeutics attributable to sustained release and enhanced skin penetration. Despite the extensive applications of the NCs, the challenges in their delivery via skin barrier (majorly stratum corneum) have persisted. To overcome all the challenges associated with the delivery of NCs, the microneedle (MN) technology has emerged as a beacon of hope. Programmable drug release, being painless, and its minimally invasive nature make it an intriguing strategy to circumvent the multiple challenges associated with the various drug delivery systems. The integration of positive traits of NCs and MNs boosts therapeutic effectiveness by evading stratum corneum, facilitating the delivery of NCs through the skin and enhancing their targeted delivery. This review discusses the barrier function of skin, the importance of MNs, the types of MNs, and the superiority of NC-loaded MNs. We highlighted the applications of NC-integrated MNs for the management of various skin ailments, combinational drug delivery, active targeting, in vivo imaging, and as theranostics. The clinical trials, patent portfolio, and marketed products of drug/NC-integrated MNs are covered. Finally, regulatory hurdles toward benchtop-to-bedside translation, along with promising prospects needed to scale up NC-integrated MN technology, have been deliberated. The current review is anticipated to deliver thoughtful visions to researchers, clinicians, and formulation scientists for the successful development of the MN-technology-based product by carefully optimizing all the formulation variables.

High mobility group box 1 cytokine targeted topical delivery of resveratrol embedded nanoemulgel for the management of atopic dermatitis.

Resveratrol is a polyphenolic compound showing anti-inflammatory activity by inhibition of high mobility group box 1 cytokine responsible for the activation of nuclear factor-κB pathway in atopic dermatitis. To evaluate the efficacy of resveratrol through topical route we have developed resveratrol-loaded nanoemulgel for the effective management of atopic dermatitis in mice model. The resveratrol-loaded nanoemulsion (0.5%, 0.75% and 1% w/w) was optimized by spontaneous nano-emulsification. The optimized resveratrol-loaded nanoemulsions showed average globule size in the 180-230 nm range and found to be monodispersed. The resveratrol nanoemulgel was prepared with a SEPINEO™ P 600 gel base and propylene glycol. Ex vivo permeation and retention study resulted in significantly higher skin retention of resveratrol from resveratrol-loaded nanoemulgel than free resveratrol-loaded gel. Preclinical efficacy of resveratrol nanoemulgel displayed promising therapeutic outcomes where, western blotting of skin tissues disclosed a significant reduction in the relative expression of high mobility group box 1, the receptor for advanced glycation end products, toll-like receptor-4 and phosphorylated nuclear factor-κB. Further, real-time polymerase chain reaction also disclosed a significant reduction in pro-inflammatory cytokines such as thymic stromal lymphopoietin, interleukin-4, interleukin-13, interleukin-31, tumor necrosis factor-α and interleukin-6. The histopathological examination of skin sections showed improvement in the skin condition. Collectively, the findings from our study showcased the significant improvement in the atopic dermatitis skin condition in mice model after topical application of resveratrol loaded nanoemulgel.

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.

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.

Neutrophil membrane-based nanotherapeutics: Propitious paradigm shift in the management of cancer.

Cancer is the leading cause of death across the globe, with 19.3 million new cancer cases and 10 million deaths in the year 2020. Conventional treatment modalities have numerous pitfalls, such as off-site cytotoxicity and poor bioavailability. Nanocarriers (NCs) have been explored to deliver various therapeutic moieties such as chemotherapeutic agents and photothermal agents, etc. However, several limitations, such as rapid clearance by the reticuloendothelial system, poor extravasation into the tumor microenvironment, and low systemic half-life are roadblocks to successful clinical translation. To circumvent the pitfalls of currently available treatment modalities, neutrophil membrane (NM)-based nanotherapeutics have emerged as a promising platform for cancer management. Their versatile features such as natural tumor tropism, tumor-specific accumulation, and prevention from rapid clearance owing to their autologous nature make them an effective anticancer NCs. In this manuscript, we have discussed various methods for isolation, coating and characterization of NM. We have discussed the role of NM-coated nanotherapeutics as neoadjuvant and adjuvant in different treatment modalities, such as chemotherapy, photothermal and photodynamic therapies with rationales behind their inclusion. Clinical hurdles faced during the bench-to-bedside translation with possible solutions have been discussed. We believe that in the upcoming years, NM-coated nanotherapeutics will open a new horizon in cancer management.

Quality by design endorsed fabrication of Ibrutinib-loaded human serum albumin nanoparticles for the management of leukemia.

Ibrutinib (IB), a BCS class II drug suffers from limited aqueous solubility, short half-life and extensive first-pass metabolism. In this project, we aim to recruit the desirable properties of human serum albumin (HSA) as a biocompatible drug carrier to circumvent nanoparticle-associated drawbacks. Quality by design and multivariate analysis was used for the optimization of IB-NPs. Cell culture studies performed on the K562 cell line revealed that the Ibrutinib-loaded HSA NPs demonstrated improved cytotoxicity, drug uptake, and reactive oxygen species generation in the leukemic K562 cells. Cell cycle analysis revealed G2/M phase retention of the leukemia cells. In vitro protein corona and hemolysis studies revealed superior hematological stability compared to the free drug which showed greater than 40 % hemolysis. In vitro drug release studies showed prolonged release profile till 48 h. Pharmacokinetic studies demonstrated a 2.31-fold increase in AUC and an increase in half-life from 0.43 h to 2.887 h with a tremendous reduction in clearance and elimination rate indicating prolonged systemic circulation which is desirable in leukemia. Hence, we conclude that IB-loaded albumin nanoparticles could be a promising approach for the management of leukemia.

Perspective insights of small molecules, phytoconstituents and biologics in the management of psoriasis: A focus on targeting major inflammatory cytokine pathways.

Psoriasis is an enduring, pruritic and papulosquamous skin ailment that poses a significant burden on public health. It is mainly characterized by hyperkeratosis, acanthosis, parakeratosis, scaly and erythematous plaques. Biomarkers like interleukin-17, interleukin-12 and -23 and tumor necrosis factor-α serve as key drivers of psoriatic pathogenesis. Triggered release of pro-inflammatory cytokines from various up-regulated pathways leads to psoriatic inflammation. Several target moieties like biologics, small molecules and herbal moieties play a fundamental role in the repression of pathogenesis of psoriasis. Biologics and small molecules engaged in the management of psoriasis have been emphasized in detail. An insight into nano-carrier interventions on herbal moieties and clinical aspects of psoriasis are also highlighted. This review emphasizes various pathological targets involved in psoriasis.

Multifaceted applications of ulvan polysaccharides: Insights on biopharmaceutical avenues.

Ulvans are water-soluble sulfated polysaccharides predominantly found in the cell wall of green algae. They hold unique characteristics that are attributed to their 3D conformation, functional groups along with the presence of saccharides and sulfate ions. Traditionally, ulvans are widely used as food supplements and probiotics owing to the high content of carbohydrates. Despite their widespread usage in food industry, an in-depth understanding is required for extrapolating their potential application as a nutraceutical and medicinal agent which could be beneficial in promoting human health and well-being. This review emphasizes novel therapeutic avenues where ulvan polysaccharides can be used beyond their nutritional applications. A collection of literature points towards multifarious applications of ulvan in various biomedical fields. Structural aspects along with extraction and purification methods have been discussed. The underlying molecular mechanisms associated with its biomedical potential in different therapeutic fields like oncology, infectious diseases, inflammation, neuroprotection and tissue engineering, etc. have been unravelled. Challenges associated with clinical translation and future perspectives have been deliberated.

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.

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.

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.

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 potentially transformative strategies for colon targeting of peptides: State-of-the-art.

Recently, peptides have attracted tremendous attention among researchers attributed to their high target specificity and efficacy compared to conventional therapeutics. The ease of self-administration and non-invasiveness confers oral as the most desirable route. However, numerous challenges associated with peptide delivery through the oral route like harsh gastrointestinal environment, enzymatic degradation, and absorption barriers hinder its clinical translation. Protease activity is more pronounced in the proximal segments of the gastrointestinal tract (GIT). Distal segments like the colon possess lower proteolytic activity, enhanced retention time, etc. which could facilitate easy absorption. However, traversing of the upper segments to reach the colon requires the circumvention of the pitfalls of the GIT. The advent of nanomedicine strategies could help in overcoming the said challenges associated with oral delivery, colon-specific targeting, and improving stability and bioavailability at the active site. Furthermore, the classification of peptides and various nanomedicine strategies for oral delivery of peptides to the colon has been conveyed. Regulatory hurdles and ways to accomplish clinical translation have been addressed.

Advancements in redox-sensitive micelles as nanotheranostics: A new horizon in cancer management.

World Health Organisation (WHO) delineated cancer as one of the foremost reasons for mortality with 10 million deaths in the year 2020. Early diagnosis and effective drug delivery are of utmost importance in cancer management. The entrapment of both bio-imaging dyes and drugs will open novel avenues in the area of tumor theranostics. Elevated levels of reactive oxygen species (ROS) and glutathione (GSH) are the characteristic features of the tumor microenvironment (TME). Researchers have taken advantage of these specific TME features in recent years to develop micelle-based theranostic nanosystems. This review focuses on the advantages of redox-sensitive micelles (RSMs) and supramolecular self-assemblies for tumor theranostics. Key chemical linkers employed for the tumor-specific release of the cargo have been discussed. In vitro characterisation techniques used for the characterization of RSMs have been deliberated. Potential bottlenecks that may present themselves in the bench-to-bedside translation of this technology and the regulatory considerations have been deliberated.