Matrix-Mediated Delivery of Silver Nanoparticles for Prevention of Staphylococcus aureus and Pseudomonas aeruginosa Biofilm Formation in Chronic Rhinosinusitis.

Chronic rhinosinusitis (CRS) is a chronic health condition affecting the sinonasal cavity. CRS-associated mucosal inflammation leads to sinonasal epithelial cell death and epithelial cell barrier disruption, which may result in recurrent bacterial infections and biofilm formation. For patients who fail medical management and elect endoscopic sinus surgery for disease control, bacterial biofilm formation is particularly detrimental, as it reduces the efficacy of surgical intervention. Effective treatments that prevent biofilm formation in post-operative patients in CRS are currently limited. To address this unmet need, we report the controlled release of silver nanoparticles (AgNps) with silk-elastinlike protein-based polymers (SELPs) to prevent bacterial biofilm formation in CRS. This polymeric network is liquid at room temperature and forms a hydrogel at body temperature, and is hence, capable of conforming to the sinonasal cavity upon administration. SELP hydrogels demonstrated sustained AgNp and silver ion release for the studied period of three days, potent in vitro antibacterial activity against Pseudomonas aeruginosa (**** p < 0.0001) and Staphylococcus aureus (**** p < 0.0001), two of the most commonly virulent bacterial strains observed in patients with post-operative CRS, and high cytocompatibility with human nasal epithelial cells. Antibacterial controlled release platform shows promise for treating patients suffering from prolonged sinonasal cavity infections due to biofilms.

Nanomedicine for the SARS-CoV-2: State-of-the-Art and Future Prospects.

The newly emerged ribonucleic acid (RNA) enveloped human beta-coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection caused the COVID-19 pandemic, severely affects the respiratory system, and may lead to death. Lacking effective diagnostics and therapies made this pandemic challenging to manage since the SARS-CoV-2 transmits via human-to-human, enters via ACE2 and TMPSSR2 receptors, and damages organs rich in host cells, spreads via symptomatic carriers and is prominent in an immune-compromised population. New SARS-CoV-2 informatics (structure, strains, like-cycles, functional sites) motivated bio-pharma experts to investigate novel therapeutic agents that act to recognize, inhibit, and knockdown combinations of drugs, vaccines, and antibodies, have been optimized to manage COVID-19. However, successful targeted delivery of these agents to avoid off-targeting and unnecessary drug ingestion is very challenging. To overcome these obstacles, this mini-review projects nanomedicine technology, a pharmacologically relevant cargo of size within 10 to 200 nm, for site-specific delivery of a therapeutic agent to recognize and eradicate the SARS-CoV-2, and improving the human immune system. Such combinational therapy based on compartmentalization controls the delivery and releases of a drug optimized based on patient genomic profile and medical history. Nanotechnology could help combat COVID-19 via various methods such as avoiding viral contamination and spraying by developing personal protective equipment (PPE) to increase the protection of healthcare workers and produce effective antiviral disinfectants surface coatings capable of inactivating and preventing the virus from spreading. To quickly recognize the infection or immunological response, design highly accurate and sensitive nano-based sensors. Development of new drugs with improved activity, reduced toxicity, and sustained release to the lungs, as well as tissue targets; and development of nano-based immunizations to improve humoral and cellular immune responses. The desired and controlled features of suggested personalized therapeutics, nanomedicine, is a potential therapy to manage COVID-19 successfully. The state-of-the-art nanomedicine, challenges, and prospects of nanomedicine are carefully and critically discussed in this report, which may serve as a key platform for scholars to investigate the role of nanomedicine for higher efficacy to manage the COVID-19 pandemic.

Therapeutic role of inflammasome inhibitors in neurodegenerative disorders.

Neuroinflammation, characterized by the activation of glial cells, is a hallmark in several neurological and neurodegenerative disorders. Inadequate inflammation cannot eliminate the infection of pathogens, while excessive or hyper-reactive inflammation can cause chronic or systemic inflammatory diseases affecting the central nervous system (CNS). In response to a brain injury or pathogen invasion, the pathogen recognition receptors (PRRs) expressed on glial cells are activated via binding to cellular damage-associated molecular patterns (DAMPs) or pathogen-associated molecular patterns (PAMPs). This subsequently leads to the activation of NOD (nucleotide-binding oligomerization domain)-like receptor proteins (NLRs). In neurodegenerative diseases such as HIV-1-associated neurocognitive disorders (HAND), Alzheimer's disease (AD), Parkinson's disease (PD), and multiple sclerosis (MS), chronic inflammation is a critical contributing factor for disease manifestation including pathogenesis. Emerging evidence points to the involvement of "inflammasomes", especially the nucleotide-binding oligomerization domain, leucine-rich repeat, and pyrin domain-containing (NLRP) complex in the development of these diseases. The activated NLRP3 results in the proteolytic activation of caspase-1 that facilitates the cleavage of pro-IL-1ß and the secretion of IL-1ß and IL-18 proinflammatory cytokines. Accordingly, these and other seminal findings have led to the development of NLRP-targeting small-molecule therapeutics as possible treatment options for neurodegenerative disorders. In this review, we will discuss the new advances and evidence-based literature concerning the role of inflammasomes in neurodegenerative diseases, its role in the neurological repercussions of CNS chronic infection, and the examples of preclinical or clinically tested NLRP inhibitors as potential strategies for the treatment of chronic neurological diseases.

Development of Chitosan-Based Hydrogel Containing Antibiofilm Agents for the Treatment of Staphylococcus aureus-Infected Burn Wound in Mice.

Methicillin-resistant Staphylococcus aureus (MRSA) is considered a common colonizer of burn wound and accounts for high morbidity and mortality all across the globe. Systemic antibiotic therapy which is generally prescribed for these patients has a number of limitations. These include high drug dose, toxicity, and chances of development of drug resistance. However, local delivery of drug not only addresses these limitations but also provides better efficacy at the site of infection. In the present study, hydrogel preparations were developed for the topical delivery of moxifloxacin for the treatment of S. aureus-infected burn wound. Moxifloxacin was characterized by UV, FTIR, DSC, hot-stage microscopy, NMR, and HPLC and loaded into conventional and Boswellia-containing novel gels. Gels were characterized by visual examination, pH, UV spectroscopy, and release assays. In vivo studies showed that both gels were effective in eradicating the bacteria completely from the wound site when treatment was started during the early stage of infection. On the contrary, delayed treatment of planktonic and biofilm cells with novel gel showed better efficacy as compared with conventional gel in S. aureus-infected burn wound. Histopathological analysis also showed better skin healing efficacy of novel gel than conventional gel. Our results show that moxifloxacin can be efficiently used topically in the management of burn wound infections along with other antibacterial agents. Since biofilm-mediated infections are on the rise especially in chronic bacterial disease, therefore, a preparation containing antibiofilm agent-like Boswellia as one of the excipients would be more meaningful.

CNS organoids: an innovative tool for neurological disease modeling and drug neurotoxicity screening.

The paradigm of central nervous system (CNS) drug discovery has mostly relied on traditional approaches of rodent models or cell-based in vitro models. Owing to the issues of species differences between humans and rodents, it is difficult to correlate the robustness of data for neurodevelopmental studies. With advances in the stem-cell field, 3D CNS organoids have been developed and explored owing to their resemblance to the human brain architecture and functions. Further, CNS organoids provide a unique opportunity to mimic the human brain physiology and serve as a modeling tool to study the normal versus pathological brain or the elucidation of mechanisms of neurological disorders. Here, we discuss the recent application of a CNS organoid explored for neurodevelopment disease or a screening tool for CNS drug development.

In-vitro blood-brain barrier models for drug screening and permeation studies: an overview.

The blood-brain barrier (BBB) is comprised of brain microvascular endothelial central nervous system (CNS) cells, which communicate with other CNS cells (astrocytes, pericytes) and behave according to the state of the CNS, by responding against pathological environments and modulating disease progression. The BBB plays a crucial role in maintaining homeostasis in the CNS by maintaining restricted transport of toxic or harmful molecules, transport of nutrients, and removal of metabolites from the brain. Neurological disorders, such as NeuroHIV, cerebral stroke, brain tumors, and other neurodegenerative diseases increase the permeability of the BBB. While on the other hand, semipermeable nature of BBB restricts the movement of bigger molecules i.e. drugs or proteins (>500 kDa) across it, leading to minimal bioavailability of drugs in the CNS. This poses the most significant shortcoming in the development of therapeutics for CNS neurodegenerative disorders. Although the complexity of the BBB (dynamic and adaptable barrier) affects approaches of CNS drug delivery and promotes disease progression, understanding the composition and functions of BBB provides a platform for novel innovative approaches towards drug delivery to CNS. The methodical and scientific interests in the physiology and pathology of the BBB led to the development and the advancement of numerous in vitro models of the BBB. This review discusses the fundamentals of BBB structure, permeation mechanisms, an overview of all the different in-vitro BBB models with their advantages and disadvantages, and rationale of selecting penetration prediction methods towards the critical role in the development of the CNS therapeutics.

Effective Topical Delivery of H-AgNPs for Eradication of Klebsiella pneumoniae-Induced Burn Wound Infection.

The aim of the present study was to explore the therapeutic efficacy of microemulsion-based delivery of histidine-capped silver nanoparticles in eradicating Klebsiella pneumoniae-induced burn wound infection. The developed microemulsion was characterized on the basis of differential light scattering, phase separation, refractive index, and specific conductance. Emulgel was prepared and characterized on the basis of thixotropy, texture, differential scanning calorimetry, and release kinetics. Emulgel was further evaluated in skin irritation and in vivo studies, namely full-thickness K. pneumoniae-induced burn wound infection treatment via topical route. Efficacy of treatment was evaluated in terms of bacterial load, histopathology, wound contraction, and other infection markers. The developed emulgel provided significant in vivo antibacterial activity of histidine-capped silver nanoparticle preparations via topical route and resulted in reduction in bacterial load, wound contraction, and enhanced skin healing as well as decrement of inflammatory markers such as malondialdehyde, myeloperoxidase, and reactive nitrogen intermediate compared to untreated animals. The present study encourages the further employment of histidine-capped silver nanoparticles along with microemulsion-based drug delivery system in combating antibiotic-resistant topical infections.

Organ-on-chip models: Implications in drug discovery and clinical applications.

Before a lead compound goes through a clinical trial, preclinical studies utilize two-dimensional (2D) in vitro models and animal models to study the pharmacodynamics and pharmacokinetics of that lead compound. However, these current preclinical studies may not accurately represent the efficacy and safety of a lead compound in humans, as there has been a high failure rate of drugs that enter clinical trials. All of these failures and the associated costs demonstrate a need for more representative models of human organ systems for screening in the preclinical phase of drug development. In this study, we review the recent advances in in vitro modeling including three-dimensional (3D) organoids, 3D microfabrication, and 3D bioprinting for various organs including the heart, kidney, lung, gastrointestinal tract (intestine-gut-stomach), liver, placenta, adipose, retina, bone, and brain as well as multiorgan models. The availability of organ-on-chip models provides a wealth of opportunities to understand the pathogenesis of human diseases and provide a potentially better model to screen a drug, as these models utilize a dynamic 3D environment similar to the human body. Although there are limitations of organ-on-chip models, the emergence of new technologies have refined their capability for translational research as well as precision medicine.

Phospholipid structured microemulsion as effective carrier system with potential in methicillin sensitive Staphylococcus aureus (MSSA) involved burn wound infection.

Burn wounds are foremost site for bacterial colonization and multiplication. Staphylococcus aureus is one of the most predominant pathogen found in burn wounds. Fusidic acid (FA) is widely employed in the treatment of complicated skin infections caused by Staphylococcus aureus. Hence, the aim of this study was to investigate the usefulness and efficacy of topical FA (2% w/w) loaded biocompatible microemulsion-based-system (FA-ME) in eradicating MSSA bacterial infections which otherwise was less effective when dealt with conventional formulations. For construction of pseudoternary phase diagram, ratio of oil (IPM):water:Smix is 20:30:50% w/w and proportion of Smix (Phospholipid:Tween 80 (T80):Ethanol) is in the ratio of 1:2:1, respectively. The hypothesis relates here to the role of phospholipids as part of the nano-scale structure of microemulsion systems to overcome the hurdles of drug delivery. The prepared FA-ME system was evaluated for its therapeutic efficacy and carrier-specific characteristics such as globule size, % transmittance, transmission electron microscopy, drug content and stability. Selected microemulsion system was incorporated into gel form and evaluated for texture analysis, drug permeation in 24 h and treatment of burn wounds. Burn wound infection was established with MSSA ATCC 25923 in BALB/c mice and the process of wound healing as well as bacterial loading in the wound was estimated. The developed nanosized FA-ME system demonstrated improved wound healing, better spreadability and enhanced therapeutic efficacy due to the changes in the behavior of the drug molecules by way of carrier-characteristics.