Recent Advances in the Lipid Nanoparticle-Mediated Delivery of mRNA Vaccines.

Lipid nanoparticles (LNPs) have recently emerged as one of the most advanced technologies for the highly efficient in vivo delivery of exogenous mRNA, particularly for COVID-19 vaccine delivery. LNPs comprise four different lipids: ionizable lipids, helper or neutral lipids, cholesterol, and lipids attached to polyethylene glycol (PEG). In this review, we present recent the advances and insights for the design of LNPs, as well as their composition and properties, with a subsequent discussion on the development of COVID-19 vaccines. In particular, as ionizable lipids are the most critical drivers for complexing the mRNA and in vivo delivery, the role of ionizable lipids in mRNA vaccines is discussed in detail. Furthermore, the use of LNPs as effective delivery vehicles for vaccination, genome editing, and protein replacement therapy is explained. Finally, expert opinion on LNPs for mRNA vaccines is discussed, which may address future challenges in developing mRNA vaccines using highly efficient LNPs based on a novel set of ionizable lipids. Developing highly efficient mRNA delivery systems for vaccines with improved safety against some severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants remains difficult.

Hyaluronic Acid-Based Bioconjugate Systems, Scaffolds, and Their Therapeutic Potential.

In recent years, the development of hyaluronic acid or hyaluronan (HA) based scaffolds, medical devices, bioconjugate systems have expanded into a broad range of research and clinical applications. Research findings over the last two decades suggest that the abundance of HA in most mammalian tissues with distinctive biological roles and chemical simplicity for modifications have made it an attractive material with a rapidly growing global market. Besides its use as native forms, HA has received much interest on so-called "HA-bioconjugates" and "modified-HA systems". In this review, the importance of chemical modifications of HA, underlying rationale approaches, and various advancements of bioconjugate derivatives with their potential physicochemical, and pharmacological advantages are summarized. This review also highlights the current and emerging HA-based conjugates of small molecules, macromolecules, crosslinked systems, and surface coating strategies with their biological implications, including their potentials and key challenges discussed in detail.

Multifrequency dielectric mapping of fixed mice colon tissues in cell culture media via scanning electrochemical microscopy.

Alternating current scanning electrochemical microscopy (AC-SECM) is a powerful tool for characterizing the electrochemical reactivity of surfaces. Here, perturbation in the sample is induced by the alternating current and altered local potential is measured by the SECM probe. This technique has been used to investigate many exotic a range of biological interfaces including live cells and tissues, as well as the corrosive degradation of various metallic surfaces, etc. In principle, AC-SECM imaging is derived from electrochemical impedance spectroscopy (EIS) which has been used for a century to describe interfacial and diffusive behaviour of molecules in solution or on a surface. Increasingly bioimpedance centric medical devices have become an important tool to detect evolution of tissue biochemistry. Predictive implications of measuring electrochemical changes within a tissue is one of the core concepts in developing minimally invasive and smart medical devices. In this study, cross sections of mice colon tissue were used for AC-SECM imaging. A 10 micron sized platinum probe was used for two-dimensional (2D) tan δ mapping of histological sections at a frequency of 10 kHz, Thereafter, multifrequency scans were performed at 100 Hz, 10 kHz, 300 kHz, and 900 kHz. Loss tangent (tan δ) mapping of mice colon revealed microscale regions within a tissue possessing a discrete tan δ signature. This tan δ map may be an immediate measure of physiological conditions in biological tissues. Multifrequency scans highlight subtle changes in protein or lipid composition as a function of frequency which was recorded as loss tangent maps. Impedance profile at different frequencies could also be used to identify optimal contrast for imaging and extracting the electrochemical signature specific for a tissue and its electrolyte.

IBD disease-modifying therapies: insights from emerging therapeutics.

Inflammatory bowel disease (IBD) pathogenesis is associated with gut mucosal inflammation, epithelial damage, and dysbiosis leading to a dysregulated gut mucosal barrier. However, the extent and underlying mechanisms remain largely unknown. Current treatment regimens have focused mainly on treating IBD symptoms; however, such treatment strategies do not address mucosal epithelial repair, barrier homeostasis, or intestinal dysbiosis. Although attempts have been made to identify new therapeutic modalities to enhance gut barrier functions, these are at an early developmental stage and have not been wholly successful. We review conventional therapies, the possible relevant role of gut barrier-protecting agents, and biomaterial strategies relating to combination therapies that may pave the way towards developing new therapeutic approaches for IBD.

Polyester-based long acting injectables: Advancements in molecular dynamics simulation and technological insights.

Long-acting injectable (LAI) delivery technologies have enabled the development of several pharmaceutical products that improve patient health by delivering therapeutics from weeks to months. Over the last decade, due to its good biocompatibility, formulation tunability, wide range of degradation rates, and extensive clinical studies, polyester-based LAI technologies including poly(lactic-co-glycolic acid) (PLGA) have made substantial progress. Herein, we discuss PLGA properties with seminal approaches in the development of LAIs, the role of molecular dynamic simulations of polymer-drug interactions, and their effects on quality attributes. We also outline the landscape of various advanced PLGA-based and a few non-PLGA LAI technologies; their design, delivery, and challenges from laboratory scale to preclinical and clinical use; and commercial products incorporating the importance of end-user preferences.

Metabolic pathway genes for editing to enhance multiple disease resistance in plants.

Diseases are one of the major constraints in commercial crop production. Genetic diversity in varieties is the best option to manage diseases. Molecular marker-assisted breeding has produced hundreds of varieties with good yields, but the resistance level is not satisfactory. With the advent of whole genome sequencing, genome editing is emerging as an excellent option to improve the inadequate traits in these varieties. Plants produce thousands of antimicrobial secondary metabolites, which as polymers and conjugates are deposited to reinforce the secondary cell walls to contain the pathogen to an initial infection area. The resistance metabolites or the structures produced from them by plants are either constitutive (CR) or induced (IR), following pathogen invasion. The production of each resistance metabolite is controlled by a network of biosynthetic R genes, which are regulated by a hierarchy of R genes. A commercial variety also has most of these R genes, as in resistant, but a few may be mutated (SNPs/InDels). A few mutated genes, in one or more metabolic pathways, depending on the host-pathogen interaction, can be edited, and stacked to increase resistance metabolites or structures produced by them, to achieve required levels of multiple pathogen resistance under field conditions.

Quercetin conjugated fluorescent nitrogen-doped carbon dots for targeted cancer therapy application.

In this work, we report the development of nitrogen-doped carbon dots (NDCDs) as a drug carrier using quercetin (QC) as a model drug for anti-cancer drug delivery application. NDCDs were prepared by a simple hydrothermal method using Luffa acutangula as a carbon source. The characterization of QC-NDCDs was done by UV-vis spectroscopy, fluorescence spectroscopy, zeta potential measurements, high-resolution transmission electron microscopy (HR-TEM), Fourier transform infrared (FT-IR) spectroscopy, X-ray diffraction (XRD), and Raman spectroscopy. The as-synthesized NDCDs have a small particle size with hydroxyl and nitrogen-containing groups (pyridinic and amide groups), enhancing the fluorescence properties, and were obtained in a good quantum yield (14%). Furthermore, the in vitro alamarBlue® assay revealed that the NDCDs-QC conjugate was nontoxic to colon cancer cells. This NDCDs-QC conjugate is able to kill cancer cells in the NDCDs-QC form compared to free QC as confirmed by in vitro MTT assay results. Thus, the developed NDCDs conjugate can be used as a promising drug delivery and bio-imaging vehicle in cancer therapy.

Inflammation-specific targeted carriers for local drug delivery to inflammatory bowel disease.

Delivering drugs directly to the inflamed intestinal sites to treat inflammatory bowel disease (IBD), particularly Crohn's and ulcerative colitis, is highly challenging. Recent advances in colitis therapy medications are expanding opportunities for improving local on-site drug availability by minimising the associated systemic side-effects. Drug delivery with targeted carrier systems has shown the potential to increase site-specificity, stability, and therapeutic efficacy. Herein, we report the development of a strong anionic charged inflammation targeted nanocarriers (IT-NCs) loaded with an immunosuppressant model drug. This system showed preferential adhesion on a charge-modified surface in vitro, and in both dextran sulfate sodium (DSS) and TNBS colitis mice in vivo models. IT-NCs showed improved colitis phenotype therapeutic efficacy in both animal models compared to free drug. Furthermore, ex vivo study of colon tissue biopsies from patients with colitis revealed that IT-NCs adhered preferentially to inflamed biopsies compared to normal. Together, our results suggest that IT-NCs have promising therapeutic potential as delivery carriers' in colitis management.

Modulation of Gut Barrier Functions in Ulcerative Colitis by Hyaluronic Acid System.

The active stages of intestinal inflammation and the pathogenesis of ulcerative colitis are associated with superficial mucosal damage and intermittent wounding that leads to epithelial barrier defects and increased permeability. The standard therapeutic interventions for colitis have focused mainly on maintaining the remission levels of the disease. Nonetheless, such treatment strategies (using anti-inflammatory, immunomodulatory agents) do not address colitis' root cause, especially the mucosal damage and dysregulated intestinal barrier functions. Restoration of barrier functionality by mucosal healing or physical barrier protecting strategies shall be considered as an initial event in the disease suppression and progression. Herein, a biphasic hyaluronan (HA) enema suspension, naïve-HA systems that protect the dysregulated gut epithelium by decreasing the inflammation, permeability, and helping in maintaining the epithelial barrier integrity in the dextran sodium sulfate-induced colitis mice model is reported. Furthermore, HA-based system modulates intestinal epithelial junctional proteins and regulatory signaling pathways, resulting in attenuation of inflammation and mucosal protection. The results suggest that HA-based system can be delivered as an enema to act as a barrier protecting system for managing distal colonic inflammatory diseases, including colitis.

Recent advances and prospects of hyaluronan as a multifunctional therapeutic system.

Hyaluronan (HA) is a naturally occurring non-sulfated glycosaminoglycan (GAG), cell-surface-associated biopolymer and is the key component of tissue extracellular matrix (ECM). Along with remarkable physicochemical properties, HA also has multifaceted biological effects that include but not limited to ECM organization, immunomodulation, and various cellular processes. Environmental cues such as tissue injury, infection or cancer change downstream signaling functionalities of HA. Unlike native HA, the fragments of HA have diversified effects on inflammation, cancer, fibrosis, angiogenesis and autoimmune response. In this review, we aim to discuss HA as a therapeutic delivery system development process, source, biophysical-chemical properties, and associated biological pathways (especially via cell surface receptors) of native and fragmented HA. We also tried to address an overview of the potential role of HA (native HA vs fragments) in the modulation of inflammation, immune response and various cancer targeting delivery applications. This review will also highlight the HA based therapeutic systems, medical devices and future perspectives of various biomedical applications were discussed in detail.

Potential immuno-nanomedicine strategies to fight COVID-19 like pulmonary infections.

COVID-19, coronavirus disease 2019, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has become a pandemic. At the time of writing this (October 14, 2020), more than 38.4 million people have become affected, and 1.0 million people have died across the world. The death rate is undoubtedly correlated with the cytokine storm and other pathological pulmonary characteristics, as a result of which the lungs cannot provide sufficient oxygen to the body's vital organs. While diversified drugs have been tested as a first line therapy, the complexity of fatal cases has not been reduced so far, and the world is looking for a treatment to combat the virus. However, to date, and despite such promise, we have received very limited information about the potential of nanomedicine to fight against COVID-19 or as an adjunct therapy in the treatment regimen. Over the past two decades, various therapeutic strategies, including direct-acting antiviral drugs, immunomodulators, a few non-specific drugs (simple to complex), have been explored to treat Acute Respiratory Distress Syndrome (ARDS), Severe Acute Respiratory Syndrome (SARS) and Middle East Respiratory Syndrome (MERS), influenza, and sometimes the common flu, thus, correlating and developing specific drugs centric to COVID-19 is possible. This review article focuses on the pulmonary pathology caused by SARS-CoV-2 and other viral pathogens, highlighting possible nanomedicine therapeutic strategies that should be further tested immediately.

A high molecular weight hyaluronic acid biphasic dispersion as potential therapeutics for interstitial cystitis.

Interstitial cystitis (IC) is a progressive bladder disease characterized by increased urothelial permeability, inflammation of the bladder with abdominal pain. While there is no consensus on the etiology of the disease, it was believed that restoring the barrier between urinary solutes and (GAG) urothelium would interrupt the progression of this disease. Currently, several treatment options include intravesical delivery of hyaluronic acid (HA) and/or chondroitin sulfate solutions, through a catheter to restore the urothelial barrier, but have shown limited success in preclinical, clinical trials. Herein we report for the first time successful engineering and characterization of biphasic system developed by combining cross-linked hyaluronic acid and naïve HA solution to decrease inflammation and permeability in an in vitro model of interstitial cystitis. The cross-linking of HA was performed by 4-arm-polyethyeleneamine chemistry. The HA formulations were tested for their viscoelastic properties and the effects on cell metabolism, inflammatory markers, and permeability. Our study demonstrates the therapeutic effects of different ratios of the biphasic system and reports their ability to increase the barrier effect by decreasing the permeability and alteration of cell metabolism with respect to relative controls. Restoring the barrier by using biphasic system of HA therapy may be a promising approach to IC.

Whole Blood DNA Methylation Signatures of Diet Are Associated With Cardiovascular Disease Risk Factors and All-Cause Mortality.

BACKGROUND: DNA methylation patterns associated with habitual diet have not been well studied. METHODS: Diet quality was characterized using a Mediterranean-style diet score and the Alternative Healthy Eating Index score. We conducted ethnicity-specific and trans-ethnic epigenome-wide association analyses for diet quality and leukocyte-derived DNA methylation at over 400 000 CpGs (cytosine-guanine dinucleotides) in 5 population-based cohorts including 6662 European ancestry, 2702 African ancestry, and 360 Hispanic ancestry participants. For diet-associated CpGs identified in epigenome-wide analyses, we conducted Mendelian randomization (MR) analysis to examine their relations to cardiovascular disease risk factors and examined their longitudinal associations with all-cause mortality. RESULTS: We identified 30 CpGs associated with either Mediterranean-style diet score or Alternative Healthy Eating Index, or both, in European ancestry participants. Among these CpGs, 12 CpGs were significantly associated with all-cause mortality (Bonferroni corrected P<1.6×10-3). Hypermethylation of cg18181703 (SOCS3) was associated with higher scores of both Mediterranean-style diet score and Alternative Healthy Eating Index and lower risk for all-cause mortality (P=5.7×10-15). Ten additional diet-associated CpGs were nominally associated with all-cause mortality (P<0.05). MR analysis revealed 8 putatively causal associations for 6 CpGs with 4 cardiovascular disease risk factors (body mass index, triglycerides, high-density lipoprotein cholesterol concentrations, and type 2 diabetes mellitus; Bonferroni corrected MR P<4.5×10-4). For example, hypermethylation of cg11250194 (FADS2) was associated with lower triglyceride concentrations (MR, P=1.5×10-14).and hypermethylation of cg02079413 (SNORA54; NAP1L4) was associated with body mass index (corrected MR, P=1×10-6). CONCLUSIONS: Habitual diet quality was associated with differential peripheral leukocyte DNA methylation levels of 30 CpGs, most of which were also associated with multiple health outcomes, in European ancestry individuals. These findings demonstrate that integrative genomic analysis of dietary information may reveal molecular targets for disease prevention and treatment.

Nanoparticles Targeting STATs in Cancer Therapy.

Over the past decades, an increase in the incidence rate of cancer has been witnessed. Although many efforts have been made to manage and treat this life threatening condition, it is still one of the leading causes of death worldwide. Therefore, scientists have attempted to target molecular signaling pathways involved in cancer initiation and metastasis. It has been shown that signal transducers and activator of transcription (STAT) contributes to the progression of cancer cells. This important signaling pathway is associated with a number of biological processes including cell cycle, differentiation, proliferation and apoptosis. It appears that dysregulation of the STAT signaling pathway promotes the migration, viability and malignancy of various tumor cells. Hence, there have been many attempts to target the STAT signaling pathway. However, it seems that currently applied therapeutics may not be able to effectively modulate the STAT signaling pathway and suffer from a variety of drawbacks such as low bioavailability and lack of specific tumor targeting. In the present review, we demonstrate how nanocarriers can be successfully applied for encapsulation of STAT modulators in cancer therapy.

An Orally Administrated Hyaluronan Functionalized Polymeric Hybrid Nanoparticle System for Colon-Specific Drug Delivery.

There is a pressing clinical need for advanced colon-specific local drug delivery systems that can provide major advantages in treating diseases associated with the colon, such as inflammatory bowel disease (IBD) and colon cancer. A precise colon targeted drug delivery platform is expected to reduce drug side effects and increase the therapeutic response at the intended disease site locally. In this study, we report the fabrication of hyaluronan (HA) functionalized polymeric hybrid nanoparticulate system (Cur-HA NPs) by using curcumin as a model fluorescent drug. The Cur-HA NPs were about 200-300 nm in size, -51.3 mV overall surface charge after HA functionalization, with 56.0% drug released after 72 h in simulated gastrointestinal fluids. The Cur-HA NPs did not exhibit any cytotoxicity by AlamarBlue, PicoGreen and Live/Dead assays. Following the Cur-HA NPs use on HT-29 monolayer cell cultures demonstrating, the efficacy of HA functionalization increases cellular interaction, uptake when compared to uncoated nanoparticulate system. These findings indicate that HA functionalized nano-hybrid particles are effective in delivering drugs orally to the lower gastrointestinal tract (GIT) in order to treat local colonic diseases.

Authoring a periodic adverse drug experience report here's what you need to know!

Aggregate reporting involves preparation and submission of safety reports for a given medicinal product to worldwide regulatory agencies and constitutes an essential part of safety monitoring of a medicinal product. There are specific aggregate safety reports required for a molecule in development called development safety update reports while Periodic Adverse Drug Experience Reports (PADERs) and Periodic Safety Update Reports/Periodic Benefit-risk Evaluation Reports (PBRERs) are submitted for products with marketing authorization. Based on the periodic analysis of worldwide safety reports, product label is updated to optimize safe use of a medicinal product. PADERs are aggregate safety reports to be submitted to the Food and Drug Administration (FDA) for products approved for marketing in the United States (US). PADER submission starts once marketing authorization approval is received for a medicinal product by the sponsor. Quarterly and annual PADERs should be submitted within 30 and 60 days of data lock point, respectively. PADERs mainly involve presentation of case reports with serious unlisted events (15-day alert reports) in the form of narratives or in a tabular format. The present article focuses on the background, scope, structure of a PADER, and its submission timelines; lists differences between PADER and PBRER; and describes the knowledge, skills, and attitudes required for a PADER writer.

Enhancement of the gut barrier integrity by a microbial metabolite through the Nrf2 pathway.

The importance of gut microbiota in human health and pathophysiology is undisputable. Despite the abundance of metagenomics data, the functional dynamics of gut microbiota in human health and disease remain elusive. Urolithin A (UroA), a major microbial metabolite derived from polyphenolics of berries and pomegranate fruits displays anti-inflammatory, anti-oxidative, and anti-ageing activities. Here, we show that UroA and its potent synthetic analogue (UAS03) significantly enhance gut barrier function and inhibit unwarranted inflammation. We demonstrate that UroA and UAS03 exert their barrier functions through activation of aryl hydrocarbon receptor (AhR)- nuclear factor erythroid 2-related factor 2 (Nrf2)-dependent pathways to upregulate epithelial tight junction proteins. Importantly, treatment with these compounds attenuated colitis in pre-clinical models by remedying barrier dysfunction in addition to anti-inflammatory activities. Cumulatively, the results highlight how microbial metabolites provide two-pronged beneficial activities at gut epithelium by enhancing barrier functions and reducing inflammation to protect from colonic diseases.

Bioresponsive drug delivery systems in intestinal inflammation: State-of-the-art and future perspectives.

Oral colon-specific delivery systems emerged as the main therapeutic cargos by making a significant impact in the field of modern medicine for local drug delivery in intestinal inflammation. The site-specific delivery of therapeutics (aminosalicylates, glucocorticoids, biologics) to the ulcerative mucus tissue can provide prominent advantages in mucosal healing (MH). Attaining gut mucosal healing and anti-fibrosis are main treatment outcomes in inflammatory bowel disease (IBD). The pharmaceutical strategies that are commonly used to achieve a colon-specific drug delivery system include time, pH-dependent polymer coating, prodrug, colonic microbiota-activated delivery systems and a combination of these approaches. Amongst the different approaches reported, the use of biodegradable polysaccharide coated systems holds great promise in delivering drugs to the ulcerative regions. The present review focuses on major physiological gastro-intestinal tract challenges involved in altering the pharmacokinetics of delivery systems, pathophysiology of MH and fibrosis, reported drug-polysaccharide cargos and focusing on conventional to advanced disease responsive delivery strategies, highlighting their limitations and future perspectives in intestinal inflammation therapy.

A theranostic nanocomposite system based on iron oxide-drug nanocages for targeted magnetic field responsive chemotherapy.

In this work, a theranostic nanocage system was developed for the targeted delivery of the anti-cancer agents camptothecin (CPT) and luotonin A (LuA). The core of the nanocage system (Fe3O4@OA-AD-SP NCs) was formed by biogenically synthesized Fe3O4 nanoparticles (NPs) decorated with a model anti-cancer drug (AD) and biosurfactant saponin (SP). The Fe3O4@OA-AD-SP NCs showed a high lipophilic AD loading efficiency (>80%) and a controlled pH-responsive drug release in stimulated cancerous cells in pH 6.4 media buffer. In addition, Fe3O4@OA-AD-SP NCs exhibited better serum protein binding efficacy at physiological pH values (7.4), furthering the important role of SP surface decoration. Particularly, these NCs showed better chemotherapeutic efficacy when examined in MCF-7 and HeLa cancer cell lines with a specific targeting capacity. Therefore, this study provides a new nano platform based on magnetic targeting and pH responsive lipophilic anticancer drug delivery to the cancer site.