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Nature Reviews. Cancer Aug 2023Due to the fact that mRNA technology allows the production of diverse vaccines and treatments in a shorter time frame and with reduced expense compared to conventional... (Review)
Review
Due to the fact that mRNA technology allows the production of diverse vaccines and treatments in a shorter time frame and with reduced expense compared to conventional approaches, there has been a surge in the use of mRNA-based therapeutics in recent years. With the aim of encoding tumour antigens for cancer vaccines, cytokines for immunotherapy, tumour suppressors to inhibit tumour development, chimeric antigen receptors for engineered T cell therapy or genome-editing proteins for gene therapy, many of these therapeutics have shown promising efficacy in preclinical studies, and some have even entered clinical trials. Given the evidence supporting the effectiveness and safety of clinically approved mRNA vaccines, coupled with growing interest in mRNA-based therapeutics, mRNA technology is poised to become one of the major pillars in cancer drug development. In this Review, we present in vitro transcribed mRNA-based therapeutics for cancer treatment, including the characteristics of the various types of synthetic mRNA, the packaging systems for efficient mRNA delivery, preclinical and clinical studies, current challenges and future prospects in the field. We anticipate the translation of promising mRNA-based treatments into clinical applications, to ultimately benefit patients.
Topics: Humans; RNA, Messenger; Immunotherapy; Neoplasms; Receptors, Chimeric Antigen; Cytokines
PubMed: 37311817
DOI: 10.1038/s41568-023-00586-2 -
Nature Nov 2023Monoamine neurotransmitters such as dopamine and serotonin control important brain pathways, including movement, sleep, reward and mood. Dysfunction of monoaminergic...
Monoamine neurotransmitters such as dopamine and serotonin control important brain pathways, including movement, sleep, reward and mood. Dysfunction of monoaminergic circuits has been implicated in various neurodegenerative and neuropsychiatric disorders. Vesicular monoamine transporters (VMATs) pack monoamines into vesicles for synaptic release and are essential to neurotransmission. VMATs are also therapeutic drug targets for a number of different conditions. Despite the importance of these transporters, the mechanisms of substrate transport and drug inhibition of VMATs have remained elusive. Here we report cryo-electron microscopy structures of the human vesicular monoamine transporter VMAT2 in complex with the antichorea drug tetrabenazine, the antihypertensive drug reserpine or the substrate serotonin. Remarkably, the two drugs use completely distinct inhibition mechanisms. Tetrabenazine binds VMAT2 in a lumen-facing conformation, locking the luminal gating lid in an occluded state to arrest the transport cycle. By contrast, reserpine binds in a cytoplasm-facing conformation, expanding the vestibule and blocking substrate access. Structural analyses of VMAT2 also reveal the conformational changes following transporter isomerization that drive substrate transport into the vesicle. These findings provide a structural framework for understanding the physiology and pharmacology of neurotransmitter packaging by synaptic vesicular transporters.
Topics: Humans; Adrenergic Uptake Inhibitors; Biological Transport; Cryoelectron Microscopy; Neurotransmitter Agents; Reserpine; Serotonin; Synaptic Transmission; Tetrabenazine; Vesicular Monoamine Transport Proteins; Substrate Specificity
PubMed: 37914936
DOI: 10.1038/s41586-023-06727-9 -
European Journal of Pharmaceutics and... Sep 2023Gene therapies offer promising therapeutic alternatives for many disorders that currently lack efficient treatment options. Due to their chemical nature and... (Review)
Review
Gene therapies offer promising therapeutic alternatives for many disorders that currently lack efficient treatment options. Due to their chemical nature and physico-chemical properties, delivery of polynucleic acids into target cells and subcellular compartments remains a significant challenge. Adeno-associated viruses (AAV) have gained a lot of interest for the efficient delivery of therapeutic single-stranded DNA (ssDNA) genomes over the past decades. More than a hundred products have been tested in clinical settings and three products have received market authorization by the US FDA in recent years. A lot of effort is being made to generate potent recombinant AAV (rAAV) vectors that show favorable safety and immunogenicity profiles for either local or systemic administration. Manufacturing processes are gradually being optimized to deliver a consistently high product quality and to serve potential market needs beyond rare indications. In contrast to protein therapeutics, most rAAV products are still supplied as frozen liquids within rather simple formulation buffers to enable sufficient product shelf life, significantly hampering global distribution and access. In this review, we aim to outline the hurdles of rAAV drug product development and discuss critical formulation and composition aspects of rAAV products under clinical evaluation. Further, we highlight recent development efforts in order to achieve stable liquid or lyophilized products. This review therefore provides a comprehensive overview on current state-of-the-art rAAV formulations and can further serve as a map for rational formulation development activities in the future.
Topics: Dependovirus; Genetic Vectors; Genetic Therapy
PubMed: 37423416
DOI: 10.1016/j.ejpb.2023.07.002 -
Nanoscale Oct 2023Although electrospinning (e-spinning) has witnessed rapid development in recent years, it has also been criticized by environmentalists due to the use of organic... (Review)
Review
Although electrospinning (e-spinning) has witnessed rapid development in recent years, it has also been criticized by environmentalists due to the use of organic solvents. Therefore, aqueous e-spinning (green e-spinning) is considered a more attractive technique. However, considering the poor water resistance and mechanical properties of electrospun (e-spun) nanofibers, cross-linking is a perfect solution. In this review, we systematically discuss the cross-linking e-spinning system for the first time, including cross-linking strategies (, liquid immersion, vapor, and spray cross-linking), cross-linking mechanism (physical and chemical cross-linking) of e-spun nanofibers, and the various applications (, tissue engineering, drug delivery, water treatment, food packaging, and sensors) of cross-linked e-spun nanofibers. Among them, we highlight several cross-linking methods, including UV light cross-linking, electron beam cross-linking, glutaraldehyde (and other commonly used cross-linking agents) chemical cross-linking, thermal cross-linking, and enzymatic cross-linking. Finally, we confirm the significance of cross-linking e-spinning and reveal the problems in the construction of this system.
PubMed: 37740390
DOI: 10.1039/d3nr03956k -
International Dental Journal Nov 2023This narrative review summarises "alternative" or "natural" over-the-counter (OTC) mouthwashes not covered elsewhere in this supplement and newly emerging products, as... (Review)
Review
This narrative review summarises "alternative" or "natural" over-the-counter (OTC) mouthwashes not covered elsewhere in this supplement and newly emerging products, as potential mouthwashes of the future. The "natural" mouthwashes reviewed include saltwater, baking soda, coconut oil, charcoal, propolis, seaweeds, and probiotics. Other than essential oils, it is apparent that their clinical effectiveness is still under debate, but there is some evidence to suggest that propolis reduces plaque and gingivitis. This review also covers the host immune response, via novel anti-inmmunomodulant mouthwashes, such as erythropoietin to reduce inflammation with oral mucositis (OM) after radiotherapy. The emerging concept of nanoparticle-containing mouthwashes, such as iron oxide, is further discussed for OM, this agent having the potential for more targeted delivery of chemical antimicrobials. Unfortunately, there are impacts on the environment of widening mouthwash use with more new products, including increased use of packaging, antimicrobial resistance, and possible detrimental effects on marine life. Further, there are roadblocks, relating to regularly approvals and side effects, that still need to be overcome for any OTC deivered immunomodulant or nanoformulation mouthwashes. Despite these caveats, there are many new mouthwashes under development, which could help manage major oral diseases such as caries, gingivitis, and periodontal disease.
Topics: Humans; Mouthwashes; Propolis; Dental Plaque; Oils, Volatile; Gingivitis
PubMed: 37867066
DOI: 10.1016/j.identj.2023.08.011 -
Advanced Science (Weinheim,... Aug 2023Pancreatic ductal adenocarcinoma (PDA) is a clinically challenging disease with limited treatment options. Despite a small percentage of cases with defective mismatch...
Pancreatic ductal adenocarcinoma (PDA) is a clinically challenging disease with limited treatment options. Despite a small percentage of cases with defective mismatch DNA repair (dMMR), PDA is included in the most immune-resistant cancer types that are poorly responsive to immune checkpoint blockade (ICB) therapy. To facilitate drug discovery combating this immunosuppressive tumor type, a high-throughput drug screen platform is established with the newly developed T cell-incorporated pancreatic tumor organoid model. Tumor-specific T cells are included in the pancreatic tumor organoids by two-step cell packaging, fully recapitulating immune infiltration in the immunosuppressive tumor microenvironment (TME). The organoids are generated with key components in the original tumor, including epithelial, vascular endothelial, fibroblast and macrophage cells, and then packaged with T cells into their outside layer mimicking a physical barrier and enabling T cell infiltration and cytotoxicity studies. In the PDA organoid-based screen, epigenetic inhibitors ITF2357 and I-BET151 are identified, which in combination with anti-PD-1 based therapy show considerably greater anti-tumor effect. The combinatorial treatment turns the TME from immunosuppressive to immunoactive, up-regulates the MHC-I antigen processing and presentation, and enhances the effector T cell activity. The standardized PDA organoid model has shown great promise to accelerate drug discovery for the immunosuppressive cancer.
Topics: Humans; T-Lymphocytes; Pancreatic Neoplasms; Carcinoma, Pancreatic Ductal; Immunotherapy; Organoids; Tumor Microenvironment
PubMed: 37271874
DOI: 10.1002/advs.202300548 -
International Journal of Biological... Aug 2023A million tonnes of plastic produced each year are disposed of after single use. Biodegradable polymers have become a promising material as an alternative to... (Review)
Review
A million tonnes of plastic produced each year are disposed of after single use. Biodegradable polymers have become a promising material as an alternative to petroleum-based polymers. Utilising biodegradable polymers will promote environmental sustainability which has emerged with potential features and performances for various applications in different sectors. Seaweed-derived polysaccharides-based composites have been the focus of numerous studies due to the composites' renewability and sustainability for industries (food packaging and medical fields like tissue engineering and drug delivery). Due to their biocompatibility, abundance, and gelling ability, seaweed derivatives such as alginate, carrageenan, and agar are commonly used for this purpose. Seaweed has distinct film-forming characteristics, but its mechanical and water vapour barrier qualities are weak. Thus, modifications are necessary to enhance the seaweed properties. This review article summarises and discusses the effect of incorporating seaweed films with different types of nanoparticles on their mechanical, thermal, and water barrier properties.
Topics: Seaweed; Polysaccharides; Carrageenan; Polymers; Nanocomposites; Vegetables
PubMed: 37355060
DOI: 10.1016/j.ijbiomac.2023.125486 -
Biotechnology Advances 2024Polyhydroxyalkanoates (PHA) have evolved into versatile biopolymers, transcending their origins as mere bioplastics. This extensive review delves into the multifaceted... (Review)
Review
Polyhydroxyalkanoates (PHA) have evolved into versatile biopolymers, transcending their origins as mere bioplastics. This extensive review delves into the multifaceted landscape of PHA applications, shedding light on the diverse industries that have harnessed their potential. PHA has proven to be an invaluable eco-conscious option for packaging materials, finding use in films foams, paper coatings and even straws. In the textile industry, PHA offers a sustainable alternative, while its application as a carbon source for denitrification in wastewater treatment showcases its versatility in environmental remediation. In addition, PHA has made notable contributions to the medical and consumer sectors, with various roles ranging from 3D printing, tissue engineering implants, and cell growth matrices to drug delivery carriers, and cosmetic products. Through metabolic engineering efforts, PHA can be fine-tuned to align with the specific requirements of each industry, enabling the customization of material properties such as ductility, elasticity, thermal conductivity, and transparency. To unleash PHA's full potential, bridging the gap between research and commercial viability is paramount. Successful PHA production scale-up hinges on establishing direct supply chains to specific application domains, including packaging, food and beverage materials, medical devices, and agriculture. This review underscores that PHA's future rests on ongoing exploration across these industries and more, paving the way for PHA to supplant conventional plastics and foster a circular economy.
Topics: Polyhydroxyalkanoates; Biopolymers; Food
PubMed: 38272380
DOI: 10.1016/j.biotechadv.2024.108320 -
Journal of Clinical Pharmacology Nov 2023Pediatric obesity is a global public health concern. Obesity-related physiological changes may affect the pharmacokinetics of drugs and lead to therapeutic failure or... (Review)
Review
Pediatric obesity is a global public health concern. Obesity-related physiological changes may affect the pharmacokinetics of drugs and lead to therapeutic failure or toxicities. An earlier review of pediatric drug development programs from 2007 to 2016 found that, of 89 programs listing obesity-related terms, only 4 (4%) products described pharmacokinetic changes associated with obesity. This review examined obesity considerations for 185 drug products for which pediatric drug development programs were submitted to the US Food and Drug Administration (FDA) between 2016 and 2021. The FDA-authored review documents and drug product labeling were queried for obesity-related terms and the review found 97/185 (52%) drug products had obesity-related terms in these sources. Of the 97 drug products, 55/97 (57%) had obesity-related terms in the FDA-authored reviews only, 13/97 (13%) had obesity-related terms in the drug product labeling only, and 29/97 (30%) had obesity-related terms in both FDA-authored reviews and drug product labeling. Most of the obesity-related information in the drug product labeling originated from data collected from adults. Only 13/185 (7%) drug product labeling contained obesity-related terms in reference to drug pharmacokinetics. Specific dosage recommendations for the use of the drug products in pediatric patients who are obese remain lacking. The dearth of available information to guide drug dosages in the obese pediatric population suggests that further research, innovative approaches, and evidence-based guidelines are needed to inform the optimal therapeutic use of drugs in this population.
Topics: Adult; United States; Child; Humans; Pharmaceutical Preparations; Drug Development; Pediatric Obesity; Drug Labeling; United States Food and Drug Administration
PubMed: 37942908
DOI: 10.1002/jcph.2305