Nitric Oxide Releasing Nanomaterials for Cardiovascular Applications.

A central paradigm of cardiovascular homeostasis is that impaired nitric oxide (NO) bioavailability results in a wide array of cardiovascular dysfunction including incompetent endothelium-dependent vasodilatation, thrombosis, vascular inflammation, and proliferation of the intima. Over the course of more than a century, NO donating formulations such as organic nitrates and nitrites have remained a cornerstone of treatment for patients with cardiovascular diseases. These donors primarily produce NO in the circulation and are not targeted to specific (sub)cellular sites of action. However, safe, and therapeutic levels of NO require delivery of the right amount to a precise location at the right time. To achieve these aims, several recent strategies aimed at therapeutically generating or releasing NO in living systems have shown that polymeric and inorganic (silica, gold) nanoparticles and nanoscale metal-organic frameworks could either generate NO endogenously by the catalytic decomposition of endogenous NO substrates or can store and release therapeutically relevant amounts of NO gas. NO-releasing nanomaterials have been developed for vascular implants (such as stents and grafts) to target atherosclerosis, hypertension, myocardial ischemia-reperfusion injury, and cardiac tissue engineering. In this review, we discuss the advances in design and development of novel NO-releasing nanomaterials for cardiovascular therapeutics and critically examine the therapeutic potential of these nanoplatforms to modulate cellular metabolism, to regulate vascular tone, inhibit platelet aggregation, and limit proliferation of vascular smooth muscle with minimal toxic effects.

Demographic changes in Australia's regulated health professions: 6-year trends.

Objective Studies of Australian health workforce demographics tend to be limited to single professions, a set geographic area, or based on incomplete data. This study aims to comprehensively describe changes to the demographic characteristics of Australia's regulated health professions over 6 years. Methods Data were sourced from the Australian Health Practitioner Regulation Agency (Ahpra) registration database, and a retrospective analysis of 15 of the 16 regulated health professions between 1 July 2015 and 30 June 2021 was conducted. Variables including profession, age, gender and state/territory locations for the practitioners' principal places of practice were analysed descriptively and via appropriate statistical tests. Results Changes in age, gender representation, and place of practice varied significantly and in different ways across the 15 professions. The total number of registered health practitioners increased by 141 161 (22%) from 2016 to 2021. The number of registered health practitioners per 100 000 population increased by 14% from 2016, with considerable variation across the professions. In 2021, women accounted for 76.3% of health practitioners across the 15 health professions, a significant increase of 0.5% points since 2016. Conclusions Changes to demographics, especially in ageing workforces and feminising professions, can have implications for workforce planning and sustainability. Future research could build on this demographic trend data by investigating causes or undertaking workforce supply or demand modelling.

Radio Wave-Activated Chemotherapy-A Novel Nanoparticle Thermoresponsive Copolymer Drug Delivery Platform.

Radio waves are highly penetrating, non-ionizing, and cause minimal damage to surrounding tissues. Radio wave control of drug release has been achieved using a novel thermoresponsive copolymer bound to a superparamagnetic iron oxide nanoparticle (SPION) core. A NIPAM-acrylamide-methacrolein copolymer underwent a coil-to-globular structure phase change upon reaching a critical temperature above the human body temperature but below hyperthermic temperatures. The copolymer was covalently bound to SPIONs which increase in temperature upon exposure to radio waves. This effect could be controlled by varying input energies and frequencies. For controlled drug release, proteins were bound via aldehyde groups on the copolymer and amine groups on the protein. The radio wave-induced heating of the complex thereby released the drug-bearing proteins. The fine-tuning of the radio wave exposure allowed multiple cycles of protein-drug release. The fluorescent tagging of the complex by FITC was also achieved in situ, allowing the tagging of the complex. The localization of the complex could also be achieved in vitro under a permanent magnetic field.

Novel epigenetic therapeutic strategies and targets in cancer.

The critical role of dysregulated epigenetic pathways in cancer genesis, development, and therapy has typically been established as a result of scientific and technical innovations in next generation sequencing. RNA interference, histone modification, DNA methylation and chromatin remodelling are epigenetic processes that control gene expression without causing mutations in the DNA. Although epigenetic abnormalities are thought to be a symptom of cell tumorigenesis and malignant events that impact tumor growth and drug resistance, physicians believe that related processes might be a key therapeutic target for cancer treatment and prevention due to the reversible nature of these processes. A plethora of novel strategies for addressing epigenetics in cancer therapy for immuno-oncological complications are currently available - ranging from basic treatment to epigenetic editing. - and they will be the subject of this comprehensive review. In this review, we cover most of the advancements made in the field of targeting epigenetics with special emphasis on microbiology, plasma science, biophysics, pharmacology, molecular biology, phytochemistry, and nanoscience.

Exploitation of High Tumour GSH Levels for Targeted siRNA Delivery in Rhabdomyosarcoma Cells.

Metastatic alveolar rhabdomyosarcoma (aRMS) is an aggressive paediatric cancer with a poor prognosis. Downregulation of critical tumour genes using targeted siRNA remains an obstacle, but association with nanoparticles could help to deliver, protect, target, and enhance penetration. siRNA towards two genes was investigated: (i) Human αB-crystallin (CRYAB) and Heat Shock Protein Family B (Small) Member 2 (HSPB2), and (ii) Keratin 17 (KRT17). A mesoporous silica based nanosystem was linked to siRNA via disulfide bonds and loaded with IR820 dye. Transfection efficiency and signalling was evaluated, and the metabolic effects and cell proliferation were monitored in 2D culture and 3D spheroid models. The bound siRNA was protected from degradation with RNase I for at least 24 h. The delivered siRNA showed significant suppression of viability; 53.21 ± 23.40% for CRYAB and HSPB2 siRNA, and 88.06 ± 17.28% for KRT17 siRNA. After 72 h this increased to >50% cell apoptosis and necrosis. Intracellular total glutathione (GSH) levels were also compared with fibroblasts, and the RMS cell lines showed a several-fold increase. IR820 cellular uptake rate and penetration depth was significantly improved by nanoparticle delivery. Targetted siRNA delivery may pave the way for less invasive and more effective treatments of aRMS.

Histological Injury to Rat Brain, Liver, and Kidneys by Gold Nanoparticles is Dose-Dependent.

Gold nanoparticles (GNPs) possess various interesting plasmonic properties that can provide a variety of diagnostic and therapeutic functionalities for biomedical applications. Compared to other inorganic metal nanoparticles (NPs), GNPs are less toxic and more biocompatible. However, the in vivo toxicity of gold nanoparticles on humans can be significant due to the size effect. This work aims to study the effect of multiple doses of small-size (≈20 nm) GNPs on the vital organs of Wistar rats. The study includes the oxidative stress in vital organs (liver, brain, and kidney) caused by GNPs and histopathology analysis. The rats were given a single caudal injection of NPs dispersed in PBS at 25, 50, 100, and 250 mg/kg of body weight. After sacrifice, both plasma and organs were collected for the determination of oxidant/antioxidant markers and histological studies. Our data show the high sensitivity of oxidative stress parameters to the GNPs in the brain, liver, and kidneys. However, the response to this stress is different between the organs and depends upon the antioxidant defense, where GSH levels control the MDA and PCO levels. Histological alterations are mild at 25, 50, and 100 mg/kg but significant at higher concentrations of 250 mg/kg. Therefore, histological impairments are shown to be dependent on the dose of GNPs. The results contribute to the understanding of oxidative stress and cellular interaction induced by nanoparticles.

Isolation of NELL 1 Aptamers for Rhabdomyosarcoma Targeting.

NELL1 (Neural epidermal growth factor-like (EGFL)-like protein) is an important biomarker associated with tissue and bone development and regeneration. NELL1 upregulation has been linked with metastasis and negative prognosis in rhabdomyosarcoma (RMS). Furthermore, multiple recent studies have also shown the importance of NELL1 in inflammatory bowel disease and membranous nephropathy, amongst other diseases. In this study, several anti-NELL1 DNA aptamers were selected from a randomized ssDNA pool using a fluorescence-guided method and evaluated for their binding affinity and selectivity. Several other methods such as a metabolic assay and confocal microscopy were also applied for the evaluation of the selected aptamers. The top three candidates were evaluated further, and AptNCan3 was shown to have a binding affinity up to 959.2 nM. Selectivity was examined in the RH30 RMS cells that overexpressed NELL1. Both AptNCan2 and AptNCan3 could significantly suppress metabolic activity in RMS cells. AptNCan3 was found to locate on the cell membrane and also on intracellular vesicles, which matched the location of NELL1 shown by antibodies in previous research. These results indicate that the selected anti-NELL1 aptamer showed strong and highly specific binding to NELL1 and therefore has potential to be used for in vitro or in vivo studies and treatments.

Augmented phytotoxic effect of nanoencapsulated ophiobolin A.

Ophiobolin A is a secondary phytotoxic metabolite produced by some pathogenic fungal species responsible for severe plant diseases, considered to play a role in disease development and symptom appearance. Herein we investigated whether the phytotoxic activities of ophiobolin A against weed species could be improved by nanoencapsulation. Given the rapid natural degradation of the compound, it was hoped that nanoencapsulation would prolong the phytotoxic effects or enhance the bioactivity, thus leading to improved weed control capabilities. This article presents an assessment of the effectiveness of encapsulated ophiobolin A on 11 commonly found weed species, compared to the pure ophiobolin, to the particle alone, and a combination of mixed particles and ophiobolin A, by applying the solution droplets to both intact or injured leaf surface, on the adaxial or abaxial side. The bioassays showed the improved efficacy of the encapsulated ophiobolin, and the need for leaf lesions to diffuse the particles into the tissues.[Formula: see text].

Mechanism of Action of the Sesquiterpene Compound Helenalin in Rhabdomyosarcoma Cells.

Rhabdomyosarcoma (RMS) is the most frequent soft tissue sarcoma in paediatric patients. Relapsed or refractory RMS shows very low 5-year survival rates, which urgently necessitates new chemotherapy agents. Herein, the sesquiterpene lactone, helenalin, was investigated as a new potential therapeutic agent against the embryonal RMS (eRMS) and alveolar RMS (aRMS) cells. We have evaluated in vitro antiproliferative efficacy of helenalin on RMS cells by the MTT and wound healing assay, and estimated several cell death pathways by flow cytometry, confocal microscopy and immunoblotting. It was shown that helenalin was able to increase reactive oxygen species levels, decrease mitochondrial membrane potential, trigger endoplasmic reticulum stress and deactivate the NF-κB pathway. Confirmation was obtained through the use of antagonistic compounds which alleviated the effects of helenalin in the corresponding pathways. Our findings demonstrate that oxidative stress is the pivotal mechanism of action of helenalin in promoting RMS cell death in vitro.

Nanoparticles as Vectors to Tackle Cancer.

The aim of this Special Issue, "Nanoparticles for cancer therapy", was to offer readers a comprehensive and up-to-date insight into the various applications of nanoparticles in cancer treatments [...].

Bioink: a 3D-bioprinting tool for anticancer drug discovery and cancer management.

'Bioinks' are important tools for the fabrication of artificial living-tissue constructs that are able to mimic all properties of native tissues via 3D bioprinting technologies. Bioinks are most commonly made by incorporating live cells of interest within a natural or synthetic biocompatible polymeric matrix. In oncology research, the ability to recreate a tumor microenvironment (TME) using by 3D bioprinting constitutes a promising approach for drug development, screening, and in vitro cancer modeling. Here, we review the different types of bioink used for 3D bioprinting, with a focus on its application in cancer management. In addition, we consider the fabrication of bioink using customized materials/cells and their properties in the field of cancer drug discovery.

Nanomedicine-driven molecular targeting, drug delivery, and therapeutic approaches to cancer chemoresistance.

Cancer cell resistance to chemotherapeutics (chemoresistance) poses a significant clinical challenge that oncology research seeks to understand and overcome. Multiple anticancer drugs and targeting agents can be incorporated in nanomedicines, in addition to different treatment modalities, forming a single nanoplatform that can be used to address tumor chemoresistance. Nanomedicine-driven molecular assemblies using nucleic acids, small interfering (si)RNAs, miRNAs, and aptamers in combination with stimuli-responsive therapy improve the pharmacokinetic (PK) profile of the drugs and enhance their accumulation in tumors and, thus, therapeutic outcomes. In this review, we highlight nanomedicine-driven molecular targeting and therapy combination used to improve the 3Rs (right place, right time, and right dose) for chemoresistant tumor therapies.

Safeguarding COVID-19 and cancer management: drug design and therapeutic approach.

Recent clinical cohort studies have highlighted that there is a three-fold greater SARS-Cov-2 infection risk in cancer patients, and overall mortality in individuals with tumours is increased by 41% with respect to general COVID-19 patients. Thus, access to therapeutics and intensive care is compromised for people with both diseases (comorbidity) and there is risk of delayed access to diagnosis. This comorbidity has resulted in extensive burden on the treatment of patients and health care system across the globe; moreover, mortality of hospitalized patients with comorbidity is reported to be 30% higher than for individuals affected by either disease. In this data-driven review, we aim specifically to address drug discoveries and clinical data of cancer management during the COVID-19 pandemic. The review will extensively address the treatment of COVID-19/cancer comorbidity; treatment protocols and new drug discoveries, including the description of drugs currently available in clinical settings; demographic features; and COVID-19 outcomes in cancer patients worldwide.

The common diabetes drug metformin can diminish the action of citral against Rhabdomyosarcoma cells in vitro.

Rhabdomyosarcoma (RMS) is a rare type of soft tissue sarcoma most commonly found in pediatric patients. Despite progress, new and improved drug regimens are needed to increase survival rates. Citral, a natural product plant oil can induce cell death in cancer cells. Another compound, metformin, isolated originally from French lilac and used by diabetics, has been shown to reduce the incidence of cancer in these patients. Application of citral to RMS cells showed increase in cell death, and RD and RH30 cells showed half maximal inhibitory concentration (IC50 ) values as low as 36.28 µM and 62.37 µM, respectively. It was also shown that the citral initiated cell apoptosis through an increase in reactive oxygen species (ROS) and free calcium. In comparison, metformin only showed moderate cell death in RMS cell lines at a very high concentration (1,000 µM). Combinatorial experiments, however, indicated that citral and metformin worked antagonistically when used together. In particular, the ability of metformin to quench the ROS induced by citral could lead to the suppression of activity. These results clearly indicate that while clinical use of citral is a promising anti-tumor therapy, caution should be exercised in patients using metformin for diabetes.

Nanoencapsulation of Plant Volatile Organic Compounds to Improve Their Biological Activities.

Plant volatile organic compounds (volatiles) are secondary plant metabolites that play crucial roles in the reproduction, defence, and interactions with other vegetation. They have been shown to exhibit a broad range of biological properties and have been investigated for antimicrobial and anticancer activities. In addition, they are thought be more environmentally friendly than many other synthetic chemicals 1. Despite these facts, their applications in the medical, food, and agricultural fields are considerably restricted due to their volatilities, instabilities, and aqueous insolubilities. Nanoparticle encapsulation of plant volatile organic compounds is regarded as one of the best strategies that could lead to the enhancement of the bioavailability and biological activity of the volatile compounds by overcoming their physical limitations and promoting their controlled release and cellular absorption. In this review, we will discuss the biosynthesis and analysis of plant volatile organic compounds, their biological activities, and limitations. Furthermore, different types of nanoparticle platforms used to encapsulate the volatiles and the biological efficacies of nanoencapsulated volatile organic compounds will be covered.

An evaluation of the activity of biologically synthesized silver nanoparticles against bacteria, fungi and mammalian cell lines.

Biogenic silver nanoparticles are used for a number of applications due to their size, surface characteristics and strong antimicrobial properties. The present study aimed to investigate the synthesis of silver nanoparticles from the indigenous bacterial strain Bacillus sp. MB353 (PRJNA357966). Detailed characterization of silver nanoparticles was performed by UV-vis Spectrophotometer, FTIR, SEM and XRD. Biogenic silver nanoparticles were crystalline with average size 49-53 nm. These silver nanoparticles demonstrated good antibacterial activity against Gram-positive and Gram-negative bacteria (E. coli, Bacillus subtilis, Staphylococcus aureus, Klebsiella pneumoniae, Enterococcus faecium, Enterococcus faecalis and Streptomyces laurentii). The nanoparticles also showed excellent antifungal activity against Aspergillus niger, Aspergillus fumigatus, Fusarium soleni. The silver nanoparticles showed negligible antioxidant activity, but ROS generation pointed to a possible mode of antimicrobial activity. Incubation of silver nanoparticles with mammalian cell lines (Rhabdomyosarcomas and fibroblast) showed cell death and inhibition of proliferation. Cytotoxicity was most likely a result of ROS generation and changes in intracellular calcium levels. These findings suggested that biogenic silver nanoparticles could be used as alternative agents for biomedical purposes such as antibacterial and antifungal agents. However, given the effects on normal mammalian cells, it is probable that they could be used as anticancer agents if applied in targeted therapies.

Comprehensive approach of hybrid nanoplatforms in drug delivery and theranostics to combat cancer.

To date, various chemically synthesized and biosynthesized nanoparticles, or hybrid nanosystems and/or nanoplatforms, have been developed under the umbrella of nanomedicine. These can be introduced into the body orally, nasally, intratumorally or intravenously. Successfully translating hybrid nanoplatforms from preclinical proof-of-concept to therapeutic value in the clinic is challenging. Having made significant advances with drug delivery technologies, we must learn from other areas of oncology drug development, where patient stratification and target-driven design have improved patient outcomes. This review aims to identify gaps in our understanding of the current strengths of nanomedicine platforms in drug delivery and cancer theranostics. We report on the current approaches of nanomedicine at preclinical and clinical stages.

Macrophage-like THP-1 cells show effective uptake of silica nanoparticles carrying inactivated diphtheria toxoid for vaccination.

Nanoparticles may be used in vaccinology as an antigen delivery and/or an immunostimulant to enhance immunity. Porous silica has been identified as an effective adjuvant for more than a decade, and we have therefore investigated the take up rate by an immortalized macrophage-like cell line of a number of mesoporous silica nanoparticles (MSNPs) with differing diameter and pore size. The MSNPs were synthesized using a sol-gel reaction and post-synthesis removal of the template. The MSNPs showed a clear distribution in take up rate peaking at 217 nm, whereas a comparison with solid spherical nanoparticles showed a similar distribution peaking at 377 nm. The MSNPs were investigated before and after loading with antigen. Diphtheria toxoid was used as a proof-of-concept antigen and showed a peak macrophage internalization of 53.42% for loaded LP3 particles which had a diameter of 217.75 ± 5.44 nm and large 16.5 nm pores. Optimal MSNP sizes appeared to be in the 200-400 nm range, and larger pores showed better antigen loading. The mesoporous silica particles were shown to be generally biocompatible, and cell viability was not altered by the loading of particles with or without antigen. Graphical abstract.

Chromosome-free bacterial cells are safe and programmable platforms for synthetic biology.

A type of chromosome-free cell called SimCells (simple cells) has been generated from Escherichia coli, Pseudomonas putida, and Ralstonia eutropha. The removal of the native chromosomes of these bacteria was achieved by double-stranded breaks made by heterologous I-CeuI endonuclease and the degradation activity of endogenous nucleases. We have shown that the cellular machinery remained functional in these chromosome-free SimCells and was able to process various genetic circuits. This includes the glycolysis pathway (composed of 10 genes) and inducible genetic circuits. It was found that the glycolysis pathway significantly extended longevity of SimCells due to its ability to regenerate ATP and NADH/NADPH. The SimCells were able to continuously express synthetic genetic circuits for 10 d after chromosome removal. As a proof of principle, we demonstrated that SimCells can be used as a safe agent (as they cannot replicate) for bacterial therapy. SimCells were used to synthesize catechol (a potent anticancer drug) from salicylic acid to inhibit lung, brain, and soft-tissue cancer cells. SimCells represent a simplified synthetic biology chassis that can be programmed to manufacture and deliver products safely without interference from the host genome.

An Assessment of Mesoporous Silica Nanoparticle Architectures as Antigen Carriers.

Mesoporous silica nanoparticles (MSNPs) have the potential to be used as antigen carriers due to their high surface areas and highly ordered pore network. We investigated the adsorption and desorption of diphtheria toxoid as a proof-of-concept. Two series of nanoparticles were prepared-(i) small pores (SP) (<10 nm) and (ii) large pores (LP) (>10 nm). SBA-15 was included as a comparison since this is commercially available and has been used in a large number of studies. External diameters of the particles ranged from 138 to 1509 nm, surface area from 632 to 1110 m2/g and pore size from 2.59 to 16.48 nm. Antigen loading was assessed at a number of different ratios of silica-to-antigen and at 4 °C, 20 °C and 37 °C. Our data showed that protein adsorption by the SP series was in general consistently lower than that shown by the large pore series. Unloading was then examined at 4 °C, 20 °C and 37 °C and a pH 1.2, 4.5, 6.8 and 7.4. There was a trend amongst the LP particles towards the smallest pores showing the lowest release of antigen. The stability of the MSNP: antigen complex was tested at two different storage temperatures, and storage in solution or after lyophilization. After 6 months there was negligible release from any of the particles under any of the storage conditions. The particles were also shown not to cause hemolysis.