Safe Nanoparticles: Are We There Yet? Najahi-Missaoui, Wided; Arnold, Robert D; Cummings, Brian S
International journal of molecular sciences,
12/2020, Letnik:
22, Številka:
1
Journal Article
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The field of nanotechnology has grown over the last two decades and made the transition from the benchtop to applied technologies. Nanoscale-sized particles, or nanoparticles, have emerged as ...promising tools with broad applications in drug delivery, diagnostics, cosmetics and several other biological and non-biological areas. These advances lead to questions about nanoparticle safety. Despite considerable efforts to understand the toxicity and safety of these nanoparticles, many of these questions are not yet fully answered. Nevertheless, these efforts have identified several approaches to minimize and prevent nanoparticle toxicity to promote safer nanotechnology. This review summarizes our current knowledge on nanoparticles, their toxic effects, their interactions with mammalian cells and finally current approaches to minimizing their toxicity.
The field of nanotechnology has grown exponentially during the last few decades, due in part to the use of nanoparticles in many manufacturing processes, as well as their potential as clinical agents ...for treatment of diseases and for drug delivery. This has created several new avenues by which humans can be exposed to nanoparticles. Unfortunately, investigations assessing the toxicological impacts of nanoparticles (i.e. nanotoxicity), as well as their possible risks to human health and the environment, have not kept pace with the rapid rise in their use. This has created a gap-in-knowledge and a substantial need for more research. Studies are needed to help complete our understanding of the mechanisms of toxicity of nanoparticles, as well as the mechanisms mediating their distribution and accumulation in cells and tissues and their elimination from the body. This review summarizes our knowledge on nanoparticles, including their various applications, routes of exposure, their potential toxicity and risks to human health.
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► Entrap drugs in pectin hydrogel matrix by ionotropic interaction between commercial and charge modified pectin and divalent calcium. ► In vitro drug release studied under simulated ...gastric and intestinal fluids. ► The most entrapment efficiency and the least drug release rate were observed with charged modified pectin beads. ► Modified pectin beads showed more dense surface morphology than commercial pectin beads.
The physical and chemical properties of commercial low methoxyl citrus pectins, CP 28 and CP 55, and a pectinmethylesterase (PME) charge modified citrus pectin (MP 38) were compared, and the differences in ability to encapsulate indomethacin in hydrogel beads was determined at 0.5 or 1.0% (w/v) indomethacin ratio, and 100, 200 or 300mM CaCl2 solution. In order to investigate the drug release characteristics, indomethacin loaded dried hydrogel beads were immersed in simulated gastric fluids (pH 1.2) for 2h, followed by immersing in simulated intestinal fluids (pH 7.4) for 3h. Pectin type was highly significant (p<0.0001) for encapsulation efficiency and in vitro release assay. Encapsulation efficiency was also highly affected (p<0.0001) by indomethacin ratio and CaCl2 concentration. The accumulative release rate of indomethacin from pectin hydrogel bead was less than 15% in simulated gastro-intestinal fluids. MP 38 beads showed significantly higher entrapment efficiency and lower release rate than beads formed from CP 28 or CP 55. MP 38 hydrogel formulated with 300mM CaCl2 and 0.5% indomethacin ratio showed the highest entrapment efficiency. These studies suggest that charge modification of pectin improves encapsulation efficiency of drugs for colon targeted drug delivery system through oral administration.
Phospholipase A2 (PLA2) cleave phospholipids preferentially at the sn-2 position, liberating free fatty acids and lysophospholipids. They are classified into six main groups based on size, location, ...function, substrate specificity and calcium requirement. These classes include secretory PLA2 (sPLA2), cytosolic (cPLA2), Ca2+-independent (iPLA2), platelet activating factor acetylhydrolases (PAF-AH), lysosomal PLA2 (LyPLA2) and adipose specific PLA2 (AdPLA2). It is hypothesized that PLA2 can serve as pharmacological targets for the therapeutic treatment of several diseases, including cardiovascular diseases, atherosclerosis, immune disorders and cancer. Special emphasis has been placed on inhibitors of sPLA2 isoforms as pharmacological moieties, mostly due to the fact that these enzymes are activated during inflammatory events and because their expression is increased in several diseases. This review focuses on understanding how sPLA2 isoform expression is altered during disease progression and the possible therapeutic interventions to specifically target sPLA2 isoforms, including new approaches using nano-particulate-based strategies.
Maximum tolerable dosing (MTD) of chemotherapeutics has long been the gold standard for aggressive malignancies. Recently, alternative dosing strategies have gained traction for their improved ...toxicity profiles and unique mechanisms of action, such as inhibition of angiogenesis and stimulation of immunity. In this article, we investigated whether extended exposure (EE) topotecan could improve long-term drug sensitivity by preventing drug resistance. To achieve significantly longer exposure times, we used a spheroidal model system of castration-resistant prostate cancer. We also used state-of-the-art transcriptomic analysis to further elucidate any underlying phenotypic changes that occurred in the malignant population following each treatment. We determined that EE topotecan had a much higher barrier to resistance relative to MTD topotecan and was able to maintain consistent efficacy throughout the study period (EE IC50 of 54.4 nM (Week 6) vs. MTD IC50 of 2200 nM (Week 6) vs. 83.8 nM IC50 for control (Week 6) vs. 37.8 nM IC50 for control (Week 0)). As a possible explanation for these results, we determined that MTD topotecan stimulated epithelial-mesenchymal transition (EMT), upregulated efflux pumps, and produced altered topoisomerases relative to EE topotecan. Overall, EE topotecan resulted in a more sustained treatment response and maintained a less aggressive malignant phenotype relative to MTD topotecan.
Objective: To determine long-term effects on substance use and substance use disorder (SUD), up to 8 years after childhood enrollment, of the randomly assigned 14-month treatments in the multisite ...Multimodal Treatment Study of Children with Attention-Deficit/Hyperactivity Disorder (MTA; n = 436); to test whether medication at follow-up, cumulative psychostimulant treatment over time, or both relate to substance use/SUD; and to compare substance use/SUD in the ADHD sample to the non-ADHD childhood classmate comparison group (n = 261). Method: Mixed-effects regression models with planned contrasts were used for all tests except the important cumulative stimulant treatment question, for which propensity score matching analysis was used. Results: The originally randomized treatment groups did not differ significantly on substance use/SUD by the 8-year follow-up or earlier (mean age = 17 years). Neither medication at follow-up (mostly stimulants) nor cumulative stimulant treatment was associated with adolescent substance use/SUD. Substance use at all time points, including use of two or more substances and SUD, were each greater in the ADHD than in the non-ADHD samples, regardless of sex. Conclusions: Medication for ADHD did not protect from, or contribute to, visible risk of substance use or SUD by adolescence, whether analyzed as randomized treatment assignment in childhood, as medication at follow-up, or as cumulative stimulant treatment over an 8-year follow-up from childhood. These results suggest the need to identify alternative or adjunctive adolescent-focused approaches to substance abuse prevention and treatment for boys and girls with ADHD, especially given their increased risk for use and abuse of multiple substances that is not improved with stimulant medication. Clinical trial registration information--Multimodal Treatment Study of Children With Attention Deficit and Hyperactivity Disorder (MTA); http://clinical trials.gov/; NCT00000388. (Contains 2 figures and 1 table.)
Assessment of anti-cancer drug efficacy in in vitro three-dimensional (3D) bioengineered cancer models provides important contextual and relevant information towards pre-clinical translation of ...potential drug candidates. However, currently established models fail to sufficiently recapitulate complex tumor heterogeneity. Here we present a chip-based tumor-mimetic platform incorporating a 3D in vitro breast cancer model with a tumor-mimetic microvascular network, replicating the pathophysiological architecture of native vascularized breast tumors. The microfluidic platform facilitated formation of mature, lumenized and flow-aligned endothelium under physiological flow recapitulating both high and low perfused tumor regions. Metastatic and non-metastatic breast cancer cells were maintained in long-term 3D co-culture with stromal fibroblasts in a poly(ethylene glycol)-fibrinogen hydrogel matrix within adjoining tissue chambers. The interstitial space between the chambers and endothelium contained pores to mimic the "leaky" vasculature found in vivo and facilitate cancer cell-endothelial cell communication. Microvascular pattern-dependent flow variations induced concentration gradients within the 3D tumor mass, leading to morphological tumor heterogeneity. Anti-cancer drugs displayed cell type- and flow pattern-dependent effects on cancer cell viability, viable tumor area and associated endothelial cytotoxicity. Overall, the developed microfluidic tumor-mimetic platform facilitates investigation of cancer-stromal-endothelial interactions and highlights the role of a fluidic, tumor-mimetic vascular network on anti-cancer drug delivery and efficacy for improved translation towards pre-clinical studies.
In this study, magnetic iron oxide nanoparticle induced hyperthermia is applied for treatment of head and neck cancer using a mouse xenograft model of human head and neck cancer (Tu212 cell line). A ...hyperthermia system for heating iron oxide nanoparticles was developed by using alternating magnetic fields. Both theoretical simulation and experimental studies were performed to verify the thermotherapy effect. Experimental results showed that the temperature of the tumor center has dramatically elevated from around the room temperature to about 40(o)C within the first 5-10 minutes. Pathological studies demonstrate epithelial tumor cell destruction associated with the hyperthermia treatment.
Metastasis accounts for the vast majority of breast cancer-related fatalities. Although the contribution of genetic and epigenetic modifications to breast cancer progression has been widely ...acknowledged, emerging evidence underscores the pivotal role of physical stimuli in driving breast cancer metastasis. In this review, we summarize the changes in the mechanics of the breast cancer microenvironment and describe the various forces that impact migrating and circulating tumor cells throughout the metastatic process. We also discuss the mechanosensing and mechanotransducing molecules responsible for promoting the malignant phenotype in breast cancer cells. Gaining a comprehensive understanding of the mechanobiology of breast cancer carries substantial potential to propel progress in prognosis, diagnosis, and patient treatment.
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