Realizing active targeting in cancer nanomedicine with ultrasmall nanoparticles.

Ultrasmall nanoparticles (usNPs) have emerged as promising theranostic tools in cancer nanomedicine. With sizes comparable to globular proteins, usNPs exhibit unique physicochemical properties and physiological behavior distinct from larger particles, including lack of protein corona formation, efficient renal clearance, and reduced recognition and sequestration by the reticuloendothelial system. In cancer treatment, usNPs demonstrate favorable tumor penetration and intratumoral diffusion. Active targeting strategies, incorporating ligands for specific tumor receptor binding, serve to further enhance usNP tumor selectivity and therapeutic performance. Numerous preclinical studies have already demonstrated the potential of actively targeted usNPs, revealing increased tumor accumulation and retention compared to non-targeted counterparts. In this review, we explore actively targeted inorganic usNPs, highlighting their biological properties and behavior, along with applications in both preclinical and clinical settings.

A new genus of Phlugidini (Insecta, Orthoptera, Tettigoniidae, Meconematinae) from the Atlantic Forest.

In the Neotropical Region, Phlugidini is the most diverse tribe of Meconematinae, with 62 valid species in 10 genera, six of them recorded from Brazil. Brachyphlugis gen. nov. is described herein based on two new species, Brachyphlugis longicercalis sp. nov. (type species) and Brachyphlugis curvata sp. nov., collected in Parque Nacional do Itatiaia and Reserva Biológica do Tinguá, both in the Atlantic Forest of Rio de Janeiro State. The new genus is most similar to Neophlugis, but it can be distinguished from the latter and other neotropical Phlugidini by the following combination of characteristics: (1) mandibles symmetrical; (2) tegmen extending beyond metanotum; (3) pronotal disk posterior margin convex; (4) tenth tergite strongly projected and downcurved; (5) male cercus pronounced with a larger base and acuminate apex; (6) paraproct modified with developed spine; (7) male subgenital plate with two distolateral projections connected to a pair of styles; and (8) female subgenital plate wider than long, posterior margin with two projections. An up-to-date key to neotropical Phlugidini genera is also provided.

Unraveling the forage productivity puzzle: Comparing fast and slow-growing grasses.

Functional traits are powerful tools for distinguishing between plants with different resource acquisition strategies. Fast-growing plants normally dominate resource-rich habitats and present trait values associated with high productivity, such as high specific leaf area (SLA), short leaf lifespan, and rapid leaf elongation rate (LER). In contrast, slow-growing species have a higher leaf weight ratio (LWR), leaf lifespan (LLS), and phyllochron, which are useful traits for survival in stressful and unfertile environments, but are normally thought to be incompatible with high productivity, even under fertile conditions. We tested the hypothesis that slow-growing forage grasses have demographic parameters (tiller population density and canopy density) that offset their slow individual traits, making them as productive as fast-growing species when grown in fertile soil. Species with contrasting growth strategies (Arrhenatherum elatius L. and Festuca arundinacea Schreb cv. Quantum II, fast and slow-growing species, respectively) were cultivated in 45 m2 field plots and subjected to the same cutting regime and nitrogen supply level. Functional traits and canopy attributes were continuously measured during 8 growing cycles after the establishment of the swards. A. elatius had higher SLA, LER, leaf senescence, and leaf appearance rates, whereas F. arundinacea had higher LLS and LWR values. Conversely, there were no differences in relative growth rate or forage accumulation. F. arundinacea was able to offset their plant functional traits, typically associated with slow-growing grasses, with some demographic parameter like higher tiller population density, allowing it to be as productive as the fast-growing A. elatius when both were grown in fertile soil. Therefore, we suggest cautionary use of traditional plant functional traits to explain and predict the annual productivity of slow-growing grasses.

A multicommuted system using bacterial cellulose for urease immobilization and copper (II)-MOF colorimetric sensor for urea spectrophotometric determination in milk.

This work describes determining urea in milk samples using a multicommuted approach with a urease enzyme immobilized in bacterial cellulose and solid MOF as a colorimetric reagent. The Cu(2+)-MOF was characterized by FTIR spectroscopy, XRD, and SEM. The urea quantification was based on the urea hydrolysis reaction catalyzed by urease and reacted with Cu(2+)-MOF forming [Cu(NH3)4]2+, monitored at 450 nm. Linear responses were obtained from 1.0 to 50.0 mg dL-1 urea (R = 0.9959, n = 11), detection and quantitation limits of 0.082 mg dL-1 and 0.272 mg dL-1 respectively, analytical frequency of 8 determinations per hour, 0.8 mL sample solution consumption. Potential interfering studies have shown the selectivity of the proposed method. Addition and recovery tests were performed obtaining variation from 90 to 103%. Applying the F-test and t-test, the results showed no significant difference at the 95% confidence level Comparing the proposed and the reference method.

Pd(II)/diphosphine/curcumin complexes as potential anticancer agents.

Palladium(II) complexes have stimulated research interest mainly due to their in vitro cytotoxicity against various cancer cell lines and their low cytotoxicity in healthy cells. Thus, in this work, we combined Pd(II)/phosphine systems with the natural product curcumin as a ligand, obtaining a series of complexes, [Pd(cur)(PPh3)2]PF6 (A1), [Pd(cur)(dppe)]PF6 (A2), [Pd(cur)(dppp)]PF6 (A3), [Pd(cur)(dppb)]PF6 (A4) and [Pd(cur)(dppf)]PF6 (A5), where dppe = 1,2-bis(diphenylphosphino)ethane, dppp = 1,3-bis(diphenylphosphino)propane, dppb = 1,4-bis(diphenylphosphino)butane, and dppf = 1,1'-bis(diphenylphosphino)ferrocene (P-P), which were characterized by elemental analysis, molar conductivity analysis, and mass, NMR (1H, 13C, 31P{1H}), UV-vis, and IR spectroscopies, and four of them (A1, A2, A4, and A5) by X-ray crystallography. The in vitro cell viability of the complexes A1-A5, cisplatin, and the free ligand curcumin against MDA-MB-231 (human triple-negative breast tumor cells), SK-BR-3 (human breast tumor cells), A549 (human lung tumor cells), MRC-5 (non-tumor human lung cells), A2780 (human ovarian carcinoma cells), and A2780cis (cisplatin-resistant human ovarian carcinoma cells), was evaluated by the MTT colorimetric assay. For the tumor cell lines tested, the complexes showed good anticancer activities. The results showed that in general the complexes had lower IC50 values than free curcumin and the precursors [PdCl2(P-P)]. IC50 results obtained for the A1-A5 complexes, in the MCF-7 cell line, are similar to those that had already been observed for some Pd/bipy/curcumin complexes. In the MDA-MB-231 cell line, complexes A1 and A5 stood out, with their lowest IC50 values, around 5 µmol L-1, and the complexes appeared to be more active (lower IC50 values) against the ovarian cell lines. Complex A1 was 23 and 22-fold more cytotoxic than cisplatin, against the A2780 and A2780cis cells, respectively. The complex A1 was studied on A2780cis cells and it was found that this complex inhibits colony formation and induces cell cycle arrest in the sub-G1 phase in a concentration-dependent manner and leads to cell death by apoptosis. The DCFDA assay revealed a potent ROS induction for complex A1.

Surgical treatment of patients with chronic rupture of the pectoralis major muscle tendon. Prospective comparative study with 2 years of follow-up.

To compare outcomes between autologous fascia lata and autologous hamstring grafts for chronic pectoralis major muscle (PMM) rupture repair, and perform histological, and imaging analyses. Forty male patients with chronic PMM ruptures (time since injury ranging from >3 months to 5 years) and a mean age of 37.3 years (SD = 9.7 years) were evaluated. One group (20 patients) received an autologous semitendinosus graft, and another group (20 patients) received an autologous fascia lata graft for PMM reconstruction. These patients with fascia lata grafts by Bak 2criterium 60% of the patients presented excellent results, 20% presented good results, 15% presented fair results, and 5% presented poor results. In the hamstring group 65% of the patients presented excellent results, 30% presented good results, and 5% presented fair results. In this comparative study, no difference was observed regarding the functional result, image, and histology between groups.

A model for bimodal rates and proportions.

The beta model is the most important distribution for fitting data with the unit interval. However, the beta distribution is not suitable to model bimodal unit interval data. In this paper, we propose a bimodal beta distribution constructed by using an approach based on the alpha-skew-normal model. We discuss several properties of this distribution, such as bimodality, real moments, entropies and identifiability. Furthermore, we propose a new regression model based on the proposed model and discuss residuals. Estimation is performed by maximum likelihood. A Monte Carlo experiment is conducted to evaluate the performances of these estimators in finite samples with a discussion of the results. An application is provided to show the modelling competence of the proposed distribution when the data sets show bimodality.

Fluorimetric determination of aqueous formaldehyde employing heating and ultrasound-assisted approach through its derivatization with a ß-diketone-nickel(2+) complex immobilized in a PMMA flow cell.

Formaldehyde (FA) is a highly toxic substance present in many matrices, including freshwater as well as found in natural mechanisms such as rainfall and combustion of organic matter. Consumption of water contaminated with high levels of FA can cause severe short-term or long-term health problems. Due to these health risks, procedures are necessary to determine and quantify FA in aqua sources This paper reports on a study of fluorimetric determination of FA using a nickel(2 + )-diketonate coordination compound immobilized as a solid precursor. The compound was characterized by electronic absorption, Fourier transform infrared (FTIR) spectroscopy, X-ray diffraction (XRD), thermogravimetry (TG), optical microscopy (OM), and scanner electron microscopy (SEM). The methodology was based on the reaction of the synthesized compound with an ammoniacal buffer generating a selective reagent for formaldehyde: fluoral-P. The product of the reaction generates 3,5-diacetyl-1,4-dihydrolutidine (DDL), which is responsible for the fluorescence of the system. Several parameters such as temperature, duration of heating time, and dilution effect with the best effects were studied to carry out FA determination. Under the optimum experimental conditions, a linear response ranging from 1.0 to 10.0 mg/L FA (R = 0.997 and n = 10), and a detection (3σ criterion) and quantification (10 σ criterion) limit estimated at 0.129 and 0.389 mg/L, respectively were achieved. The FA analysis was able to be conducted in 05 min with a relative standard deviation estimated at 1.10 %.

Characterization of a new anellovirus species infecting an ocelot (Leopardus pardalis) in Brazil.

A complete genome of the first anellovirus infecting the wild felid Leopardus pardalis (ocelot) and a partial genome were assembled and annotated through high-throughput sequencing protocols followed by Sanger sequencing validation. The full-length virus obtained comprises 2,003 bp, while the partial genome comprises 1,224 bp. Phylogenetic analysis grouped these two sequences in two distinct clusters related to previously described Felidae anelloviruses. The ORF1 of the partial genome was identified as a new species provisionally called Torque teno ocelot virus, with 53.6% identity with its sister lineage. The complete genome was inferred as a new representative of the Torque teno felid virus 3 species, with 73.28% identity to the closest reference. This study expands known virus diversity and the host span of anelloviruses.

Lessons from a Multilaboratorial Task Force for Diagnosis of a Fatal Toxoplasmosis Outbreak in Captive Primates in Brazil.

Toxoplasmosis is an important zoonotic disease caused by the parasite Toxoplasma gondii and is especially fatal for neotropical primates. In Brazil, the Ministry of Health is responsible for national epizootic surveillance, but some diseases are still neglected. Here, we present an integrated investigation of an outbreak that occurred during the first year of the COVID-19 pandemic among eleven neotropical primates housed at a primatology center in Brazil. After presenting non-specific clinical signs, all animals died within four days. A wide range of pathogens were evaluated, and we successfully identified T. gondii as the causative agent within four days after necropsies. The liver was the most affected organ, presenting hemorrhage and hepatocellular necrosis. Tachyzoites and bradyzoite cysts were observed in histological examinations and immunohistochemistry in different organs; in addition, parasitic DNA was detected through PCR in blood samples from all specimens evaluated. A high prevalence of Escherichia coli was also observed, indicating sepsis. This case highlights some of the obstacles faced by the current Brazilian surveillance system. A diagnosis was obtained through the integrated action of researchers since investigation for toxoplasmosis is currently absent in national guidelines. An interdisciplinary investigation could be a possible model for future epizootic investigations in animals.

Self-assembly of perovskite nanoplates in colloidal suspensions.

In recent years, perovskite nanocrystal superlattices have been reported with collective optical phenomena, offering a promising platform for both fundamental science studies and device engineering. In this same avenue, superlattices of perovskite nanoplates can be easily prepared on different substrates, and they too present an ensemble optical response. However, the self-assembly and optical properties of these aggregates in solvents have not been reported to date. Here, we report on the conditions for this self-assembly to occur and show a simple strategy to induce the formation of these nanoplate stacks in suspension in different organic solvents. We combined wide- and small-angle X-ray scattering and scanning transmission electron microscopy to evaluate CsPbBr3 and CsPbI3 perovskite nanoplates with different thickness distributions. We observed the formation of these stacks by changing the concentration of nanoplates and the viscosity of the colloidal suspensions, without the need for antisolvent addition. We found that, in hexane, the concentration for the formation of the stacks is rather high and approximately 80 mg mL-1. In contrast, in decane, dodecane, and hexadecane, we observe a much easier self-assembly of the nanoplates, presenting a clear correlation between the degree of aggregation and viscosity. We, then, discuss the impact of the self-assembly of perovskite nanoplates on Förster resonant energy transfer. Our predictions suggest an energy transfer efficiency higher than 50% for all the donor-acceptor systems evaluated. In particular, we demonstrate how the aggregation of these particles in hexadecane induces FRET for CsPbBr3 nanowires. For the n = 2 nanowires (donor) to the n = 3 nanowires (acceptor), the FRET rate was found to be 4.1 ns-1, with an efficiency of 56%, in agreement with our own predictions.

Synergism in Two-Component Insecticides with Dillapiole against Fall Armyworm.

The fall armyworm (Spodoptera frugiperda), a polyphagous insect pest, is a major threat to food production, rapidly spreading through all the tropical areas in the world. Resistance has developed to the control protocols used so far (pyrethroids, organophosphorus, and genetically modified plants), and alternative strategies must be found. The bioactivity in essential oils is usually associated with the major constituents, but synergistic interactions among the constituents (even minor ones) can improve the levels of activity considerably. Herein, we tested the insecticidal activity of several constituents of the essential oil from Piper aduncum, an Amazonian Piperaceae, both separately and as binary mixtures, through their application on the dorsal side of the larva pronotum. Dillapiole proved to be, isolated, the most active compound in this oil (LD50 = 0.35 ppm). In binary mixtures, a strong synergistic effect was observed for the pairs of dillapiole with ß-caryophyllene (LD50 = 0.03 ppm), methyl eugenol (LD50 = 0.05 ppm), and α-humulene (LD50 = 0.05 ppm). In some cases, however, antagonism was recorded, as for dillapiole + ß-pinene (LD50 = 0.44 ppm). The use of binary mixtures of essential oil constituents as low-environmental-toxicity insecticides allows a fine tuning of the insecticidal activity, and the exploitation of synergy effects.

Biomimetic catalysis of nitrite reductase enzyme using copper complexes in chemical and electrochemical reduction of nitrite.

Copper nitrite reductase mimetics were synthesized using three new tridentate ligands sharing the same N,N,N motif of coordination. The ligands were based on L-proline modifications, attaching a pyridine and a triazole to the pyrrolidine ring, and differ by a pendant group (R = phenyl, n-butyl and n-propan-1-ol). All complexes coordinate nitrite, as evidenced by cyclic voltammetry, UV-Vis, FTIR and electron paramagnetic resonance (EPR) spectroscopies. The coordination mode of nitrite was assigned by FTIR and EPR as κ2O chelate mode. Upon acidification, EPR experiments indicated a shift from chelate to monodentate κO mode, and 15N NMR experiments of a Zn2+ analogue, suggested that the related Cu(II) nitrous acid complex may be reasonably stable in solution, but in equilibrium with free HONO under non catalytic conditions. Reduction of nitrite to NO was performed both chemically and electrocatalytically, observing the highest catalytic activities for the complex with n-propan-1-ol as pendant group. These results support the hypothesis that a hydrogen bond moiety in the secondary coordination sphere may aid the protonation step.

Vitellogenin genes are transcribed in Culex quinquefasciatus ovary.

BACKGROUND: Culex quinquefasciatus, a cosmopolitan, domestic, and highly anthropophilic mosquito, is a vector of pathogenic arboviruses such as West Nile virus and Rift Valley virus, as well as lymphatic filariasis. The current knowledge on its reproductive physiology regarding vitellogenin expression in different tissues is still limited. OBJECTIVES: In this study, we analysed the transcriptional profiles of vitellogenin genes in the fat body and ovaries of C. quinquefasciatus females during the first gonotrophic cycle. METHODS: C. quinquefasciatus ovaries and/or fat bodies were dissected in different times during the first gonotrophic cycle and total RNA was extracted and used for reverse transcription polymerase chain reaction, quantitative real time-PCR, and in situ hybridisation. FINDINGS: We confirmed the classical descriptions of the vitellogenic process in mosquitoes by verifying that vitellogenin genes are transcribed in the fat bodies of C. quinquefasciatus females. Using RNA in situ hybridisation approach, we showed that vitellogenin genes are also transcribed in developing ovaries, specifically by the follicle cells. MAIN CONCLUSIONS: This is the first time that vitellogenin transcripts are observed in mosquito ovaries. Studies to determine if Vg transcripts are translated into proteins and their contribution to the reproductive success of the mosquito need to be further investigated.

All-cause and cause-specific mortality among people with bipolar disorder: a large-scale systematic review and meta-analysis.

OBJECTIVE: Bipolar disorder (BD) is associated with premature mortality. All-cause and specific mortality risks in this population remain unclear, and more studies are still needed to further understand this issue and guide individual and public strategies to prevent mortality in bipolar disorder Thus, a systematic review and meta-analysis of studies assessing mortality risk in people with BD versus the general population was conducted. The primary outcome was all-cause mortality, whilst secondary outcomes were mortality due to suicide, natural, unnatural, and specific-causes mortality. RESULTS: Fifty-seven studies were included (BD; n = 678,353). All-cause mortality was increased in people with BD (RR = 2.02, 95% CI: 1.89-2.16, k = 39). Specific-cause mortality was highest for suicide (RR = 11.69, 95% CI: 9.22-14.81, k = 25). Risk of death due to unnatural causes (RR = 7.29, 95% CI: 6.41-8.28, k = 17) and natural causes (RR = 1.90, 95% CI: 1.75-2.06, k = 17) were also increased. Among specific natural causes analyzed, infectious causes had the higher RR (RR = 4,38, 95%CI: 1.5-12.69, k = 3), but the analysis was limited by the inclusion of few studies. Mortality risk due to respiratory (RR = 3.18, 95% CI: 2.55-3.96, k = 6), cardiovascular (RR = 1.76, 95% CI: 1.53-2.01, k = 27), and cerebrovascular (RR = 1.57, 95% CI: 1.34-1.84, k = 13) causes were increased as well. No difference was identified in mortality by cancer (RR = 0.99, 95% CI: 0.88-1.11, k = 16). Subgroup analyses and meta-regression did not affect the findings. CONCLUSION: Results presented in this meta-analysis show that risk of premature death in BD is not only due to suicide and unnatural causes, but somatic comorbidities are also implicated. Not only the prevention of suicide, but also the promotion of physical health and the prevention of physical conditions in individuals with BD may mitigate the premature mortality in this population. Notwithstanding this is to our knowledge the largest synthesis of evidence on BD-related mortality, further well-designed studies are still warranted to inform this field.

The association between post-traumatic stress disorder (PTSD) and cognitive impairment: A systematic review of neuroimaging findings.

BACKGROUND: Accumulating evidence suggests that post-traumatic stress disorder (PTSD) may increase the risk of various types of dementia. Despite the large number of studies linking these critical conditions, the underlying mechanisms remain unclear. The past decade has witnessed an exponential increase in interest on brain imaging research to assess the neuroanatomical underpinnings of PTSD. This systematic review provides a critical assessment of available evidence of neuroimaging correlates linking PTSD to a higher risk of dementia. METHODS: The EMBASE, PubMed/MEDLINE, and SCOPUS electronic databases were systematically searched from 1980 to May 22, 2021 for original references on neuroimaging correlates of PTSD and risk of dementia. Literature search, screening of references, methodological quality appraisal of included articles as well as data extractions were independently conducted by at least two investigators. Eligibility criteria included: 1) a clear PTSD definition; 2) a subset of included participants must have developed dementia or cognitive impairment at any time point after the diagnosis of PTSD through any diagnostic criteria; and 3) brain imaging protocols [structural, molecular or functional], including whole-brain morphologic and functional MRI, and PET imaging studies linking PTSD to a higher risk of cognitive impairment/dementia. RESULTS: Overall, seven articles met eligibility criteria, comprising findings from 366 participants with PTSD. Spatially convergent structural abnormalities in individuals with PTSD and co-occurring cognitive dysfunction involved primarily the bilateral frontal (e.g., prefrontal, orbitofrontal, cingulate cortices), temporal (particularly in those with damage to the hippocampi), and parietal (e.g., superior and precuneus) regions. LIMITATIONS: A meta-analysis could not be performed due to heterogeneity and paucity of measurable data in the eligible studies. CONCLUSIONS: Our systematic review provides putative neuroimaging correlates associated with PTSD and co-occurring dementia/cognitive impairment particularly involving the hippocampi. Further research examining neuroimaging features linking PTSD to dementia are clearly an unmet need of the field. Future imaging studies should provide a better control for relevant confounders, such as the selection of more homogeneous samples (e.g., age, race, education), a proper control for co-occurring disorders (e.g., co-occurring major depressive and anxiety disorders) as well as the putative effects of psychotropic medication use. Furthermore, prospective studies examining imaging biomarkers associated with a higher rate of conversion from PTSD to dementia could aid in the stratification of people with PTSD at higher risk for developing dementia for whom putative preventative interventions could be especially beneficial.

Subacute exposure to Roundup® changes steroidogenesis and gene expression of the glutathione-glutaredoxin system in rat ovaries: Implications for ovarian toxicity of this glyphosate-based herbicide.

Studies have indicated that glyphosate induces endocrine disruption and may adversely affect the male reproductive system. However, evidence of its effects on ovarian function is poorly understood so far, making further studies necessary on the mechanisms of the glyphosate toxicity in the female reproductive system. The aim of this work was to evaluate the effect of a subacute exposure (28 days) to the glyphosate-based formulation Roundup® (1.05, 10.5 and 105 µg/kg b.w. of glyphosate) on steroidogenesis, oxidative stress, systems involved in cell redox control and histopathological parameters in rat ovaries. Hence we quantify plasma estradiol and progesterone by chemiluminescence; non-protein thiol levels, TBARS, superoxide dismutase and catalase activity by spectrophotometry; gene expression of steroidogenic enzymes and redox systems by real-time PCR; and ovarian follicles by optical microscopy. Our results demonstrated that oral exposure increased progesterone levels and the mRNA expression of 3ß-hydroxysteroid dehydrogenase. Histopathological analysis revealed a decrease in the number of primary follicles and an increase in the number of corpus luteum in rats exposed to Roundup®. An imbalance of the oxidative status was also evidenced by decreasing the catalase activity at all groups exposed to the herbicide. Increased lipid peroxidation and gene expression of glutarredoxin and decreased of glutathione reductase were also observed. Our results indicate that Roundup® causes endocrine disruption of hormones related to female fertility and reproduction and changes the oxidative status by altering antioxidant activity, inducing lipid peroxidation, as well as changing the gene expression of the glutathione-glutarredoxin system in rat ovaries.

Time Evolution of Ultrasmall Gold Nanoparticle-Protein Interactions.

To date, much effort has been devoted toward the study of protein corona formation onto large gold nanoparticles (GNPs). However, the protein corona concept breaks down for GNPs in the ultrasmall size regime (<3 nm), and, as a result, our understanding of ultrasmall GNP (usGNP)-protein interactions remains incomplete. Herein, we used anionic usGNPs and six different proteins as model systems to systematically investigate usGNP-protein interactions, with particular focus on the time evolution and long-term behavior of complex formation. The different proteins comprised chymotrypsin (Cht), trypsin (Try), thrombin (Thr), serum albumin (HSA), cytochrome c (Cyt c), and factor XII (FXII). We used a range of biochemical and biophysical methods to estimate binding affinities, determine the effects of usGNPs on protein structure and function, assess the reversibility of any protein structural and functional changes, and evaluate usGNP-protein complex stability. Among the main findings, we observed that prolonged (24 h)─but not short-term (10 min)─interactions between proteins and usGNPs permanently altered protein function, including enzyme activities (Try, Thr, and FXIIa), peroxidase-like activity (Cyt c), and ligand-binding properties (HSA). Remarkably, this occurred without any large-scale loss of the native global conformation, implying time-dependent effects of usGNPs on local protein conformation or dynamics. We also found that both short-(10 min) and long-term (24 h) interactions between proteins and usGNPs yielded short-lived complexes, i.e., there was no time-dependent "hardening" of the interactions at the binding interface as usually seen with large GNPs. The present study increases our fundamental understanding of nano-bio interactions in the ultrasmall size regime, which may assist the safe and effective translation of usGNPs into the clinic.

"Half-Sandwich" Ruthenium Complexes with Alizarin as Anticancer Agents: In Vitro and In Vivo Studies.

Upon exploration of the chemistry of the combination of ruthenium/arene with anthraquinone alizarin (L), three new complexes with the general formulas [Ru(L)Cl(η6-p-cymene)] (C1), [Ru(L)(η6-p-cymene)(PPh3)]PF6 (C2), and [Ru(L)(η6-p-cymene)(PEt3)]PF6 (C3) were synthesized and characterized using spectroscopic techniques (mass, IR, and 1D and 2D NMR), molar conductivity, elemental analysis, and X-ray diffraction. Complex C1 exhibited fluorescence, such as free alizarin, while in C2 and C3, the emission was probably quenched by monophosphines and the crystallographic data showed that hydrophobic interactions are predominant in intermolecular contacts. The cytotoxicity of the complexes was evaluated in the MDA-MB-231 (triple-negative breast cancer), MCF-7 (breast cancer), and A549 (lung) tumor cell lines and MCF-10A (breast) and MRC-5 (lung) nontumor cell lines. Complexes C1 and C2 were more selective to the breast tumor cell lines, and C2 was the most cytotoxic (IC50 = 6.5 µM for MDA-MB-231). In addition, compound C1 performs a covalent interaction with DNA, while C2 and C3 present only weak interactions; however, internalization studies by flow cytometry and confocal microscopy showed that complex C1 does not accumulate in viable MDA-MB-231 cells and is detected in the cytoplasm only after cell permeabilization. Investigations of the mechanism of action of the complexes indicate that C2 promotes cell cycle arrest in the Sub-G1 phase in MDA-MB-231, inhibits its colony formation, and has a possible antimetastatic action, impeding cell migration in the wound-healing experiment (13% of wound healing in 24 h). The in vivo toxicological experiments with zebrafish indicate that C1 and C3 exhibit the most zebrafish embryo developmental toxicity (inhibition of spontaneous movements and heartbeats), while C2, the most promising anticancer drug in the in vitro preclinical tests, revealed the lowest toxicity in in vivo preclinical screening.