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Chronic myeloid leukemia (CML) is a rare malignant proliferative hematopoietic disease due to overexpression of a tyrosine kinase (TK) derived from the breakpoint cluster region (BCR)‐abelson tyrosine‐protein kinase 1 (ABL1) gene fusion. Imatinib (IM), blocks this tyrosine kinase, and is the first line TK inhibitor (TKI) used in CML treatment. In a high percentage of CML patients, a poor response with relapse and disease progression is associated to acquisition of resistance through different mechanisms, including dysregulation of c‐MYC proto‐oncogene. Gold nanoparticles (AuNPs) are shown to allow improved efficacy in gene silencing approaches toward cancer therapy. Herein, the silencing potential of AuNPs functionalized with antisense oligonucleotides selectively targeting the e14a2 BCR‐ABL1 or the c‐MYC, alone and combination is evaluated. It is demonstrated efficient silencing of gene expression that translated to a downregulation of protein levels in IM resistant CML cells (K562‐IM). This combination allowed for increased death of the malignant cells. These Au‐nanoconjugates may be useful to tackle IM‐resistance mechanisms, providing an additional tool for future combinatory schemes to fight CML with imatinib resistance. [ABSTRACT FROM AUTHOR]

Eight new amorphous organic salts of folic acid (FA) were prepared by mechanochemistry. FA can prevent cardiovascular and neurological diseases. Mechanochemistry overcomes serious FA solubility issues avoiding the use of toxic solvents. Due to low FA solubility, therapeutic effects in supplements and drugs are not achieved. Current strategies to improve FA solubility include its derivatization by using complex synthetic procedures. Herein, a simple and green procedure, avoiding structural modifications, was designed using mechanochemistry. Biocompatible amine‐derivative coformers were strategically combined with FA to obtain salts with good physicochemical properties. New 1 : 1 and 1 : 2 amorphous FA salts offer 10 to 10,000 times better aqueous solubility and 10 to 100 times better octanol‐water partition coefficient values (Koctanol/water) than FA alone. Koctanol/water is considered as a surrogate of cell permeability. No toxic effects in normal human primary dermal fibroblasts were detected for the prepared FA salts. Our findings suggest that 1 : 2 FA salts of choline hydroxide and derivatives could be good candidates for future pharmaceutical/nutraceutical applications. [ABSTRACT FROM AUTHOR]

Preterm birth is a major clinical and public health challenge, with a prevalence of 11% worldwide. It is the leading cause of death in children younger than 5 years old and represents 70% of neonatal deaths and 75% of neonatal morbidity. Despite the clinical and public health significance, this condition's etiology is still unclear, and most of the cases are spontaneous. There are several known preterm birth risk factors, including inflammatory diseases and the genetic background, although the underlying molecular mechanisms are far from understood. The present review highlights the research advances on the association between inflammatory‐related genes and the increased risk for preterm delivery. The most associated genetic variants are the TNFα rs1800629, the IL1α rs17561, and the IL1RN rs2234663. Moreover, many of the genes discussed in this review are also implicated in pathologies involving inflammatory or autoimmune systems, such as periodontal disease, bowel inflammatory disease, and autoimmune rheumatic diseases. This review presents evidence suggesting a common genetic background to preterm birth, autoimmune and inflammatory diseases susceptibility. [ABSTRACT FROM AUTHOR]

Cancer treatment has yet to find a "silver bullet" capable of selectively and effectively kill tumor cells without damaging healthy cells. Nanomedicine is a promising field that can combine several moieties in one system to produce a multifaceted nanoplatform. The tumor microenvironment (TME) is considered responsible for the ineffectiveness of cancer therapeutics and the difficulty in the translation from the bench to bed side of novel nanomedicines. A promising approach is the use of combinatorial therapies targeting the TME with the use of stimuli‐responsive nanomaterials which would increase tumor targeting. Contemporary combined strategies for TME‐targeting nanoformulations are based on the application of external stimuli therapies, such as photothermy, hyperthermia or ultrasounds, in combination with stimuli‐responsive nanoparticles containing a core, usually composed by metal oxides or graphene, and a biocompatible stimuli‐responsive coating layer that could also contain tumor targeting moieties and a chemotherapeutic agent to enhance the therapeutic efficacy. The obstacles that nanotherapeutics must overcome in the TME to accomplish an effective therapeutic cargo delivery and the proposed strategies for improved nanotherapeutics will be reviewed. This article is categorized under:Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic DiseaseNanotechnology Approaches to Biology > Nanoscale Systems in BiologyTherapeutic Approaches and Drug Discovery > Emerging Technologies [ABSTRACT FROM AUTHOR]

POXylated polyurea dendrimer nanoparticles (PUREG4OOx48) are loaded with sildenafil (SDF) by a supercritical carbon dioxide–assisted (scCO2) impregnation. Further supercritical CO2‐assisted spray drying (SASD) leads to hybrid nano‐in‐micro dry powder formulations that are investigated aiming at efficient pulmonary delivery of SDF in pulmonary arterial hypertension treatment. This is the first report of the production of poly(D,L‐lactide‐co‐glycolide)‐cholesterol (PLGA‐Chol) microparticles processed by SASD. The optimized formulation of nano‐in‐microparticles is composed of PLGA, Chol, and PUREG4OOx48, loaded with SDF solutions in a 77:23 ratio (PLGA‐Chol:dendrimer, w/w). The dry powders are fully characterized and found to be highly biodegradable and biocompatible, and the SDF release profile evaluates under different pH values. The median mass average diameter (MMAD) of the nano‐in‐micro systems varies between 2.57 and 5 µm and the fine particle fraction (FPF) between 36% and 29% for PUREG4OMeOx48[PLGA‐Chol] and PUREG4OEtOx48[PLGA‐Chol], respectively. The data validate the potential use of these new formulations in inhalation therapy. In vitro studies are also carried out in order to evaluate the effect of the free drug in cell viability and formulations cytotoxicity. [ABSTRACT FROM AUTHOR]

Abstract: A series of 4‐ethynylaniline gold(I) complexes containing monophosphane (1,3,5‐triaza‐7‐phosphaadamantane (pta; 2), 3,7‐diacetyl‐1,3,7‐triaza‐5‐phosphabicyclo[3.3.1]nonane (3), and PR3, with R=naphthyl (4), phenyl (5), and ethyl (6)) and diphosphane (bis(diphenylphosphino)acetylene (dppa; 7), trans‐1,2‐bis(diphenylphosphino)ethene (dppet; 8), 1,2‐bis(diphenylphosphino)ethane (dppe; 9), and 1,3‐bis(diphenylphosphino)propane (dppp; 10)) ligands have been synthesized and their efficiency against tumor cells evaluated. The cytotoxicity of complexes 2–10 was evaluated in human colorectal (HCT116) and ovarian (A2780) carcinoma as well as in normal human fibroblasts. All the complexes showed a higher antiproliferative effect in A2780 cells, with the cytotoxicity decreasing in the following order 5>6=9=10>8>2>4>7>3. Complex 4 stands out for its very high selectivity towards ovarian carcinoma cells (IC50=2.3 μ m) compared with colorectal carcinoma and normal human fibroblasts (IC50>100 μ m), which makes this complex very attractive for ovarian cancer therapy. Its cytotoxicity in these cells correlates with the induction of the apoptotic process and an increase of intracellular reactive oxygen species (ROS). The effects of the nuclearity, rigidity, and solubility of these complexes on their biological activity were also analyzed. X‐ray crystal structure determination allowed the identification of short N−H⋅⋅⋅π contacts as the main driving forces for the three‐dimensional packing in these molecules. [ABSTRACT FROM AUTHOR]

POxylated polyurea dendrimer (PUREG4OOx48)‐based nanoparticles were loaded with paclitaxel (PTX) and doxorubicin (DOX) and micronized with chitosan (CHT) by using supercritical CO2‐assisted spray drying (SASD). Respirable, biocompatible, and biodegradable dry powder formulations (DPFs) were produced to effectively transport and deliver the chemotherapeutics with a controlled rate to the deep lung. In vitro studies performed with the use of the lung adenocarcinoma cell line showed that DOX@PUREG4OOx48 nanoparticles were much more cytotoxic than the free drug. Additionally, the DPFs did not show higher cytotoxicity than the respective nanoparticles, and DOX‐DPFs showed a higher chemotherapeutic effect than PTX formulations in adenocarcinoma cells. Inhalation chemotherapeutics: Micronized POxylated polyurea dendrimers loaded with anticancer agents (paclitaxel or doxorubicin) are fabricated by using green methodologies. These drug‐delivery systems reveal enhanced drug accumulation into neoplastic cells and allow a reduction in drug dosages and undesired side effects. [ABSTRACT FROM AUTHOR]

A new and never before reported hetero-arylidene-9(10H)-anthrone structure (4) was unexpectedly isolated on reaction of 1,2-dimethyl-3-ethylimidazolium iodide (2) and 9-anthracenecarboxaldehyde (3) under basic conditions. Its structure was unequivocally confirmed by X-ray crystallography. No cytotoxicity in human healthy fibroblasts and in two different cancer cell lines was observed, indicating its applicability in biological systems. Compound 4 interacts with CT-DNA by intercalation between the adjacent base pairs of DNA with a high binding affinity [Kb = 2.0 (±0.20) x 105 M-1], which is 10 x higher than that described for doxorubicin [Kb = 3.2 (±0.23) x 104 M-1]. Furthermore, compound 4 quenches the fluorescence emission of a GelRed--CT-DNA system with a quenching constant (KSV) of 3.3 (±0.3) x 10³ M-1 calculated by the Stern--Volmer equation. [ABSTRACT FROM AUTHOR]

The optical and physico‐chemical properties of gold nanoparticles (AuNPs) have prompted new and improved approaches which have greatly evolved the fields of biosensing and molecular detection. In this study, the authors took advantage of AuNPs' ease of modification and functionalised it with selected DNA aptamers using a salt aging method to produce gold‐aptamer nanoprobes. After characterisation, these nanoprobes were subsequently used for biomolecular detection of glycidamide (GA)–guanine (Gua) adducts generated in vitro. The results are based on differences in nanoprobe stabilisation against salt‐induced aggregation, similar to the non‐cross‐linking method developed by Baptista for discrimination of specific sequences. Alkylated Guas were efficiently discriminated from deoxyguanosine and GA in solution. Despite this, a clear identification of DNA adducts derived from genomic DNA alkylation has proven to be a more challenging task. [ABSTRACT FROM AUTHOR]

ABSTRACT Acrylamide is an amide used in several industrial applications making it easily discharged to aquatic ecosystems. The toxicity of acrylamide to aquatic organisms is scarcely known, although previous studies with murine models provided evidence for deleterious effects. To assess the effects of acrylamide to freshwater fish, goldfish ( Carassius auratus L.) were exposed to several concentrations of waterborne acrylamide and analysed for genotoxic damage, alterations to detoxifying enzymes and histopathology. Results revealed a dose-dependent increase in total DNA strand breakage, the formation of erythrocytic nuclear abnormalities and in the levels of hepatic cytochrome P4501A (CYP1A) and glutathione S-transferase (GST) activity. In addition, acrylamide induced more histopathological changes to pancreatic acini than to the hepatic parenchyma, regardless of exposure concentration, whereas hepatic tissue only endured significant alterations at higher concentrations of exposure. Thus, results confirm the genotoxic potential of acrylamide to fish and its ability to induce CYP1A, probably as a direct primary defence mechanism. This strongly suggests the substance's pro-mutagenic potential in fish, similarly to what is known for rodents. However, the deleterious effects observed in the pancreatic acini, more severe than in the liver, could indicate a specific, albeit unknown toxic mechanism of acrylamide to fish that overran the organism's metabolic defences against a chemical agent rather than causing a general systemic failure. Copyright © 2013 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

The Cover Feature shows engineered nano‐in‐microparticles specially designed for inhalation chemotherapy. The dry powder formulations, produced by supercritical CO2‐assisted co‐atomization of chitosan and polyurea dendrimers, deliver anticancer drugs to the deep lung. More information can be found in the Full Paper by R. B. Restani et al. on page 772 in Issue 10, 2018 (DOI: 10.1002/open.201800093). [ABSTRACT FROM AUTHOR]