Functionalized carbon nanotubes: From intracellular uptake and cell-related toxicity to systemic brain delivery

AbstractCarbon nanotubes (CNTs) have long been regarded as promising carriers in biomedicine. Due to their high surface area and unique needle-like structure, CNTs are uniquely equipped to carry therapeutic molecules across biological membranes and, therefore, have been widely researched for use in theranostic applications. The attractive properties of the CNTs entice also their use in the brain environment. Cutting edge brain-specific therapies, capable of circumventing the physical and biochemical blockage of the blood-brain barrier, could be a precious tool to tackle brain disorders. With an increasing number of applications and expanding production, the effects of direct and indirect exposure to CNTs on cellular and molecular levels and more globally the general health, must be carefully assessed and limited.In this chapter, we review the most recent trends on the development and application of CNT-based nanotechnologies, with a particular focus on the carrier properties, cell internalisation and processing, and mechanisms involved in cell toxicity. Novel approaches for CNT-based systemic therapeutic brain delivery following intravenous administration are also reviewed. Moreover, we highlight fundamental questions that should be addressed in future research involving CNTs, aiming at achieving its safe introduction into the clinics

Triple-Modal Imaging of Magnetically-Targeted Nanocapsules in Solid Tumours In Vivo

Triple-modal imaging magnetic nanocapsules, encapsulating hydrophobic superparamagnetic iron oxide nanoparticles, are formulated and used to magnetically target solid tumours after intravenous administration in tumour-bearing mice. The engineered magnetic polymeric nanocapsules m-NCs are ~200 nm in size with negative Zeta potential and shown to be spherical in shape. The loading efficiency of superparamagnetic iron oxide nanoparticles in the m-NC was ~100%. Up to ~3- and ~2.2-fold increase in tumour uptake at 1 and 24 h was achieved, when a static magnetic field was applied to the tumour for 1 hour. m-NCs, with multiple imaging probes (e.g. indocyanine green, superparamagnetic iron oxide nanoparticles and indium-111), were capable of triple-modal imaging (fluorescence/magnetic resonance/nuclear imaging) in vivo. Using triple-modal imaging is to overcome the intrinsic limitations of single modality imaging and provides complementary information on the spatial distribution of the nanocarrier within the tumour. The significant findings of this study could open up new research perspectives in using novel magnetically-responsive nanomaterials in magnetic-drug targeting combined with multi-modal imaging

A new view of electrochemistry at highly oriented pyrolytic graphite

Major new insights on electrochemical processes at graphite electrodes are reported, following extensive investigations of two of the most studied redox couples, Fe(CN)64–/3– and Ru(NH3)63+/2+. Experiments have been carried out on five different grades of highly oriented pyrolytic graphite (HOPG) that vary in step-edge height and surface coverage. Significantly, the same electrochemical characteristic is observed on all surfaces, independent of surface quality: initial cyclic voltammetry (CV) is close to reversible on freshly cleaved surfaces (>400 measurements for Fe(CN)64–/3– and >100 for Ru(NH3)63+/2+), in marked contrast to previous studies that have found very slow electron transfer (ET) kinetics, with an interpretation that ET only occurs at step edges. Significantly, high spatial resolution electrochemical imaging with scanning electrochemical cell microscopy, on the highest quality mechanically cleaved HOPG, demonstrates definitively that the pristine basal surface supports fast ET, and that ET is not confined to step edges. However, the history of the HOPG surface strongly influences the electrochemical behavior. Thus, Fe(CN)64–/3– shows markedly diminished ET kinetics with either extended exposure of the HOPG surface to the ambient environment or repeated CV measurements. In situ atomic force microscopy (AFM) reveals that the deterioration in apparent ET kinetics is coupled with the deposition of material on the HOPG electrode, while conducting-AFM highlights that, after cleaving, the local surface conductivity of HOPG deteriorates significantly with time. These observations and new insights are not only important for graphite, but have significant implications for electrochemistry at related carbon materials such as graphene and carbon nanotubes

Pleiotropic functions of the tumor- and metastasis-suppressing Matrix Metalloproteinase-8 in mammary cancer in MMTV-PyMT transgenic mice

Matrix metalloproteinase-8 (MMP-8; neutrophil collagenase) is an important regulator of innate immunity which has onco-suppressive actions in numerous tumor types

Brain arteriolosclerosis

Brain arteriolosclerosis (B-ASC), characterized by pathologic arteriolar wall thickening, is a common finding at autopsy in aged persons and is associated with cognitive impairment. Hypertension and diabetes are widely recognized as risk factors for B-ASC. Recent research indicates other and more complex risk factors and pathogenetic mechanisms. Here we describe aspects of the unique architecture of brain arterioles, histomorphologic features of B-ASC, relevant neuroimaging findings, epidemiology and association with aging, established genetic risk factors, and the co-occurrence of B-ASC with other neuropathologic conditions such as Alzheimer’s disease and limbic-predominant age-related TDP-43 encephalopathy (LATE). There may also be complex physiologic interactions between metabolic syndrome (e.g. hypertension and inflammation) and brain arteriolar pathology. Although there is no universally applied diagnostic methodology, several classification schemes and neuroimaging techniques are used to diagnose and categorize cerebral small vessel disease pathologies that include B-ASC, microinfarcts, microbleeds, lacunar infarcts, and cerebral amyloid angiopathy (CAA). In clinical-pathologic studies that include consideration of comorbid diseases, B-ASC is independently associated with impairments in global cognition, episodic memory, working memory, and perceptual speed, and has been linked to autonomic dysfunction and motor symptoms including parkinsonism. We conclude by discussing critical knowledge gaps related to B-ASC and suggest that there are probably subcategories of B-ASC that differ in pathogenesis. Observed in over 80% of autopsied individuals beyond 80 years of age, B-ASC is a complex and under-studied contributor to neurologic disability

Fifteen new risk loci for coronary artery disease highlight arterial-wall-specific mechanisms

Coronary artery disease (CAD) is a leading cause of morbidity and mortality worldwide. Although 58 genomic regions have been associated with CAD thus far, most of the heritability is unexplained, indicating that additional susceptibility loci await identification. An efficient discovery strategy may be larger-scale evaluation of promising associations suggested by genome-wide association studies (GWAS). Hence, we genotyped 56,309 participants using a targeted gene array derived from earlier GWAS results and performed meta-analysis of results with 194,427 participants previously genotyped, totaling 88,192 CAD cases and 162,544 controls. We identified 25 new SNP-CAD associations (P < 5 × 10(-8), in fixed-effects meta-analysis) from 15 genomic regions, including SNPs in or near genes involved in cellular adhesion, leukocyte migration and atherosclerosis (PECAM1, rs1867624), coagulation and inflammation (PROCR, rs867186 (p.Ser219Gly)) and vascular smooth muscle cell differentiation (LMOD1, rs2820315). Correlation of these regions with cell-type-specific gene expression and plasma protein levels sheds light on potential disease mechanisms

Critical Perspective: Named Reactions Discovered and Developed by Women

Named organic reactions. As chemists, we’re all familiar with them: who can forget the Diels−Alder reaction? But how much do we know about the people behind the names? For example, can you identify a reaction named for a woman? How about a reaction discovered or developed by a woman but named for her male adviser? Our attempts to answer these simple questions started us on the journey that led to this Account. We introduce you to four reactions named for women and nine reactions discovered or developed by women. Using information obtained from the literature and, whenever possible, through interviews with the chemists themselves, their associates, and their advisers, we paint a more detailed picture of these remarkable women and their outstanding accomplishments. Some of the women you meet in this Account include Irma Goldberg, the only woman unambiguously recognized with her own named reaction. Gertrude Maud Robinson, the wife of Robert Robinson, who collaborated with him on several projects including the Piloty−Robinson pyrrole synthesis. Elizabeth Hardy, the Bryn Mawr graduate student who discovered the Cope rearrangement. Dorothee Felix, a critical member of Albert Eschenmoser’s research lab for over forty years who helped develop both the Eschenmoser−Claisen rearrangement and the Eschenmoser−Tanabe fragmentation. Jennifer Loebach, the University of Illinois undergraduate who was part of the team in Eric Jacobsen’s lab that discovered the Jacobsen−Katsuki epoxidation. Keiko Noda, a graduate student in Tsutomu Katsuki’s lab who also played a key role in the development of the Jacobsen−Katsuki epoxidation. Lydia McKinstry, a postdoc in Andrew Myers’s lab who helped develop the Myers asymmetric alkylation. Rosa Lockwood, a graduate student at Boston College whose sole publication is the discovery of the Nicholas reaction. Kaori Ando, a successful professor in Japan who helped develop the Roush asymmetric alkylation as a postdoc at MIT. Bianka Tchoubar, a critically important member of the organic chemistry community in France who developed the Tiffeneau−Demjanov rearrangement. The accomplishments of the women in this Account illustrate the key roles women have played in the discovery and development of reactions used daily by organic chemists around the world. These pioneering chemists represent the vanguard of women in the field, and we are confident that many more of the growing number of current and future female organic chemists will be recognized with their own named reactions