Study of the cap structure of (3,3), (4,4) and (5,5)-SWCNTs: application of the sphere-in-contact model

We have applied the sphere-in-contact model supported by hybrid Density Functional Theory (DFT) calculations to elucidate the cap geometry of the sub-nanometer in dimension (3,3), (4,4) and (5,5) single-wall carbon-nanotubes (SWCNTs). Our approach predicts certain cap-geometries that do not comprise of the commonly known for their stability combination of pentagonal and hexagonal carbon rings but also tetragonal, trigonal and all-pentagonal structures. Based on hybrid-DFT calcula-tions carbon atoms in these new cap geometries have similar stability to carbon found in other fullerene-like capped zig-zag and arm-chair nanotubes (i.e., (5,5), (6,6), (9,0) and (10,0)) that are known to be stable and synthetically accessible. We find that the cap structure of the (3,3)-CNTs is a pointy carbon geometry comprised of six pentagonal rings with a single carbon atom at the tip apex. In this tip geome-try the carbon atom at the tip apex does not have the usual sp2 or sp3 geometry but an unusual trigonal pyramidal configuration. DFT calculations of the molecular orbitals and density-of-states of the tip show that this tip structure apart from being stable can be used in scanning probe microscopies such as STM for very high resolution imaging

Argyrin B a non-competitive inhibitor of the human immunoproteasome exhibiting preference for β1i

Inhibitors of the proteasome have found broad therapeutic applications however, they show severe toxicity due to the abundance of proteasomes in healthy cells. In contrast, inhibitors of the immunoproteasome, which is upregulated during disease states, are less toxic and have increased therapeutic potential including against autoimmune disorders. In this project, we report argyrin B, a natural product cyclic peptide to be a reversible, non-competitive inhibitor of the immunoproteasome. Argyrin B showed selective inhibition of the β5i and β1i sites of the immunoproteasome over the β5c and β1c sites of the constitutive proteasome with nearly 20-fold selective inhibition of β1i over the homologous β1c. Molecular modelling attributes the β1i over β1c selectivity to the small hydrophobic S1 pocket of β1i and β5i over β5c to site-specific amino acid variations that enable additional bonding interactions and stabilization of the binding conformation. These findings facilitate the design of immunoproteasome selective and reversible inhibitors that may have a greater therapeutic potential and lower toxicity

Size-dependent bond dissociation enthalpies in single-walled carbon nanotubes

We report the bond dissociation enthalpy (BDE) and the local electronic properties of Single-Walled Carbon Nanotubes (SWCNT) using density functional theory. Our analysis shows that there is a strong size-dependence of the BDE of these SWCNTs, which is inversely proportional to the radius-squared (1/r2) and the length (1/l) of SWCNT. We derive quantitative relationships from which the BDE can be calculated as a function of size and radius of the SWCNT. We find that the BDE of SWCNT outside the size-dependent region is about 480 kJ mol−1, which can be used for thermochemical calculations

Photodynamic therapy in 3D cancer models and the utilisation of nanodelivery systems

Photodynamic therapy (PDT) is the subject of considerable research in experimental cancer models mainly for the treatment of solid cancerous tumours. Recent studies on the use of nanoparticles as photosensitiser carriers have demonstrated improved PDT efficacy in experimental cancer therapy. Experiments typically employ conventional monolayer cell culture but there is increasing interest in testing PDT using three dimensional (3D) cancer models. 3D cancer models can better mimic in vivo models than 2D cultures by for example enabling cancer cell interactions with a surrounding extracellular matrix which should enable the treatment to be optimised prior to in vivo studies. The aim of this review is to discuss recent research using PDT in different types of 3D cancer models, from spheroids to nano-fibrous scaffolds, using a range of photosensitisers on their own or incorporated in nanoparticles and nanodelivery systems

Genetic variation in genes interacting with BRCA1/2 and risk of breast cancer in Cypriot population.

Inability to correctly repair DNA damage is known to play a role in the development of breast cancer. Single nucleotide polymorphisms (SNPs) of DNA repair genes have been identified, which modify the DNA repair capacity, which in turn may affect the risk of developing breast cancer. To assess whether alterations in DNA repair genes contribute to breast cancer, we genotyped 62 SNPs in 29 genes in 1,109 Cypriot women with breast cancer and 1,177 age-matched healthy controls. Five SNPs were associated with breast cancer. SNPs rs13312840 and rs769416 in the NBS1 gene were associated with a decrease in breast cancer risk (OR TT vs. TC/CC = 0.58; 95% CI, 0.37-0.92; P = 0.019 and OR GG vs. GT/TT = 0.23, 95% CI 0.06-0.85, P = 0.017, respectively). The variant allele of MRE11A rs556477 was also associated with a reduced risk of developing the disease (OR AA vs. AG/GG = 0.76; 95% CI, 0.64-0.91; P = 0.0022). MUS81 rs545500 and PBOV1 rs6927706 SNPs were associated with an increased risk of developing breast cancer (OR GG vs. GC/CC = 1.21, 95% CI, 1.02-1.45; P = 0.031; OR AA vs. AG/GG = 1.53, 95% CI, 1.07-2.18; P = 0.019, respectively). Finally, haplotype-based tests identified significant associations between specific haplotypes in MRE11A and NBS1 genes and breast cancer risk. Further large-scale studies are needed to confirm these results

Nanoparticle-infused-biodegradable-microneedles as drug-delivery systems: preparation and characterisation

For almost two decades, scientists were exploring the use of nanoparticles as drug vesicles capable of protecting their cargo and deliver it to the target site while evading detection by the body. However, their translation to clinical use has been slower than expected. To a large degree, this is due to the difficulty to formulate the nanomaterial into a usable form, in which they retain their unique, size-dependent properties without aggregating into a bulk material. In this work, we describe a simple methodology for synthesising novel biodegradable microneedle systems infused with silica nanoparticles (SiNP). SiNP were doped with small library of model anti-cancer drugs or drug surrogates before being characterised and encapsulated into biodegradable microneedles. Detailed preparation and characterisation methods for both the nanoparticles and the microneedles-infused with nanoparticles is presented here. We demonstrated the distribution of the nanoparticles within the microneedle matrix in a uniform, un-aggregated form, which enabled the release of the nanoparticles in a sustained manner. Formulating nanomaterial into biodegradable, hydrogel-like microneedles showed to be effective in preserving their colloidal properties, whilst simultaneously enabling the transdermal delivery of the nanomaterial into the body. Although the concepts of nanoparticles and biodegradable microneedles have been researched individually, the combination of the two, to the best of our knowledge, offers a new pathway to nanomedicine-related applications

Nanomedicines and microneedles: a guide to their analysis and application

The fast-advancing progress in the research of nanomedicine and microneedles application in the past two decades have suggested that the combination of the two concepts could help to overcome some of the challenges we are facing in healthcare. These include poor patient compliance with medication and the lack of appropriate administration forms that enable the optimal dose to reach the target site. Nanoparticles as drug vesicles can protect their cargo and deliver it to the target site, while evading the body’s defence mechanisms. Unfortunately, despite intense research on nanomedicine in the past 20 years, we still haven’t answered some crucial questions, e.g. about their colloidal stability in solution and their optimal formulation, which makes the translation of this exciting technology from lab bench to a viable product difficult. Dissolvable microneedles could be an effective way to maintain and stabilise nano-sized formulations, whilst enhancing the ability of nanoparticles to penetrate the stratum corneum barrier. Both concepts have been individually investigated fairly well and many analytical techniques for tracking the fate of the nanomaterial with their precious cargo, both in vitro and in vivo, have been established. Yet, to the best of our knowledge, a comprehensive overview of the analytical tools encompassing the concepts of microneedles and nanoparticles with specific and successful examples is missing. In this review, we have attempted to briefly analyse the challenges associated with nanomedicine itself but crucially, we provide an easy-to-navigate scheme of methods, suitable for characterisation and imaging the physico-chemical properties of the material matrix

Detection of cell surface calreticulin as a potential cancer biomarker using near-infrared emitting gold nanoclusters

Calreticulin (CRT) is a cytoplasmic calcium-binding protein. The aim of this study was to investigate CRT presence in cancer with the use of fluorescent gold nanoclusters (AuNCs) and to explore AuNC synthesis using mercaptosuccinic acid (MSA) as a coating agent. MSA-coated AuNCs conferred well-dispersed, bio-stable, water-soluble nanoparticles with bioconjugation capacity and 800-850 nm fluorescence after broad-band excitation. Cell-viability assay revealed good AuNC tolerability. A native CRT amino-terminus corresponding peptide sequence was synthesised and used to generate rabbit site-specific antibodies. Target specificity was demonstrated with antibody blocking in colorectal and breast cancer cell models; human umbilical vein endothelial cells served as controls. We demonstrated a novel route of AuNC/MSA manufacture and CRT presence on colonic and breast cancerous cell surface. AuNCs served as fluorescent bio-probes specifically recognising surface-bound CRT. These results are promising in terms of AuNC application in cancer theranostics and CRT use as surface biomarker in human cancer

Therapeutic enhancement of a cytotoxic agent using Photochemical internalisation in 3D compressed collagen constructs of ovarian cancer

Photochemical internalisation (PCI) is a method for enhancing delivery of drugs to their intracellular target sites of action. In this study we investigated the efficacy of PCI using a porphyrin photosensitiser and a cytotoxic agent on spheroid and non-spheroid compressed collagen 3D constructs of ovarian cancer versus conventional 2D culture. The therapeutic responses of two human carcinoma cell lines (SKOV3 and HEY) were compared using a range of assays including optical imaging. The treatment was shown to be effective in non-spheroid constructs of both cell lines causing a significant and synergistic reduction in cell viability measured at 48 or 96 hours post-illumination. In the larger spheroid constructs, PCI was still effective but required higher saporin and photosensitiser doses. Moreover, in contrast to the 2D and non-spheroid experiments, where comparable efficacy was found for the two cell lines, HEY spheroid constructs were found to be more susceptible to PCI and a lower dose of saporin could be used. PCI treatment was observed to induce death principally by apoptosis in the 3D constructs compared to the mostly necrotic cell death caused by PDT. At low oxygen levels (1%) both PDT and PCI were significantly less effective in the constructs