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

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

Peroxisome proliferator-activated receptor gamma-2 P12A polymorphism and risk of acute myocardial infarction, coronary heart disease and ischemic stroke: A case-cohort study and meta-analyses

The alanine allele of P12A polymorphism in PPARG gene in a few studies has been associated with a reduced or increased risk of acute myocardial infarction (AMI). Yet, the risk relation has not been confirmed, and data on ischemic stroke (IS) is scarce. We therefore investigated the role of this polymorphism on occurrence of AMI, coronary heart disease (CHD) and IS. We performed a case-cohort study in 15,236 initially healthy Dutch women and applied a Cox proportional hazards model to study the relation of the P12A polymorphism and AMI (n = 71), CHD (n = 211), and IS (n = 49) under different inheritance models. In addition, meta-analyses of published studies were performed. Under the dominant inheritance model, carriers of the alanine allele compared with those with the more common genotype were not at increased or decreased risk of CHD (hazard ratio [HR] = 0.82; 95% confidence interval [CI], 0.58 to 1.17) and of IS (HR = 1.03; 95% CI, 0.14 to 7.74). In addition no relations were found under the recessive and additive models. Our meta-analyses corroborated these findings by showing no significant association. For AMI we found a borderline significant association under dominant (HR = 0.49; 95% CI, 0.26 to 0.94), and additive (HR = 0.51; 95% CI, 0.26 to 1.00) models which could be due to chance, because of small cases in this subgroup. The meta-analysis did not show any association between the polymorphism and risk of AMI under the different genetic models. Our study in healthy Dutch women in combination with the meta-analyses of previous reports does not provide support for a role of P12A polymorphism in PPARG gene in MI and CHD risk. Also our study shows that the polymorphism has no association with IS ris

Cetuximab-Ag₂S quantum dots for fluorescence imaging and highly effective combination of ALA-based photodynamic/chemo-therapy of colorectal cancer cells

Colorectal cancer (CRC) has a poor prognosis and urgently needs better therapeutic approaches. 5-Aminolevulinic acid (ALA) induced protoprophyrin IX (PpIX) based photodynamic therapy (PDT) is already approved in the clinic for several cancers but not yet well investigated for CRC. Currently, systemic administration of ALA offers a limited degree of tumour selectivity, except for intracranial tumours, limiting its wider use in the clinic. Combination of effective ALA-PDT with chemotherapy may provide a promising alternative approach for CRC treatment. Herein, theranostic Ag2S quantum dots (AS-2MPA) optically trackable in near-infrared (NIR), conjugated with endothelial growth factor receptor (EGFR) targeting Cetuximab (Cet) and loaded with ALA for PDT monotherapy or ALA/5-fluorouracil (5FU) for the combination therapy is proposed for enhanced treatment of EGFR(+) CRC. AS-2MPA-Cet endowed excellent targeting of the high EGFR expressing cells and showed a strong intracellular signal for NIR optical detection in a comparative study performed on SW480, HCT116, and HT29 cells, which are high, medium and low EGFR expressers. Targeting provided enhanced uptake of the ALA loaded nanoparticles by strong EGFR expressing cells and formation of higher levels of PpIX. Cells also differ in their efficiency to convert ALA to PpIX, and SW480 was the best, followed by HT29, while HCT116 were determined as unsuitable for ALA-PDT. The therapeutic efficacy was evaluated in 2D cell cultures and 3D spheroids of SW480 and HT29 cells using AS-2MPA with either electrostatically loaded, hydrazone or amide linked ALA to achieve different levels of pH or enzyme sensitive release. Most effective phototoxicity was observed in SW480 cells using AS-2MPA-ALA-electrostatic-Cet due enhanced uptake of the particles, fast ALA release and effective ALA-to-PpIX conversion. Targeted delivery reduced the effective ALA concentration significantly which was further reduced with codelivery of 5FU. Delivery of ALA via covalent linkage was also effective for PDT, but required longer incubation time for the release of ALA in therapeutic doses. Phototoxicity was correlated with high levels of reactive oxygen species (ROS) and apoptotic/necrotic cell death. Hence, both AS-2MPA-ALA-Cet based PDT and AS-2MPA-ALA-Cet-5FU based Chemo/PDT combination therapy coupled with strong NIR tracking of the nanoparticles demonstrate an exceptional therapeutic effect on CRC cells and an excellent potential for synergistic multistage tumour targeting therapy

Liquid metal embrittlement in laser lap joining of TWIP and medium-manganese TRIP steel: The role of stress and grain boundaries

The final publication is available at Elsevier via https://dx.doi.org/10.1016/j.matchar.2018.09.018 © 2018. This manuscript version is made available under the CC-BY-NC-ND 4.0 license https://creativecommons.org/licenses/by-nc-nd/4.0/High-Manganese austenite-containing steels with superior combination of strength and ductility have shown potential for enhancement of passenger safety and body-in-white (BIW) weight reduction. Even though Zn-coated austenitic steels have improved corrosion resistance, they are highly susceptible to liquid metal embrittlement (LME) during welding. The present work is aimed to address LME susceptibility during restrained laser lap joining of high-Mn twinning induced plasticity (TWIP) and medium-Mn transformation induced plasticity (MMn-TRIP) steels. Electron probe micro-analysis (EPMA) results showed that stress-assisted diffusion of Zn into the austenite grain boundaries and further liquid Zn formation by a peritectic reaction lead to grain boundary decohesion. Electron backscatter diffraction (EBSD) results demonstrated that high angle and special grain boundaries are prone to Zn-penetration within the heat-affected-zone (HAZ). Additionally, LME sensitivity was observed to be highly dependent on the magnitude of applied stress.Natural Sciences and Engineering Research Council of Canad

Minería metálica a cielo abierto

[No abstract available

Photobactericidal activity activated by thiolated gold nanoclusters at low flux levels of white light

The emergence of antibiotic resistant bacteria is a major threat to the practice of modern medicine. Photobactericidal agents have obtained significant attention as promising candidates to kill bacteria, and they have been extensively studied. However, to obtain photobactericidal activity, an intense white light source or UV-activation is usually required. Here we report a photobactericidal polymer containing crystal violet (CV) and thiolated gold nanocluster ([Au25(Cys)18]) activated at a low flux levels of white light. It was shown that the polymer encapsulated with CV do not have photobactericidal activity under white light illumination of an average 312 lux. However, encapsulation of [Au25(Cys)18] and CV into the polymer activates potent photobactericidal activity. The study of the photobactericidal mechanism shows that additional encapsulation of [Au25(Cys)18] into the CV treated polymer promotes redox reactions through generation of alternative electron transfer pathways, while it reduces photochemical reaction type-ІІ pathways resulting in promotion of hydrogen peroxide (H2O2) production