Pharmacological development of target-specific delocalized lipophilic cation-functionalized carboranes for cancer therapy

PURPOSE: Tumor cell heterogeneity and microenvironment represent major hindering factors in the clinical setting toward achieving the desired selectivity and specificity to malignant tissues for molecularly targeted cancer therapeutics. In this study, the cellular and molecular evaluation of several delocalized lipophilic cation (DLC)-functionalized carborane compounds as innovative anticancer agents is presented. METHODS: The anticancer potential assessment of the DLC-carboranes was performed in established normal (MRC-5, Vero), cancer (U-87 MG, HSC-3) and primary glioblastoma cancer stem (EGFRpos, EGFRneg) cultures. Moreover, the molecular mechanism of action underlying their pharmacological response is also analyzed. RESULTS: The pharmacological anticancer profile of DLC-functionalized carboranes is characterized by: a) a marked in vitro selectivity, due to lower concentration range needed (ca. 10 fold) to exert their cell growth-arrest effect on U-87 MG and HSC-3, as compared with that on MRC-5 and Vero; b) a similar selective growth inhibition behavior towards EGFRpos and EGFRneg cultures (>10 fold difference in potency) without, however, the activation of apoptosis in cultures; c) notably, in marked contrast to cancer cells, normal cells are capable of recapitulating their full proliferation potential following exposure to DLC-carboranes; and, d) such pharmacological effects of DLC-carboranes has been unveiled to be elicited at the molecular level through activation of the p53/p21 axis. CONCLUSIONS: Overall, the data presented in this work indicates the potential of the DLC-functionalized carboranes to act as new selective anticancer therapeutics that may be used autonomously or in therapies involving radiation with thermal neutrons. Importantly, such bifunctional capacity may be beneficial in cancer therapy

Biomedical informatics and translational medicine

Biomedical informatics involves a core set of methodologies that can provide a foundation for crossing the "translational barriers" associated with translational medicine. To this end, the fundamental aspects of biomedical informatics (e.g., bioinformatics, imaging informatics, clinical informatics, and public health informatics) may be essential in helping improve the ability to bring basic research findings to the bedside, evaluate the efficacy of interventions across communities, and enable the assessment of the eventual impact of translational medicine innovations on health policies. Here, a brief description is provided for a selection of key biomedical informatics topics (Decision Support, Natural Language Processing, Standards, Information Retrieval, and Electronic Health Records) and their relevance to translational medicine. Based on contributions and advancements in each of these topic areas, the article proposes that biomedical informatics practitioners ("biomedical informaticians") can be essential members of translational medicine teams

Development of a nanoporous and multilayer drug-delivery platform for medical implants

Biodegradable polymers can be applied to a variety of implants for controlled and local drug delivery. The aim of this study is to develop a biodegradable and nanoporous polymeric platform for a wide spectrum of drug-eluting implants with special focus on stent-coating applications. It was synthesized by poly(DL-lactide-co-glycolide) (PLGA 65:35, PLGA 75:25) and polycaprolactone (PCL) in a multilayer configuration by means of a spin-coating technique. The antiplatelet drug dipyridamole was loaded into the surface nanopores of the platform. Surface characterization was made by atomic force microscopy (AFM) and spectroscopic ellipsometry (SE). Platelet adhesion and drug-release kinetic studies were then carried out. The study revealed that the multilayer films are highly nanoporous, whereas the single layers of PLGA are atomically smooth and spherulites are formed in PCL. Their nanoporosity (pore diameter, depth, density, surface roughness) can be tailored by tuning the growth parameters (eg, spinning speed, polymer concentration), essential for drug-delivery performance. The origin of pore formation may be attributed to the phase separation of polymer blends via the spinodal decomposition mechanism. SE studies revealed the structural characteristics, film thickness, and optical properties even of the single layers in the triple-layer construct, providing substantial information for drug loading and complement AFM findings. Platelet adhesion studies showed that the dipyridamole-loaded coatings inhibit platelet aggregation that is a prerequisite for clotting. Finally, the films exhibited sustained release profiles of dipyridamole over 70 days. These results indicate that the current multilayer phase therapeutic approach constitutes an effective drug-delivery platform for drug-eluting implants and especially for cardiovascular stent applications. © 2012 Cárdenas et al, publisher and licensee Dove Medical Press Ltd

Development of a nanoporous and multilayer drug-delivery platform for medical implants

Varvara Karagkiozaki,1 Eleftherios Vavoulidis,1 Panagiotis G Karagiannidis,1 Maria Gioti,1 Dimitrios G Fatouros,2 Ioannis S Vizirianakis,3 Stergios Logothetidis11Lab for Thin Films–Nanosystems and Nanometrology, Physics Department, 2Department of Pharmaceutical Technology, 3Laboratory of Pharmacology, School of Pharmacy, Aristotle University of Thessaloniki, GreeceAbstract: Biodegradable polymers can be applied to a variety of implants for controlled and local drug delivery. The aim of this study is to develop a biodegradable and nanoporous polymeric platform for a wide spectrum of drug-eluting implants with special focus on stent-coating applications. It was synthesized by poly(DL-lactide-co-glycolide) (PLGA 65:35, PLGA 75:25) and polycaprolactone (PCL) in a multilayer configuration by means of a spin-coating technique. The antiplatelet drug dipyridamole was loaded into the surface nanopores of the platform. Surface characterization was made by atomic force microscopy (AFM) and spectroscopic ellipsometry (SE). Platelet adhesion and drug-release kinetic studies were then carried out. The study revealed that the multilayer films are highly nanoporous, whereas the single layers of PLGA are atomically smooth and spherulites are formed in PCL. Their nanoporosity (pore diameter, depth, density, surface roughness) can be tailored by tuning the growth parameters (eg, spinning speed, polymer concentration), essential for drug-delivery performance. The origin of pore formation may be attributed to the phase separation of polymer blends via the spinodal decomposition mechanism. SE studies revealed the structural characteristics, film thickness, and optical properties even of the single layers in the triple-layer construct, providing substantial information for drug loading and complement AFM findings. Platelet adhesion studies showed that the dipyridamole-loaded coatings inhibit platelet aggregation that is a prerequisite for clotting. Finally, the films exhibited sustained release profiles of dipyridamole over 70 days. These results indicate that the current multilayer phase therapeutic approach constitutes an effective drug-delivery platform for drug-eluting implants and especially for cardiovascular stent applications.Keywords: drug delivery, implants, stents, polymers, spin-coating, atomic force microscop

Pharmacogenetics, the next challenge for pharmacy?

This commentary draws attention to and raises awareness of forthcoming pharmacogenetic technologies amongst the pharmacy profession. It aims to stimulate debate around the potential role that the pharmacy profession can play in the introduction of pharmacogenetic technologies into primary healthcare. This commentary discusses potential new roles for pharmacists involving pharmacogenetic technologies, giving attention to the way the profession may need to adapt to accommodate these

Exploration of the perceptions, barriers and drivers of pharmacogenomics practice among hospital pharmacists in Adelaide, South Australia

There is little literature regarding the barriers to the uptake of pharmacogenomics (PG) in pharmacy practice, especially with respect to Australia. To date, pharmacists have seldom been engaged in discussions of these issues. This study aimed to obtain an in-depth understanding of these barriers by interviewing pharmacists in Adelaide, South Australia. Ethics approved semistructured interviews were carried out with 21 public hospital pharmacists. Analysis of the data identified themes including: confidence to engage in PG, clinician acceptance of a pharmacist PG role, and the importance of timely and relevant PG education. Interviewees thought that pharmacists could have a greater participation in PG in the future, but they questioned whether this would be possible at the moment given, among other factors, existing time and work constraintsMM Dias, HM Ward, MJ Sorich, and RA McKinno

A role for atm in E-cadherin-mediated contact inhibition in epithelial cells

Ataxia telangiectasia is a hereditary pleiomorphic syndrome caused by loss of Atm, a phosphoprotein involved in multiple signaling pathways. Here, we propose a novel role for atm in cultured epithelial cells, namely the regulation of cell growth by contact inhibition. We show that atm is upregulated in epithelial cells reaching confluence. Conditional expression of the PI 3-Kinase domain of atm in non-confluent Tac-2 epithelial cells increases the expression of the anti-proliferative gene Tis-21 and downregulates key cell cycle regulator genes, such as cyclins A, B1, B2, E and E2. Finally, we demonstrate that upregulation of atm, and thus Tis-21, in confluent Tac-2 cells can be inhibited by an E-cadherin antibody blocking specifically homophilic E-cadherin interactions between adjacent cell surfaces. Altogether, these results suggest that atm could participate in a molecular pathway linking extracellular signalling to cell cycle control and may help further clarify the role of Atm in epithelial cell biology and carcinogenesis