Subcellular Targeting of Theranostic Radionuclides

The last decade has seen rapid growth in the use of theranostic radionuclides for the treatment and imaging of a wide range of cancers. Radionuclide therapy and imaging rely on a radiolabeled vector to specifically target cancer cells. Radionuclides that emit β particles have thus far dominated the field of targeted radionuclide therapy (TRT), mainly because the longer range (μm–mm track length) of these particles offsets the heterogeneous expression of the molecular target. Shorter range (nm–μm track length) α- and Auger electron (AE)-emitting radionuclides on the other hand provide high ionization densities at the site of decay which could overcome much of the toxicity associated with β-emitters. Given that there is a growing body of evidence that other sensitive sites besides the DNA, such as the cell membrane and mitochondria, could be critical targets in TRT, improved techniques in detecting the subcellular distribution of these radionuclides are necessary, especially since many β-emitting radionuclides also emit AE. The successful development of TRT agents capable of homing to targets with subcellular precision demands the parallel development of quantitative assays for evaluation of spatial distribution of radionuclides in the nm–μm range. In this review, the status of research directed at subcellular targeting of radionuclide theranostics and the methods for imaging and quantification of radionuclide localization at the nanoscale are described

Metallointercalator [Ru(dppz)2(PIP)]2+ Renders BRCA Wild-Type Triple-Negative Breast Cancer Cells Hypersensitive to PARP Inhibition

There is a need to improve and extend the use of clinically-approved poly(ADP-ribose) polymerase (PARP) inhibitors (PARPi), including for BRCA wild-type triple-negative breast cancer (TNBC). The demonstration that ruthenium(II) polypyridyl complex (RPC) metallo-intercalators can rapidly stall DNA replication fork progression provides the rationale for their combination alongside DNA damage response (DDR) inhibitors to achieve synergism in cancer cells. The aim of the present study was to evaluate use of the multi-intercalator [Ru(dppz)2(PIP)]2+ (dppz = dipyrido[3,2-a:2′,3′-c]phenazine, PIP = (2-(phenyl)imidazo[4,5-f][1,10]phenanthroline, Ru-PIP) alongside the PARP inhibitors (PARPi) olaparib and NU1025. Cell proliferation and clonogenic survival assays indicated a synergistic relationship between Ru-PIP and olaparib in MDA-MB-231 TNBC and MCF7 human breast cancer cells. Strikingly, low dose Ru-PIP renders both cell lines hypersensitive to olaparib, with a 300-fold increase in olaparib potency in TNBC; the largest non-genetic PARPi enhancement effect described to date. Negligible impact on the viability of normal human fibroblasts was observed for any combination tested. Increased levels of DNA double-strand break (DSB) damage and olaparib abrogation of Ru-PIP activated pChk1 signalling is consistent with PARPi-facilitated collapse of Ru-PIP-associated stalled replication forks. This results in enhanced G2/M cell-cycle arrest, apoptosis and decreased cell motility for the combination treatment compared to single-agent conditions. This work establishes that an RPC metallo-intercalator can be combined with PARPi for potent synergy in BRCA-proficient breast cancer cells, including TNBC

111In-labelled polymeric nanoparticles incorporating a ruthenium-based radiosensitizer for EGFR-targeted combination therapy in oesophageal cancer cells

Radiolabelled, drug-loaded nanoparticles may combine the theranostic properties of radionuclides, the controlled release of chemotherapy and cancer cell targeting. Here, we report the preparation of poly(lactic-co-glycolic acid) (PLGA) nanoparticles surface conjugated to DTPA-hEGF (DTPA = diethylenetriaminepentaacetic acid, hEGF = human epidermal growth factor) and encapsulating the ruthenium-based DNA replication inhibitor and radiosensitizer Ru(phen)2(tpphz)2+ (phen = 1,10-phenanthroline, tpphz = tetrapyridophenazine) Ru1. The functionalized PLGA surface incorporates the metal ion chelator DTPA for radiolabelling and the targeting ligand for EGF receptor (EGFR). Nanoparticles radiolabelled with 111In are taken up preferentially by EGFR-overexpressing oesophageal cancer cells, where they exhibit radiotoxicity through the generation of cellular DNA damage. Moreover, nanoparticle co-delivery of Ru1 alongside 111In results in decreased cell survival compared to single-agent formulations; an effect that occurs through DNA damage enhancement and an additive relationship between 111In and Ru1. Substantially decreased uptake and radiotoxicity of nanoparticles towards normal human fibroblasts and oesophageal cancer cells with normal EGFR levels is observed. This work demonstrates nanoparticle co-delivery of a therapeutic radionuclide plus a ruthenium-based radiosensitizer can achieve combinational and targeted therapeutic effects in cancer cells that overexpress EGFR

Estrategias organizativas y didácticas para atender a la diversidad: una mirada desde el dirección escolar

Desde o início dos anos 90, as escolas têm registrado um crescimento significativo de estudantes imigrantes (até 9,53%), alunos com necessidades educativas especiais, alunos com diferenças de gênero, habilidade e cultura, chegando a ser uma característica da maioria das escolas o seu carácter diversificado. O presente artigo descreve uma pesquisa qualitativa realizada em uma educação infantil e primária considerada como promotor das boas práticas para o desenvolvimento de estratégias e didáticas para atender à diversidade. Para este fim, foi realizado um estudo de caso no referido centro, utilizando como instrumentos entrevistas, observações e análise de documentos com foco neste artigo, com o objetivo de analisar e apresentar boas práticas de gestão da diversidade pela direção escolar, particularmente aquelas que são referência em estratégias educacionais e organizacionais para lidar com a diversidade dos alunos. Os resultados mostram diferentes estratégias organizacionais e didátias ao nível da escola e da sala de aula, atendendo à diversidade dos alunos, tais como a organização de apoio, envolvimento da família na sala de aula ou o desenvolvimento de grupos interativos. As conclusões giram em torno da importância de a equipe diretora promover uma cultura organizacional que considere estratégias didáticas e organizacionais que respondam às necessidades de todos os alunos

Myocardial infarction risk and tamoxifen therapy for breast cancer

Tamoxifen prevents recurrence after breast cancer and breast cancer among high-risk women, and may prevent myocardial infarction (MI). To assess the impact of tamoxifen on MI risk, we conducted a case–control study of first MI after breast cancer nested among women diagnosed with breast cancer, while enrolled in a health maintenance organisation from 1980 to 2000. We obtained information on breast cancer treatment and MI risk factors through medical record reviews and interviews. Data were analysed using conditional logistic regression. Of 11 045 women with breast cancer, 134 met MI criteria and were matched to two MI-free control subjects on year of birth and breast cancer diagnosis. After adjusting for smoking, hypertension and diabetes, tamoxifen was unassociated with MI (odds ratio (OR)=1.2, 95% confidence interval (CI)=0.7–1.9). Duration, cumulative dose and recency of use were not associated with MI. Radiation therapy was associated with MI (OR=2.0, 95% CI=1.1–3.5), an association that varied slightly but not statistically significantly by tamoxifen use (radiation with tamoxifen, OR=2.0, 95% CI=0.9–4.4; radiation without tamoxifen, OR=2.9, 95% CI=1.2–7.5). Tamoxifen treatment for breast cancer does not appear to increase or decrease MI risk, although radiation therapy appears to increase MI risk

International challenges without borders: a descriptive study of family physicians' educational needs in the field of diabetes

<p>Abstract</p> <p>Background</p> <p>The optimal care of persons with diabetes by general practitioners and family physicians (GP/FP) is complex and requires multiple competencies. This is a fairly unrecognized key challenge in the healthcare systems. In some cases, local and national Continuous Professional Development (CPD) initiatives target these challenges; however there have been few international initiatives, possibly because challenges emerging from different studies have not been linked across national boundaries. In this context, the authors have compiled data about gaps and/or barriers inherent to GP/FP care of persons with type 2 diabetes from Austria, Canada, Germany and the United Kingdom.</p> <p>Methods</p> <p>Secondary analyzes of pre-existing studies were conducted to identify challenges in the care of patients with type 2 diabetes as faced by GPs/FPs. Two sources of data were reviewed: unpublished research data from collaborating organizations and articles from a literature search (in English and German). Articles retrieved were scanned by the research team for relevance to the study objectives and to extract existing gaps and barriers. The identified challenges were then categorized along three major axes: (1) phase of the continuum of care {from screening to management}; (2) learning domain {knowledge, skills, attitudes, behavior, context}; and (3) by country/region. Compilation and categorization were performed by qualitative researchers and discrepancies were resolved through discussion until concordance was achieved.</p> <p>Results and discussion</p> <p>Thirteen challenges faced by GPs/FPs in the care for patients with type 2 diabetes were common in at least 3 of the 4 targeted countries/regions. These issues were found across the entire continuum of care and included: pathophysiology of diabetes, diagnostic criteria, treatment targets assessment, drugs' modes of action, decision-making in therapies, treatment guidelines, insulin therapy, adherence, management of complications, lifestyle changes, team integration, bureaucracy and third-party payers. The issues reported were not restricted to the physicians' knowledge, but also related to their skills, attitudes, behaviours and context.</p> <p>Conclusions</p> <p>This study revealed challenges faced by GPs/FPs when caring for patients with diabetes, which were similar across international and health system borders. Common issues might be addressed more efficiently through international educational designs, adapted to each country's healthcare system, helping develop and maintain physicians' competencies.</p

Molecular radiotherapy using cleavable radioimmunoconjugates that target eGFR and γH2AX

Many anticancer therapies, including ionizing radiation (IR), cause cytotoxicity through generation ofDNA double-strand breaks (DSB). Delivery of therapeutic radionuclides to DNA DSB sites can amplify this DNA damage, for additional therapeutic gain. Herein,wereport on two radiopharmaceuticals, radiolabeled with the Auger electron emitter 111In, with dual specificity for both the intranuclear, DNA damage repair signaling protein γH2AX and the EGF receptor (EGFR). The EGFR ligand EGF was conjugated to a fluorophore- or 111In-labeled anti-γH2AX antibody, linked via a nuclear localization sequence (NLS) to ensure nuclear translocation. EGF conjugation was achieved either through a noncleavable PEG linker (PEO6) or a cleavable disulfide bond. Both conjugates selectively bound EGFR on fixed cells and γH2AX in cell extracts. Both compounds enter EGFR-expressing cells in an EGF/EGFR-dependent manner. However, only the cleavable compound was seen to associate with γH2AX foci in the nuclei of irradiated cells. Intracellular retention of the cleavable compound was prolonged in γH2AX-expressing cells. Clonogenic survival was significantly reduced when cells were exposed to IR (to induce γH2AX) plus 111In-labeled cleavable compound compared to either alone and compared to nonspecific controls. In vivo, uptake of 111In-labeled cleavable compound in MDA-MB-468 xenografts in athymic mice was 2.57 ± 0.47 percent injected dose/g (%ID/Υ) but increased significantly to 6.30 ± 1.47%ID/g in xenografts where γH2AX was induced by IR (P &lt; 0.01). This uptake was dependent on EGF/EGFR and anti-γH2AX/γH2AX interactions. We conclude that tumor-specific delivery of radiolabeled antibodies directed against intranuclear epitopes is possible using cleavable antibody-peptide conjugates. Mol Cancer Ther; 12(11); 2472-82. © 2013 AACR