A Selective Carborane-Functionalized Gastrin-Releasing Peptide Receptor Agonist as Boron Delivery Agent for Boron Neutron Capture Therapy.

Boron neutron capture therapy (BNCT) allows the selective elimination of malignant tumor cells without affecting healthy tissue. Although this binary radiotherapy approach has been known for decades, BNCT failed to reach the daily clinics to date. One of the reasons is the lack of selective boron delivery agents. Using boron loaded peptide conjugates, which address G protein-coupled receptors overexpressed on tumor cells allow the intracellular accumulation of boron. The gastrin-releasing peptide receptor (GRPR) is a well-known target in cancer diagnosis and can potentially be used for BNCT. Here, we present the successful introduction of multiple bis-deoxygalactosyl-carborane building blocks to the GRPR-selective ligand [d-Phe6, ß-Ala11, Ala13, Nle14]Bn(6-14) (sBB2L) generating peptide conjugates with up to 80 boron atoms per molecule. Receptor activation was retained, metabolic stability was increased, and uptake into PC3 cells was proven without showing any intrinsic cytotoxicity. Furthermore, undesired uptake into liver cells was suppressed by using l-deoxygalactosyl modified carborane building blocks. Due to its high boron loading and excellent GRPR selectivity, this conjugate can be considered as a promising boron delivery agent for BNCT.

Selective Neuropeptide Y Conjugates with Maximized Carborane Loading as Promising Boron Delivery Agents for Boron Neutron Capture Therapy.

G-protein-coupled receptors like the human Y1 receptor (hY1R) are promising targets in cancer therapy due to their high overexpression on cancer cells and their ability to internalize together with the bound ligand. This mechanism was exploited to shuttle boron atoms into cancer cells for the application of boron neutron capture therapy (BNCT), a noninvasive approach to eliminate cancer cells. A maximized number of carboranes was introduced to the hY1R-preferring ligand [F7,P34]-NPY by solid phase peptide synthesis. Branched conjugates loaded with up to 80 boron atoms per peptide molecule exhibited a maintained receptor activation profile, and the selective uptake into hY1R-expressing cells was demonstrated by internalization studies. In order to ensure appropriate solubility in aqueous solution, we proved the need for eight hydroxyl groups per carborane. Thus, we suggest the utilization of bis-deoxygalactosyl-carborane building blocks in solid phase peptide synthesis to produce selective boron delivery agents for BNCT.

Fluorescently labeled adrenomedullin allows real-time monitoring of adrenomedullin receptor trafficking in living cells.

The human adrenomedullin (ADM) is a 52 amino acid peptide hormone belonging to the calcitonin family of peptides, which plays a major role in the development and regulation of cardiovascular and lymphatic systems. For potential use in clinical applications, we aimed to investigate the fate of the peptide ligand after binding and activation of the adrenomedullin receptor (AM1), a heterodimer consisting of the calcitonin receptor-like receptor (CLR), a G protein-coupled receptor, associated with the receptor activity-modifying protein 2 (RAMP2). Full length and N-terminally shortened ADM peptides were synthesized using Fmoc/tBu solid phase peptide synthesis and site-specifically labeled with the fluorophore carboxytetramethylrhodamine (Tam) either by amide bond formation or copper(I)-catalyzed azide alkyne cycloaddition. For the first time, Tam-labeled ligands allowed the observation of co-internalization of the whole ligand-receptor complex in living cells co-transfected with fluorescent fusion proteins of CLR and RAMP2. Application of a fluorescent probe to track lysosomal compartments revealed that ADM together with the CLR/RAMP2-complex is routed to the degradative pathway. Moreover, we found that the N-terminus of ADM is not a crucial component of the peptide sequence in terms of AM1 internalization behavior.

[The critical incident reporting system (CIRS) as a measure to improve quality in medicine]. / Das Critical Incident Reporting System (CIRS) als Mittel zur Qualitätsverbesserung in der Medizin.

It may be seen as regrettable that a measure which is suitable for improvement of quality in medicine is broadly discussed only in the context of risk avoidance. The system of reporting adverse events (incidents), known under its internationally used term CIRS, is based on the observation that there is a close correlation between the occurrence of severe incidents with consequences and milder incidents or near misses without consequences. By avoiding mild incidents the severe incidents will automatical also be reduced. In contrast to a classic analysis of mistakes and errors the consequence itself only plays a minor role with CIRS. In Germany mistakes are usually seen under the aspects of a personal responsibility and they are prone to sanctions. But only when mistakes are accepted as occurring everywhere and with everybody and when they are regarded under the aspect of how to be avoided in future the necessary transparency can grow and an open dealing with mistakes can arise. This enables analyses with the only goal of quality improvement by avoidance of mistakes.

[Influence of the reimbursement system on medical quality]. / Einfluss von Vergütungssystemen auf die medizinische Qualität.

BACKGROUND: The relationship between reimbursement for medical care and the quality of medicine is mostly discussed if there are warnings about underuse as a consequence of underpayment. By various examples it can be illustrated that not only a lack of services but also an overuse of medical care may be hazardous and reduce quality in medicine. This relates to the risk, which is part of each medical intervention. PRESENT SITUATION: The introduction of the Diagnosis Related Groups (DRGs) in Germany is at present mostly discussed under the aspect of a possible risk of underuse. On the other hand, there are chances for the quality of medicine as a result from a lean diagnostic and therapy, which will be the consequence of economic changes induced by the DRGs. A guideline-oriented medicine will often avoid unnecessary procedures and thereby improve the quality of medical services. CONCLUSION: Loss of quality and improvement of quality arise in the field of medicine from overuse as well as from underuse. Most important for an optimal quality is a quantitatively appropriate treatment. In general, we observe that medical decisions are more and more oriented on economic frames. It has to be observed during forthcoming years to what extent ethical problems arise by this situation.