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ConCept: de Novo Design of Synthetic Receptors for Targeted Ligands.

Development of agents for imaging and radiotherapy involves identification of biological process and target underlying the pathology as well as respective lead compound. Then the radioactive lead compound counterpart must be designed, chemically characterized as well as preclinically and clinically validated. In particular, the specific targeting and pre-targeted imaging require information on biomarkers and is dependent on their discovery. Thus, advances in biological research and biotechnology are crucial. Proteomics and genomics considerably contribute to the expansion due to the increasing knowledge and access to the vectors and targets such as receptors, enzymes, antigens as well as their ligands and substrates. Proteins demonstrate remarkable capability of molecular recognition. Advances in genetic and biochemical techniques resulted in a large number of antibody radioimmunotherapeutics. That in turn triggered further development with the objective to overcome the drawbacks related to antibody high molecular weight, slow pharmacokinetics and clearance that cause high radiation dose to normal tissue and poor image contrast. Thus, large libraries of high affinity small proteins have been created using combinatorial engineering and phage display techniques that provide efficient screening of ligands as well as identification and selection of antibodies and receptors for drug discovery and therapy. A number of non-immunoglobulin scaffolds has also been studied that resulted in libraries as, for example Affibody® molecules originating from Z domain scaffold of staphylococcal protein A. Thirteen surface-exposed residues of the scaffold were randomized resulting in a library (3x109 members) of high-affinity binders to various targets []. Radiolabelled Affibody molecules have extensively been investigated preclinically, and 68Ga- and 111In-labelled analogues with high affinity to HER2 receptors up-regulated in breast cancer has also been studied in patients []. This is a strong evidence for the future fruitful development of engineered high affinity proteins and abundant source of ligands to various receptors expressed in diseased tissues.

(Note that absent vitamin K from malabsorption also prevents synthesis of II, VII, IX, and X.) Monitor all this by following the prothrombin times (rather than PTT, since factor VII is first to go and to return).

Synthesis of [C-11]-granisetron as a possible PET ligand for the 5-HT3 receptor.

H., His6 tag-assisted chemical protein synthesis.

“Synthesis of [C-11]-granisetron as a Possible PET Ligand for the 5-HT3 Receptor.” .

Antibodies are proteins with special Y- shapes. They can specifically recognize and bind to antigens in both the recognition phase (cellular receptors) and during the effectors phase (synthesis and secretion) of humoral immunity. Active targeting by monoclonal antibodies (mAbs) combined with SPION is a promising technology for magnetic resonance imaging.

Monosaccharides have been used as targeting ligands for sensing proteins and bacteria. A versatile approach for the immobilization of unmodified monosaccharides onto SPIONs was reported by Yan team []. Covalent coupling of D-mannose onto SPIONs by using CH insertion reaction of photochemically activated phosphate-functionalized perfluorophenylazides (PFPAs) resulted in glyco-NPs. The surface-bound D-mannose had mannose-specific receptor and showed the recognition ability toward and strain ORN178. These studies imply that the carbohydrate-conjugated SPIONs might be useful in clinical diagnosis, sensing and decontamination.

18 F-FPP: A PET Ligand for the 5-HT 2C Receptor?

(DOTANOC - DOTA-1-Nal3-octreotide; SSTR - somatostatin receptor; NETs - neuroendocrine tumors; * - first in human study; AMBA - DO3A-CH2CO-G-4-aminobenzoyl-Q-W-A-V-G-H-L-M-NH2; GRP - Gastrin releasing peptide; NMB - Neuromedin B; BPAMD - ((4-{[bis-(phosphonomethyl)) carbamoyl]methyl}-7,10 bis(carboxymethyl)-1,4,7,10-tetraazacyclododec-1-yl)acetic acid; MAA - macro aggregated albumin; FDG - fluorodeoxyglucose; JR 10 - somatostatin receptor antagonist (Courtesy Helmut Maecke, Basel, Switzerland); MSH - melanocyte stimulating hormone; RGD - arginine-glycine-aspartic acid; HER-2 - human epidermal growth factor receptor 2; SHAL - selective high affinity ligand; DOTATOC - DOTA-D-Phe1-Tyr3-octreotide; PRRNT - peptide receptor radionuclide therapy)

T1 - Synthesis and in vivo evaluation of a PET radioligand for imaging the endothelin-A receptor

The study of semiconductor nanocrystals (NCs) is a very active research field, due to the wide range of applications, related to light-emission and absorption, photodetection, solar cells, light emitting diode or tunable emitters for bio-labeling1. One area is the development of detection techniques with high spatial resolution enabled by the small size of nanomaterials. As a representative example, nanometer probes of temperature can be very useful to obtain an accurate local value of temperature, particularly in catalysis where the activity and selectivity are temperature dependent. The key is to obtain the value of the local temperature inside the solution or inside the solid at the surface of the reactants. Certain catalytic reactions require high temperatures to occur so another challenge is to build a high local temperature probe (> 373 K). In this context, semiconductor NCs are promising objects to provide this precision due to the temperature dependence of their optical properties. We present here the synthesis of different types of NCs (Cd3P22, InP@ZnS3 and CdSe@CdS4), their capacities as nanothermometers for high temperatures (>340 K) and the conditions which have to be fullfilled for accurate measurements. Different parameters such as the wavelength, the intensity, the area and the full width at half maximum of emission were studied as a function of temperature. The studied temperatures ranges from room temperature to 540 K and the comparison between the different NCs is discussed.

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A PET Ligand for the 5-HT 2C Receptor

Cold-Activated Brown Adipose Tissue in Healthy Men — …

Peptides are one of the commonly employed targeting ligands for cell labeling applications. RGD peptides, cell penetrating and nuclear localizing signaling peptides are mostly used to coat the NPs for increased cell uptake via receptor-mediated endocytosis.

Program | 6th World Congress and Expo on …

5. Hofmann M, Maecke H, Borner R. . Biokinetics and imaging with the somatostatin receptor PET radioligand (68)Ga-DOTATOC: preliminary data. 2001;28:1751-7

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Our group has been actively involved in the synthesis of QDs and magnetic QDs (MQDs) [-]. We have successfully demonstrated the magnetic and fluorescent properties of Fe2O3-CdSe MQDs, silica -coated QDs or MQDs and their application in cell labeling (Figure ) []. The silanization using aminopropyl triethoxysilane (APS) in a reverse microemulsion produced thin silica coating on bare CdSe QDs or Fe2O3-CdSe MQD with surface NH2 groups. The methoxy groups of APS were hydrolyzed and condensed with another APS, exposing surface amine groups on the silanized QDs (SiO2/QDs) for conjugation with oleyl-O-poly(ethyleneglycol)-succinyl-N-hydroxysuccinimidyl ester, denoted as bio-anchored membrane (BAM). The reaction between the amine group and NHS ester resulted in a covalent amide bond formation, leaving the exposed oleyl group for the effective targeting of cell membrane. The labeling of live cell membranes (HepG2 human liver cancer cells and NIH-3T3 mouse fibroblast cells) using confocal laser scanning microscopy (CLSM) indicated the successful conjugation of silica-coated QDs or MQDs with BAM.

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Theranostics in nuclear medicine has manifested in pre-therapeutic diagnosis for PRRT. In this context the diagnosis and radiotherapy are conducted with the same ligand labelled respectively with imaging radionuclide, e.g. 68Ga and therapeutic one, e.g. 177Lu (Figure B). The radiopharmaceuticals bind to tumour-type specific receptors enabling personalized approach of accurate quantitative diagnosis and staging for subsequent selection and planning of therapeutic means as well as monitoring response to the treatment. The dosimetry estimation prior to PRRT is one of the most important prerequisites of successful treatment, and the higher spatial resolution and inherent quantitative accuracy of 68Ga/PET are of paramount importance for the dosimetry precision and treatment response evaluation. The common perception is that 68Ga is not applicable for the pre-therapeutic dosimetry due to the short half-life of 68Ga (68 min) mismatching that of therapeutic radionuclides 90Y (64 h) and 117Lu (6.71 d), and consequently resulting in different time windows of the pharmacokinetics. However, e.g. in the case of somatostatin analogues their fast pharmacokinetics may enable the utilization of kinetic analysis of 68Ga-labelled peptide for the prediction of radiation doses during PRRT with the 177Lu-labelled analogue. This might be accomplished by the combination of the respective agents, namely by either co-injection or separate use of 68Ga- and 177Lu-labelled peptides. The high accuracy at early time points could be achieved by 68Ga/PET quantitation with an error of less than 5% since the tracer accumulation in the organs at risk reaches its maximum within 2-3 half-lives of 68Ga []. The kinetics at later time points could be obtained by either blood sampling during the radiotherapy with 177Lu-labelled analogue or by imaging gammas emitted by 177Lu. The dual-tracer examination is possible since the gamma energy of 177Lu is outside the PET detection window and thus would not interfere with 68Ga/PET-CT quantitation. Such combination of the tracers would provide highly improved internal dosimetry.

ERBB2 Gene - GeneCards | ERBB2 Protein | ERBB2 …

Zhang reported PEG coated SPIONs for both MRI and optical imaging. The biocompatible PEG coating bearing amine functional group could serve as a platform to incorporate a variety of targeting, therapeutic or imaging ligands []. In this case, chlorotoxin was conjugated to PEG@SPION and Cy5.5 (a near-infrared fluorescent dye). These SPIONs have shown specifically to accumulate in xenograft tumors of a brain tumor mouse model. Furthermore, they did not have any toxicity or negative health effects from the results of histopathology and blood toxicity assays. Huang and coworkers have designed hyaluronic acid (HA) coated SPIONs for targeting activated macrophages []. The HA-coated SPIONs had specific biological recognition with the receptor CD44. The cell uptake studies showed a significant uptake of SPIONs by activated macrophage cell line THP-1 and enabled MRI of THP-1 cells. The dual modal probes could be used to track the magnetite core and cargo individually. The magnetite core was only present inside the cells while the cargo fluorescein was found to be delivered to the cell nucleus. This study reveals the fact that the HA-based SPIONs have great potential in nucleus targeting drug delivery.

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