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Pharmaceuticals, Volume 7, Issue 3 (March 2014) – 7 articles , Pages 220-365

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532 KiB  
Article
Folate Receptor Targeted Alpha-Therapy Using Terbium-149
by Cristina Müller, Josefine Reber, Stephanie Haller, Holger Dorrer, Ulli Köster, Karl Johnston, Konstantin Zhernosekov, Andreas Türler and Roger Schibli
Pharmaceuticals 2014, 7(3), 353-365; https://doi.org/10.3390/ph7030353 - 13 Mar 2014
Cited by 63 | Viewed by 8709
Abstract
Terbium-149 is among the most interesting therapeutic nuclides for medical applications. It decays by emission of short-range α-particles (Eα = 3.967 MeV) with a half-life of 4.12 h. The goal of this study was to investigate the anticancer efficacy of a 149 [...] Read more.
Terbium-149 is among the most interesting therapeutic nuclides for medical applications. It decays by emission of short-range α-particles (Eα = 3.967 MeV) with a half-life of 4.12 h. The goal of this study was to investigate the anticancer efficacy of a 149Tb-labeled DOTA-folate conjugate (cm09) using folate receptor (FR)-positive cancer cells in vitro and in tumor-bearing mice. 149Tb was produced at the ISOLDE facility at CERN. Radiolabeling of cm09 with purified 149Tb resulted in a specific activity of ~1.2 MBq/nmol. In vitro assays performed with 149Tb-cm09 revealed a reduced KB cell viability in a FR-specific and activity concentration-dependent manner. Tumor-bearing mice were injected with saline only (group A) or with 149Tb-cm09 (group B: 2.2 MBq; group C: 3.0 MBq). A significant tumor growth delay was found in treated animals resulting in an increased average survival time of mice which received 149Tb-cm09 (B: 30.5 d; C: 43 d) compared to untreated controls (A: 21 d). Analysis of blood parameters revealed no signs of acute toxicity to the kidneys or liver in treated mice over the time of investigation. These results demonstrated the potential of folate-based α-radionuclide therapy in tumor-bearing mice. Full article
(This article belongs to the Special Issue Radiopharmaceutical Chemistry between Imaging and Radioendotherapy)
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868 KiB  
Article
Synthesis and Preliminary Evaluation of a 2-Oxoquinoline Carboxylic Acid Derivative for PET Imaging the Cannabinoid Type 2 Receptor
by Linjing Mu, Roger Slavik, Adrienne Müller, Kasim Popaj, Stjepko Čermak, Markus Weber, Roger Schibli, Stefanie D. Krämer and Simon M. Ametamey
Pharmaceuticals 2014, 7(3), 339-352; https://doi.org/10.3390/ph7030339 - 06 Mar 2014
Cited by 17 | Viewed by 7331
Abstract
Cannabinoid receptor subtype 2 (CB2) has been shown to be up-regulated in activated microglia and therefore plays an important role in neuroinflammatory and neurodegenerative diseases such as multiple sclerosis, amyotrophic lateral sclerosis and Alzheimer’s disease. The CB2 receptor is therefore considered as a [...] Read more.
Cannabinoid receptor subtype 2 (CB2) has been shown to be up-regulated in activated microglia and therefore plays an important role in neuroinflammatory and neurodegenerative diseases such as multiple sclerosis, amyotrophic lateral sclerosis and Alzheimer’s disease. The CB2 receptor is therefore considered as a very promising target for therapeutic approaches as well as for imaging. A promising 2-oxoquinoline derivative designated KP23 was synthesized and radiolabeled and its potential as a ligand for PET imaging the CB2 receptor was evaluated. [11C]KP23 was obtained in 10%–25% radiochemical yield (decay corrected) and 99% radiochemical purity. It showed high stability in phosphate buffer, rat and mouse plasma. In vitro autoradiography of rat and mouse spleen slices, as spleen expresses a high physiological expression of CB2 receptors, demonstrated that [11C]KP23 exhibits specific binding towards CB2. High spleen uptake of [11C]KP23 was observed in dynamic in vivo PET studies with Wistar rats. In conclusion, [11C]KP23 showed promising in vitro and in vivo characteristics. Further evaluation with diseased animal model which has higher CB2 expression levels in the brain is warranted. Full article
(This article belongs to the Special Issue Radiopharmaceutical Chemistry between Imaging and Radioendotherapy)
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211 KiB  
Review
Radiolabeled Cetuximab Conjugates for EGFR Targeted Cancer Diagnostics and Therapy
by Wiebke Sihver, Jens Pietzsch, Mechthild Krause, Michael Baumann, Jörg Steinbach and Hans-Jürgen Pietzsch
Pharmaceuticals 2014, 7(3), 311-338; https://doi.org/10.3390/ph7030311 - 05 Mar 2014
Cited by 56 | Viewed by 10640
Abstract
The epidermal growth factor receptor (EGFR) has evolved over years into a main molecular target for the treatment of different cancer entities. In this regard, the anti-EGFR antibody cetuximab has been approved alone or in combination with: (a) chemotherapy for treatment of colorectal [...] Read more.
The epidermal growth factor receptor (EGFR) has evolved over years into a main molecular target for the treatment of different cancer entities. In this regard, the anti-EGFR antibody cetuximab has been approved alone or in combination with: (a) chemotherapy for treatment of colorectal and head and neck squamous cell carcinoma and (b) with external radiotherapy for treatment of head and neck squamous cell carcinoma. The conjugation of radionuclides to cetuximab in combination with the specific targeting properties of this antibody might increase its therapeutic efficiency. This review article gives an overview of the preclinical studies that have been performed with radiolabeled cetuximab for imaging and/or treatment of different tumor models. A particularly promising approach seems to be the treatment with therapeutic radionuclide-labeled cetuximab in combination with external radiotherapy. Present data support an important impact of the tumor micromilieu on treatment response that needs to be further validated in patients. Another important challenge is the reduction of nonspecific uptake of the radioactive substance in metabolic organs like liver and radiosensitive organs like bone marrow and kidneys. Overall, the integration of diagnosis, treatment and monitoring as a theranostic approach appears to be a promising strategy for improvement of individualized cancer treatment. Full article
(This article belongs to the Special Issue Radiopharmaceutical Chemistry between Imaging and Radioendotherapy)
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299 KiB  
Review
Antimicrobial Peptides from Fish
by Jorge A. Masso-Silva and Gill Diamond
Pharmaceuticals 2014, 7(3), 265-310; https://doi.org/10.3390/ph7030265 - 03 Mar 2014
Cited by 247 | Viewed by 17736
Abstract
Antimicrobial peptides (AMPs) are found widely distributed through Nature, and participate in the innate host defense of each species. Fish are a great source of these peptides, as they express all of the major classes of AMPs, including defensins, cathelicidins, hepcidins, histone-derived peptides, [...] Read more.
Antimicrobial peptides (AMPs) are found widely distributed through Nature, and participate in the innate host defense of each species. Fish are a great source of these peptides, as they express all of the major classes of AMPs, including defensins, cathelicidins, hepcidins, histone-derived peptides, and a fish-specific class of the cecropin family, called piscidins. As with other species, the fish peptides exhibit broad-spectrum antimicrobial activity, killing both fish and human pathogens. They are also immunomodulatory, and their genes are highly responsive to microbes and innate immuno-stimulatory molecules. Recent research has demonstrated that some of the unique properties of fish peptides, including their ability to act even in very high salt concentrations, make them good potential targets for development as therapeutic antimicrobials. Further, the stimulation of their gene expression by exogenous factors could be useful in preventing pathogenic microbes in aquaculture. Full article
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715 KiB  
Review
Lucifensins, the Insect Defensins of Biomedical Importance: The Story behind Maggot Therapy
by Václav Čeřovský and Robert Bém
Pharmaceuticals 2014, 7(3), 251-264; https://doi.org/10.3390/ph7030251 - 27 Feb 2014
Cited by 53 | Viewed by 12756
Abstract
Defensins are the most widespread antimicrobial peptides characterised in insects. These cyclic peptides, 4–6 kDa in size, are folded into α-helical/β-sheet mixed structures and have a common conserved motif of three intramolecular disulfide bridges with a Cys1-Cys4, Cys2-Cys5 and Cys3-Cys6 connectivity. They have [...] Read more.
Defensins are the most widespread antimicrobial peptides characterised in insects. These cyclic peptides, 4–6 kDa in size, are folded into α-helical/β-sheet mixed structures and have a common conserved motif of three intramolecular disulfide bridges with a Cys1-Cys4, Cys2-Cys5 and Cys3-Cys6 connectivity. They have the ability to kill especially Gram-positive bacteria and some fungi, but Gram-negative bacteria are more resistant against them. Among them are the medicinally important compounds lucifensin and lucifensin II, which have recently been identified in the medicinal larvae of the blowflies Lucilia sericata and Lucilia cuprina, respectively. These defensins contribute to wound healing during a procedure known as maggot debridement therapy (MDT) which is routinely used at hospitals worldwide. Here we discuss the decades-long story of the effort to isolate and characterise these two defensins from the bodies of medicinal larvae or from their secretions/excretions. Furthermore, our previous studies showed that the free-range larvae of L. sericata acutely eliminated most of the Gram-positive strains of bacteria and some Gram-negative strains in patients with infected diabetic foot ulcers, but MDT was ineffective during the healing of wounds infected with Pseudomonas sp. and Acinetobacter sp. The bactericidal role of lucifensins secreted into the infected wound by larvae during MDT and its ability to enhance host immunity by functioning as immunomodulator is also discussed. Full article
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Editorial
Acknowledgement to Reviewers of Pharmaceuticals in 2013
by Pharmaceuticals Editorial Office
Pharmaceuticals 2014, 7(3), 248-250; https://doi.org/10.3390/ph7030248 - 27 Feb 2014
Cited by 4 | Viewed by 3662
Abstract
The editors of Pharmaceuticals would like to express their sincere gratitude to the following reviewers for assessing manuscripts in 2013. [...] Full article
614 KiB  
Review
Avian Antimicrobial Host Defense Peptides: From Biology to Therapeutic Applications
by Guolong Zhang and Lakshmi T. Sunkara
Pharmaceuticals 2014, 7(3), 220-247; https://doi.org/10.3390/ph7030220 - 27 Feb 2014
Cited by 95 | Viewed by 12585
Abstract
Host defense peptides (HDPs) are an important first line of defense with antimicrobial and immunomoduatory properties. Because they act on the microbial membranes or host immune cells, HDPs pose a low risk of triggering microbial resistance and therefore, are being actively investigated as [...] Read more.
Host defense peptides (HDPs) are an important first line of defense with antimicrobial and immunomoduatory properties. Because they act on the microbial membranes or host immune cells, HDPs pose a low risk of triggering microbial resistance and therefore, are being actively investigated as a novel class of antimicrobials and vaccine adjuvants. Cathelicidins and β-defensins are two major families of HDPs in avian species. More than a dozen HDPs exist in birds, with the genes in each HDP family clustered in a single chromosomal segment, apparently as a result of gene duplication and diversification. In contrast to their mammalian counterparts that adopt various spatial conformations, mature avian cathelicidins are mostly α-helical. Avian β-defensins, on the other hand, adopt triple-stranded β-sheet structures similar to their mammalian relatives. Besides classical β-defensins, a group of avian-specific β-defensin-related peptides, namely ovodefensins, exist with a different six-cysteine motif. Like their mammalian counterparts, avian cathelicidins and defensins are derived from either myeloid or epithelial origin expressed in a majority of tissues with broad-spectrum antibacterial and immune regulatory activities. Structure-function relationship studies with several avian HDPs have led to identification of the peptide analogs with potential for use as antimicrobials and vaccine adjuvants. Dietary modulation of endogenous HDP synthesis has also emerged as a promising alternative approach to disease control and prevention in chickens. Full article
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