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Pharmaceuticals, Volume 5, Issue 1 (January 2012), Pages 1-113

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Research

Jump to: Review

Open AccessArticle Pre-Clinical Assessment of 177Lu-Labeled Trastuzumab Targeting HER2 for Treatment and Management of Cancer Patients with Disseminated Intraperitoneal Disease
Pharmaceuticals 2012, 5(1), 1-15; doi:10.3390/ph5010001
Received: 4 November 2011 / Revised: 6 December 2011 / Accepted: 14 December 2011 / Published: 22 December 2011
Cited by 12 | PDF Full-text (422 KB) | HTML Full-text | XML Full-text
Abstract
Studies from this laboratory have demonstrated the potential of targeting HER2 for therapeutic and imaging applications with medically relevant radionuclides. To expand the repertoire of trastuzumab as a radioimmunoconjugate (RIC) vector, use of 177Lu was investigated. The combination of a 6.7 d
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Studies from this laboratory have demonstrated the potential of targeting HER2 for therapeutic and imaging applications with medically relevant radionuclides. To expand the repertoire of trastuzumab as a radioimmunoconjugate (RIC) vector, use of 177Lu was investigated. The combination of a 6.7 d half-life, lower energy β-emissions (500 keV max; 130 keV ave), and an imagable γ-emission make 177Lu an attractive candidate for radioimmunotherapy (RIT) regimens for treatment of larger tumor burdens not possible with α-particle radiation. Radiolabeling trastuzumab-CHX-A″-DTPA with 177Lu was efficient with a specific binding of 60.8 ± 6.8% with HER2 positive SKOV-3 cells. Direct quantitation of tumor targeting and normal tissue uptake was performed with athymic mice bearing subcutaneous and intraperitoneal LS-174T xenografts; a peak tumor %ID/g of 24.70 ± 10.29 (96 h) and 31.70 ± 16.20 (72 h), respectively, was obtained. Normal tissue uptake of the RIC was minimal. Tumor targeting was also demonstrated by γ-scintigraphy. A therapy study administering escalating doses of 177Lu-trastuzumab to mice bearing three day LS-174T i.p. xenografts established the effective therapeutic dose of i.p. administered 177Lu-trastuzumab at 375 μCi with a median survival of 124.5 d while a median survival of 10 d was noted for the control (untreated) group. In conclusion, trastuzumab radiolabeled with 177Lu has potential for treatment of disseminated, HER2 positive, peritoneal disease. Full article
(This article belongs to the Special Issue Antibody Conjugates)
Open AccessArticle Anti-HCV RNA Aptamers Targeting the Genomic cis-Acting Replication Element
Pharmaceuticals 2012, 5(1), 49-60; doi:10.3390/ph5010049
Received: 28 November 2011 / Revised: 15 December 2011 / Accepted: 22 December 2011 / Published: 28 December 2011
Cited by 3 | PDF Full-text (456 KB) | HTML Full-text | XML Full-text
Abstract
Hepatitis C virus (HCV) replication is dependent on the existence of several highly conserved functional genomic RNA domains. The cis-acting replication element (CRE), located within the 3' end of the NS5B coding region of the HCV genome, has been shown essential for
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Hepatitis C virus (HCV) replication is dependent on the existence of several highly conserved functional genomic RNA domains. The cis-acting replication element (CRE), located within the 3' end of the NS5B coding region of the HCV genome, has been shown essential for efficient viral replication. Its sequence and structural features determine its involvement in functional interactions with viral RNA-dependent RNA polymerase and distant RNA domains of the viral genome. This work reports the use of an in vitro selection strategy to select aptamer RNA molecules against the complete HCV-CRE. After six selection cycles, five potential target sites were identified within this domain. Inhibition assays using a sample of representative aptamers showed that the selected RNAs significantly inhibit the replication (>80%) of a subgenomic HCV replicon in Huh-7 cell cultures. These results highlight the potential of aptamer RNA molecules as therapeutic antiviral agents. Full article
(This article belongs to the Special Issue Aptamer-Based Therapeutics)
Open AccessArticle 89Zr-Radiolabeled Trastuzumab Imaging in Orthotopic and Metastatic Breast Tumors
Pharmaceuticals 2012, 5(1), 79-93; doi:10.3390/ph5010079
Received: 16 November 2011 / Revised: 14 December 2011 / Accepted: 22 December 2011 / Published: 5 January 2012
Cited by 22 | PDF Full-text (699 KB) | HTML Full-text | XML Full-text
Abstract
The human epidermal growth factor receptor 2 (HER2/neu) is overexpressed in 20–30% of breast cancers and is associated with tumor growth, angiogenesis, and development of distant metastases. Trastuzumab, an anti-HER2 monoclonal antibody, is used for the treatment of HER2 positive breast cancer and
[...] Read more.
The human epidermal growth factor receptor 2 (HER2/neu) is overexpressed in 20–30% of breast cancers and is associated with tumor growth, angiogenesis, and development of distant metastases. Trastuzumab, an anti-HER2 monoclonal antibody, is used for the treatment of HER2 positive breast cancer and clinical efficacy of this agent is dependent on HER2 expression. Targeted PET imaging of HER2 with radiolabeled trastuzumab may be used to determine HER2 expression levels and guide therapy selection. The purpose of the current study was to evaluate a facile 89Zr-trastuzumab preparation method that can be efficiently applied for clinical grade production. Also, relative HER2 expression levels in orthotopic and metastatic breast cancer models were assessed by PET imaging using the 89Zr-trastuzumab produced by this simpler method. Full article
(This article belongs to the Special Issue Biologics)

Review

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Open AccessReview New Strategies to Develop Novel Pain Therapies: Addressing Thermoreceptors from Different Points of View
Pharmaceuticals 2012, 5(1), 16-48; doi:10.3390/ph5010016
Received: 16 November 2011 / Revised: 16 December 2011 / Accepted: 21 December 2011 / Published: 27 December 2011
Cited by 5 | PDF Full-text (1565 KB) | HTML Full-text | XML Full-text
Abstract
One approach to develop successful pain therapies is the modulation of dysfunctional ion channels that contribute to the detection of thermal, mechanical and chemical painful stimuli. These ion channels, known as thermoTRPs, promote the sensitization and activation of primary sensory neurons known as
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One approach to develop successful pain therapies is the modulation of dysfunctional ion channels that contribute to the detection of thermal, mechanical and chemical painful stimuli. These ion channels, known as thermoTRPs, promote the sensitization and activation of primary sensory neurons known as nociceptors. Pharmacological blockade and genetic deletion of thermoTRP have validated these channels as therapeutic targets for pain intervention. Several thermoTRP modulators have progressed towards clinical development, although most failed because of the appearance of unpredicted side effects. Thus, there is yet a need to develop novel channel modulators with improved therapeutic index. Here, we review the current state-of-the art and illustrate new pharmacological paradigms based on TRPV1 that include: (i) the identification of activity-dependent modulators of this thermoTRP channel; (ii) the design of allosteric modulators that interfere with protein-protein interaction involved in the functional coupling of stimulus sensing and gate opening; and (iii) the development of compounds that abrogate the inflammation-mediated increase of receptor expression in the neuronal surface. These new sites of action represent novel strategies to modulate pathologically active TRPV1, while minimizing an effect on the TRPV1 subpopulation involved in physiological and protective roles, thus increasing their potential therapeutic use. Full article
(This article belongs to the Special Issue Emerging Pain Targets and Therapy)
Figures

Open AccessReview Potential Use of Polyamidoamine Dendrimer Conjugates with Cyclodextrins as Novel Carriers for siRNA
Pharmaceuticals 2012, 5(1), 61-78; doi:10.3390/ph5010061
Received: 31 October 2011 / Revised: 20 December 2011 / Accepted: 21 December 2011 / Published: 30 December 2011
Cited by 11 | PDF Full-text (572 KB) | HTML Full-text | XML Full-text
Abstract
Cyclodextrin (CyD)-based nanoparticles and polyamidoamine (PAMAM) starburst dendrimers (dendrimers) are used as novel carriers for DNA and RNA. Recently, small interfering RNA (siRNA) complex with β-CyD-containing polycations (CDP) having adamantine-PEG or adamantine-PEG-transferrin underwent a phase I study for treatment of solid tumors. Multifunctional
[...] Read more.
Cyclodextrin (CyD)-based nanoparticles and polyamidoamine (PAMAM) starburst dendrimers (dendrimers) are used as novel carriers for DNA and RNA. Recently, small interfering RNA (siRNA) complex with β-CyD-containing polycations (CDP) having adamantine-PEG or adamantine-PEG-transferrin underwent a phase I study for treatment of solid tumors. Multifunctional dendrimers can be used for a wide range of biomedical applications, including the interaction and intracellular delivery of DNA and RNA. The present review will address the latest developments in dendrimer conjugates with cyclodextrins for siRNA delivery including the novel sustained release system. Full article
(This article belongs to the Special Issue RNAi-Based Therapeutics)
Figures

Open AccessReview DNA Methylation as Clinically Useful Biomarkers—Light at the End of the Tunnel
Pharmaceuticals 2012, 5(1), 94-113; doi:10.3390/ph5010094
Received: 6 December 2011 / Revised: 10 January 2012 / Accepted: 11 January 2012 / Published: 18 January 2012
Cited by 21 | PDF Full-text (225 KB) | HTML Full-text | XML Full-text
Abstract
A recent expansion of our knowledge about epigenetic changes strongly suggests that epigenetic rather than genetic features better reflect disease development, and consequently, can become more conclusive biomarkers for the detection and diagnosis of different diseases. In this paper we will concentrate on
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A recent expansion of our knowledge about epigenetic changes strongly suggests that epigenetic rather than genetic features better reflect disease development, and consequently, can become more conclusive biomarkers for the detection and diagnosis of different diseases. In this paper we will concentrate on the current advances in DNA methylation studies that demonstrate a direct link between abnormal DNA methylation and a disease. This link can be used to develop diagnostic biomarkers that will precisely identify a particular disease. It also appears that disease-specific DNA methylation patterns undergo unique changes in response to treatment with a particular drug, thus raising the possibility of DNA methylation-based biomarkers for the monitoring of treatment efficacy, for prediction of response to treatment, and for the prognosis of outcome. While biomarkers for oncology are the most obvious applications, other fields of medicine are likely to benefit as well. This potential is demonstrated by DNA methylation-based biomarkers for neurological and psychiatric diseases. A special requirement for a biomarker is the possibility of longitudinal testing. In this regard cell-free circulating DNA from blood is especially interesting because it carries methylation markers specific for a particular disease. Although only a few DNA methylation-based biomarkers have attained clinical relevance, the ongoing efforts to decipher disease-specific methylation patterns are likely to produce additional biomarkers for detection, diagnosis, and monitoring of different diseases in the near future. Full article
(This article belongs to the Special Issue Epigenetic Therapies and Biomarkers)

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