The Experts below are selected from a list of 132 Experts worldwide ranked by ideXlab platform

Haifa Shen - One of the best experts on this subject based on the ideXlab platform.

  • Abstract 5697: Multistage vectored nanotherapeutics of breast cancer lung metastasis
    Cancer Research, 2012
    Co-Authors: Haifa Shen
    Abstract:

    Breast cancer metastasis to remote organs is the major cause of cancer death. Although significant progresses have been made on survival of patients with Stage I-III breast cancer, the situation with breast cancer metastasis is discouraging. Nanotechnology has played an important role in the fight against breast cancer in the last decade. The first nano-liposomal formulation of doxorubicin (Dox), Doxil, was FDA approved in 1994, and is currently used to treat multiple cancer types including recurrent and refractory breast cancers. More nano-formulated drugs have since been approved. These nanotherapeutics work based on the enhanced permeability and retention (EPR) Effect, and still cause severe toxicity to the body, however. To overcome these defects of the first generation of nanotherapeutics, we have developed a silicon-based multistage vector (MSV) system with the aim to specifically delivery drugs to cancer tissues with the least toxicity to the normal organs. We have demonstrated highly reproducible therapeutic efficacy with this system to deliver the conventional chemotherapy drugs and siRNA oligos in nanoparticles. We have generated mouse lung metastasis models with the human breast cancer cell line MDA-MB-231 which was engineered with a luciferase gene, and used multiple doxorubicin formulations to treat the tumor mice. These included free doxorubicin (3 mg/kg weekly), Doxil (6 mg/kg biweekly), a doxorubicin prodrug (proDox, 6 mg/kg biweekly), and proDox in MSV (MSV/proDox, 6 mg/kg biweekly). Tumor growth in the lung was monitored by bioluminescence with a Xenogen IVIS200 optical in vivo imaging system. As expected, treatment with free Dox caused significant weight loss indicating drug toxicity, most likely to the heart. Tumor growth in the free Dox treatment group halted initially, but resumed two weeks later. The tumor cells in these animals might have developed resistance to Dox during the treatment. Doxil treatment also triggered weight loss initially. This correlates with reduced the Cardiac Side Effect of the drug observed in clinic comparing to free Dox. Neither proDox nor MSV/proDox caused weight loss. Fifty percent of the untreated mice died of lung metastasis by 11 weeks. The free Dox- and proDox-treated mice extended life by 2 weeks. Half of Doxil-treated mice died by 15 weeks, when all MSV/proDox-treated mice have survived. These results indicate that we have developed a powerful system for tumor-specific delivery of therapeutic in the treatment of breast cancer metastasis. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5697. doi:1538-7445.AM2012-5697

  • P1-15-03: Multistage Vectored Nanotherapeutics for Breast Cancer Metastasis.
    Cancer Research, 2011
    Co-Authors: Haifa Shen
    Abstract:

    Significant progresses have been made on overall survival rates in breast cancer. The five-year survival rate of women diagnosed with Stage I-III breast cancer has been steadily improving decades over decades. These improvements in survival have primarily been attributed to availability of modern diagnostic tools that allow for early detection, and the increased use of adjuvant systemic therapies. However, the situation with breast cancer metastasis is discouraging, with only marginal improvement in some reports to no improvement at all in other studies in survival of the relapsed metastatic patients. More breast cancer patients are killed by cancer metastasis than by the primary cancer. Nanotechnology has played an important role in the fight against breast cancer in the last decade. The first nano-liposomal formulation of doxorubicin (Dox), Doxil, was FDA approved in 1994, and is currently used to treat multiple cancer types including recurrent and refractory breast cancers. More nano-formulated drugs have since been approved. These nanotherapeutics work based on the enhanced permeability and retention (EPR) Effect, and still cause severe toxicity to the body, however. To overcome these defects of the first generation of nanotherapeutics, we have developed a silicon-based multistage vector (MSV) system with the aim to specifically delivery drugs to cancer tissues with the least toxicity to the normal organs. These are particle-in-particle “Russian Doll” systems with each stage designed to provide transport across a set of sequential biological barriers, and provide associated levels of targeting specificity. We have demonstrated highly reproducible therapeutic efficacy with this system to deliver the conventional chemotherapy drugs and siRNA oligos. We have generated mouse lung metastasis models with the human breast cancer cell line MDA-MB-231 which was engineered with a luciferase gene, and used multiple doxorubicin formulations to treat the tumor mice. These included free doxorubicin (3 mg/kg weekly), Doxil (6 mg/kg biweekly), a new formulation of doxorubicin in micelles (miDox, 6 mg/kg biweekly), and miDox in MSV (MSV/Dox, 6 mg/kg biweekly). Tumor growth in the lung was monitored by bioluminescence with a Xenogen IVIS200 optical in vivo imaging system. As expected, treatment with free Dox caused significant weight loss indicating drug toxicity, most likely to the heart. Tumor growth in the free Dox treatment group halted initially, but resumed two weeks later. The tumor cells in these animals might have developed resistance to Dox during the treatment. Doxil treatment also triggered weight loss initially. This correlates with the Cardiac Side Effect of the drug observed in clinic. Neither miDox or MSV/Dox caused weight loss. Tumor growth was also inhibited in mice treated with both formulations. The result was much more significant with MSV/Dox than with miDox. No tumor cells were observed in the lung after a 6-week treatment with MSV/Dox, while 40% of the miDox-treated mice still had residue, but detectable tumor cells in the lung. These results indicate that we have developed a powerful system for tumor-specific delivery of therapeutic in the treatment of breast cancer metastasis. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P1-15-03.

James J. Hickman - One of the best experts on this subject based on the ideXlab platform.

  • A phenotypic in vitro model for the main determinants of human whole heart function.
    Biomaterials, 2015
    Co-Authors: Maria Stancescu, Peter Molnar, Christopher W. Mcaleer, William Mclamb, Christopher J. Long, Carlota Oleaga, Jean-matthieu Prot, James J. Hickman
    Abstract:

    This article details the construction and testing of a phenotypic assay system that models in vivo Cardiac function in a parallel in vitro environment with human stem cell derived cardiomyocytes. The major determinants of human whole-heart function were experimentally modeled by integrating separate 2D cellular systems with BioMicroelectromechanical Systems (BioMEMS) constructs. The model features a serum-free defined medium to enable both acute and chronic evaluation of drugs and toxins. The integration of data from both systems produced biologically relevant predictions of Cardiac function in response to varying concentrations of selected drugs. Sotalol, norepinephrine and verapamil were shown to affect the measured parameters according to their specific mechanism of action, in agreement with clinical data. This system is applicable for Cardiac Side Effect assessment, general toxicology, efficacy studies, and evaluation of in vitro cellular disease models in body-on-a-chip systems.

  • Patterned Cardiomyocytes on Microelectrode Arrays as a Functional, High Information Content Drug Screening Platform
    Biomaterials, 2011
    Co-Authors: Anupama Natarajan, Maria Stancescu, James J. Hickman, Vipra Dhir, Christopher Armstrong, Frank Sommerhage, Peter Molnar
    Abstract:

    Cardiac Side Effects are one of the major causes of drug candidate failures in preclinical drug development or in clinical trials and are responsible for the retraction of several already marketed therapeutics. Thus, the development of a relatively high-throughput, high information content tool to screen drugs and toxins would be important in the field of Cardiac research and drug development. In this study, recordings from commercial multielectrode arrays were combined with surface patterning of Cardiac myocyte monolayers to enhance the information content of the method; specifically, to enable the measurement of conduction velocity, refractory period after action potentials and to create a functional re-entry model. Two drugs, 1-Heptanol, a gap junction blocker, and Sparfloxacin, a fluoroquinone antibiotic, were tested in this system. 1-Heptanol administration resulted in a marked reduction in conduction velocity, whereas Sparfloxacin caused rapid, irregular and unsynchronized activity, indicating fibrillation. As shown in these experiments, patterning of Cardiac myocyte monolayers solved several inherent problems of multielectrode recordings, increased the temporal resolution of conduction velocity measurements, and made the synchronization of external stimulation with action potential propagation possible for refractory period measurements. This method could be further developed as a Cardiac Side Effect screening platform after combination with human cardiomyocytes.

Hansguenter Zerwes - One of the best experts on this subject based on the ideXlab platform.

Maria Stancescu - One of the best experts on this subject based on the ideXlab platform.

  • A phenotypic in vitro model for the main determinants of human whole heart function.
    Biomaterials, 2015
    Co-Authors: Maria Stancescu, Peter Molnar, Christopher W. Mcaleer, William Mclamb, Christopher J. Long, Carlota Oleaga, Jean-matthieu Prot, James J. Hickman
    Abstract:

    This article details the construction and testing of a phenotypic assay system that models in vivo Cardiac function in a parallel in vitro environment with human stem cell derived cardiomyocytes. The major determinants of human whole-heart function were experimentally modeled by integrating separate 2D cellular systems with BioMicroelectromechanical Systems (BioMEMS) constructs. The model features a serum-free defined medium to enable both acute and chronic evaluation of drugs and toxins. The integration of data from both systems produced biologically relevant predictions of Cardiac function in response to varying concentrations of selected drugs. Sotalol, norepinephrine and verapamil were shown to affect the measured parameters according to their specific mechanism of action, in agreement with clinical data. This system is applicable for Cardiac Side Effect assessment, general toxicology, efficacy studies, and evaluation of in vitro cellular disease models in body-on-a-chip systems.

  • Patterned Cardiomyocytes on Microelectrode Arrays as a Functional, High Information Content Drug Screening Platform
    Biomaterials, 2011
    Co-Authors: Anupama Natarajan, Maria Stancescu, James J. Hickman, Vipra Dhir, Christopher Armstrong, Frank Sommerhage, Peter Molnar
    Abstract:

    Cardiac Side Effects are one of the major causes of drug candidate failures in preclinical drug development or in clinical trials and are responsible for the retraction of several already marketed therapeutics. Thus, the development of a relatively high-throughput, high information content tool to screen drugs and toxins would be important in the field of Cardiac research and drug development. In this study, recordings from commercial multielectrode arrays were combined with surface patterning of Cardiac myocyte monolayers to enhance the information content of the method; specifically, to enable the measurement of conduction velocity, refractory period after action potentials and to create a functional re-entry model. Two drugs, 1-Heptanol, a gap junction blocker, and Sparfloxacin, a fluoroquinone antibiotic, were tested in this system. 1-Heptanol administration resulted in a marked reduction in conduction velocity, whereas Sparfloxacin caused rapid, irregular and unsynchronized activity, indicating fibrillation. As shown in these experiments, patterning of Cardiac myocyte monolayers solved several inherent problems of multielectrode recordings, increased the temporal resolution of conduction velocity measurements, and made the synchronization of external stimulation with action potential propagation possible for refractory period measurements. This method could be further developed as a Cardiac Side Effect screening platform after combination with human cardiomyocytes.

Peter Molnar - One of the best experts on this subject based on the ideXlab platform.

  • A phenotypic in vitro model for the main determinants of human whole heart function.
    Biomaterials, 2015
    Co-Authors: Maria Stancescu, Peter Molnar, Christopher W. Mcaleer, William Mclamb, Christopher J. Long, Carlota Oleaga, Jean-matthieu Prot, James J. Hickman
    Abstract:

    This article details the construction and testing of a phenotypic assay system that models in vivo Cardiac function in a parallel in vitro environment with human stem cell derived cardiomyocytes. The major determinants of human whole-heart function were experimentally modeled by integrating separate 2D cellular systems with BioMicroelectromechanical Systems (BioMEMS) constructs. The model features a serum-free defined medium to enable both acute and chronic evaluation of drugs and toxins. The integration of data from both systems produced biologically relevant predictions of Cardiac function in response to varying concentrations of selected drugs. Sotalol, norepinephrine and verapamil were shown to affect the measured parameters according to their specific mechanism of action, in agreement with clinical data. This system is applicable for Cardiac Side Effect assessment, general toxicology, efficacy studies, and evaluation of in vitro cellular disease models in body-on-a-chip systems.

  • Patterned Cardiomyocytes on Microelectrode Arrays as a Functional, High Information Content Drug Screening Platform
    Biomaterials, 2011
    Co-Authors: Anupama Natarajan, Maria Stancescu, James J. Hickman, Vipra Dhir, Christopher Armstrong, Frank Sommerhage, Peter Molnar
    Abstract:

    Cardiac Side Effects are one of the major causes of drug candidate failures in preclinical drug development or in clinical trials and are responsible for the retraction of several already marketed therapeutics. Thus, the development of a relatively high-throughput, high information content tool to screen drugs and toxins would be important in the field of Cardiac research and drug development. In this study, recordings from commercial multielectrode arrays were combined with surface patterning of Cardiac myocyte monolayers to enhance the information content of the method; specifically, to enable the measurement of conduction velocity, refractory period after action potentials and to create a functional re-entry model. Two drugs, 1-Heptanol, a gap junction blocker, and Sparfloxacin, a fluoroquinone antibiotic, were tested in this system. 1-Heptanol administration resulted in a marked reduction in conduction velocity, whereas Sparfloxacin caused rapid, irregular and unsynchronized activity, indicating fibrillation. As shown in these experiments, patterning of Cardiac myocyte monolayers solved several inherent problems of multielectrode recordings, increased the temporal resolution of conduction velocity measurements, and made the synchronization of external stimulation with action potential propagation possible for refractory period measurements. This method could be further developed as a Cardiac Side Effect screening platform after combination with human cardiomyocytes.