Development and Characterization of a Novel Contrast Agent

Summary

Principal Investigator: Margaret Wheatley
Abstract: DESCRIPTION (provided by applicant): The long-term objective is to develop diagnostic ultrasound contrast agents (CA) to fulfill the diverse needs of the medical community, and provide useful tools for medical and scientific inquiry. An agent of nano dimensions could fulfill an important diagnostic role by gaining access to areas of pathology from which current micron sized agents are excluded. We published data showing we can produce nano CA (CA-N) with a mean size of 450 nm that have excellent imaging properties. Our most recent studies have produced bubbles of 250 nm. Further investigation is planned. Aim 1: Develop methods to produce 10-500 nm diameter CA by adaptation of the current method for micron- sized agent composed of surfactant-stabilized gas bubbles. ST68-N, upon which preliminary studies have been conducted, is one nano-scale agent composed of Span60 and TweenSO stabilizing an insoluble perfluorocarbon gas bubble. Other members of the Span and Tween family of surfactants are available with differing fatty acid tail groups, and other gases such as sulfur hexafluoride. The hypothesis to be tested is that the wall constituents will dictate the packing density and strength of inter-molecular forces around the gas, hence bubble size and stability. Aim 2: Characterize/optimize in vitro stability and echogenicity. Identify key parameters contributing to the echogenicity of CA-N. Aim 3: Develop methods to incorporate disease- state specific targeting molecules into the bubble wall (tCA), and test them against tissue culture. Solid tumor targeting will be the main focus. Three advantages are gained from targeting: fixation increases the local concentration and allows for greater contrast;in vivo lifetime of tCA is increased by sequestration away from pressure, shear forces, and many of the components of the immune system;and pivotal, it enables distinction between malignant and benign. Aim 4: In vivo characterization including dose response, attenuation, backscatter and Doppler enhancement, study both passive and active targeting of tCA and conduct a nonclinical acute toxicity assessment. We hypothesize that our in vitro cell work will allow us to identify key candidates for CA-N and tCA to be tested in vivo. A large percentage of cancers (approximately 85%) involve solid tumors, and roughly 50% of these lead to metastasis and death. A diagnostic tool that could safely and non-invasively detect tumors at an early stage, before metastasis, would be a great advance in health care.
Funding Period: 1994-09-01 - 2010-06-30
more information: NIH RePORT

Top Publications

  1. ncbi Cellular signal transduction can be induced by TRAIL conjugated to microcapsules
    Margaret A Wheatley
    School of Biomedical Engineering, Science and Health Systems, Drexel University, Philadelphia, Pennsylvania 19104, USA
    J Biomed Mater Res A 100:2602-11. 2012
  2. pmc Disposition of ultrasound sensitive polymeric drug carrier in a rat hepatocellular carcinoma model
    Michael C Cochran
    School of Biomedical Engineering Science and Health Systems, Drexel University, Philadelphia, PA, USA
    Acad Radiol 18:1341-8. 2011
  3. pmc Doxorubicin and paclitaxel loaded microbubbles for ultrasound triggered drug delivery
    Michael C Cochran
    School of Biomedical Engineering Science and Health Systems, Drexel University, Philadelphia, PA 19104, United States
    Int J Pharm 414:161-70. 2011
  4. pmc Preserving enhancement in freeze-dried contrast agent ST68: Examination of excipients
    Carl Solis
    School of Biomedical Engineering, Science and Health Systems, Drexel University, 3141 Chestnut St, Philadelphia, PA 19104, United States
    Int J Pharm 396:30-8. 2010
  5. ncbi Nano-sized ultrasound contrast agent: salting-out method
    Margaret A Wheatley
    School of Biomedical Engineering, Science and Health Systems, Drexel University, Philadelphia, PA, USA
    Mol Imaging 9:96-107. 2010
  6. pmc Development and optimization of a doxorubicin loaded poly(lactic acid) contrast agent for ultrasound directed drug delivery
    J R Eisenbrey
    School of Biomedical Engineering, Science and Health Systems, Drexel University, 3141 Chestnut Street, Philadelphia, PA 19104, USA
    J Control Release 143:38-44. 2010
  7. pmc Ultrasound triggered cell death in vitro with doxorubicin loaded poly lactic-acid contrast agents
    J R Eisenbrey
    School of Biomedical Engineering, Science and Health Systems, Drexel University, Philadelphia, PA 19104, United States
    Ultrasonics 49:628-33. 2009
  8. ncbi Preclinical acute toxicology study of surfactant-stabilized ultrasound contrast agents in adult rats
    Flemming Forsberg
    Department of Radiology, Thomas Jefferson University, Philadelphia, PA, USA
    Int J Toxicol 29:32-9. 2010
  9. pmc Plasma sterilization of poly lactic acid ultrasound contrast agents: surface modification and implications for drug delivery
    John R Eisenbrey
    School of Biomedical Engineering, Science and Health Systems, Drexel University, Philadelphia, PA 19128, USA
    Ultrasound Med Biol 35:1854-62. 2009
  10. ncbi Comparison of in vitro and in vivo acoustic response of a novel 50:50 PLGA contrast agent
    Margaret A Wheatley
    School of Biomedical Engineering, Science and Health Systems, Drexel University, Philadelphia, PA 19104, USA
    Ultrasonics 44:360-7. 2006

Scientific Experts

Detail Information

Publications11

  1. ncbi Cellular signal transduction can be induced by TRAIL conjugated to microcapsules
    Margaret A Wheatley
    School of Biomedical Engineering, Science and Health Systems, Drexel University, Philadelphia, Pennsylvania 19104, USA
    J Biomed Mater Res A 100:2602-11. 2012
    ..01) compared to unmodified UCA, similar to positive controls and bortezomib significantly increased apoptosis in combination with TRAIL-UCA. We conclude that TRAIL-ligated UCA show exciting potential as a new therapy...
  2. pmc Disposition of ultrasound sensitive polymeric drug carrier in a rat hepatocellular carcinoma model
    Michael C Cochran
    School of Biomedical Engineering Science and Health Systems, Drexel University, Philadelphia, PA, USA
    Acad Radiol 18:1341-8. 2011
    ..This study uses a rat liver cancer model to examine the biodistribution and tumoral delivery of this microbubble platform compared with de novo drug-loaded polymer nanoparticles and free doxorubicin...
  3. pmc Doxorubicin and paclitaxel loaded microbubbles for ultrasound triggered drug delivery
    Michael C Cochran
    School of Biomedical Engineering Science and Health Systems, Drexel University, Philadelphia, PA 19104, United States
    Int J Pharm 414:161-70. 2011
    ..0016). This study has shown that PTX loaded UCA triggered with focused ultrasound have the potential to provide a targeted and sustained delivery of drug to tumors...
  4. pmc Preserving enhancement in freeze-dried contrast agent ST68: Examination of excipients
    Carl Solis
    School of Biomedical Engineering, Science and Health Systems, Drexel University, 3141 Chestnut St, Philadelphia, PA 19104, United States
    Int J Pharm 396:30-8. 2010
    ..For the first time this contrast agent can be successfully freeze-dried yielding a longer self-life without the need for refrigeration...
  5. ncbi Nano-sized ultrasound contrast agent: salting-out method
    Margaret A Wheatley
    School of Biomedical Engineering, Science and Health Systems, Drexel University, Philadelphia, PA, USA
    Mol Imaging 9:96-107. 2010
    ..Optimization will require compromise among size, echogenicity, and stability...
  6. pmc Development and optimization of a doxorubicin loaded poly(lactic acid) contrast agent for ultrasound directed drug delivery
    J R Eisenbrey
    School of Biomedical Engineering, Science and Health Systems, Drexel University, 3141 Chestnut Street, Philadelphia, PA 19104, USA
    J Control Release 143:38-44. 2010
    ..15 ml/kg. While the drug-incorporated agent is thought to be well suited for future drug delivery experiments, this study has shown that agent properties can be tailored for specific applications based on choice of drug loading method...
  7. pmc Ultrasound triggered cell death in vitro with doxorubicin loaded poly lactic-acid contrast agents
    J R Eisenbrey
    School of Biomedical Engineering, Science and Health Systems, Drexel University, Philadelphia, PA 19104, United States
    Ultrasonics 49:628-33. 2009
    ..This study has shown that a polymer UCA with drug housed within the shell may be used for US-triggered cell death. US activation can be used to make a carrier significantly more potent once in the area of need...
  8. ncbi Preclinical acute toxicology study of surfactant-stabilized ultrasound contrast agents in adult rats
    Flemming Forsberg
    Department of Radiology, Thomas Jefferson University, Philadelphia, PA, USA
    Int J Toxicol 29:32-9. 2010
    ..1 mL/kg and the ST68 0.8-1.0 mL/kg groups (P < .01). It is concluded that the prudent choice for future nonrodent, toxicology studies and potentially for human clinical trials is ST68 (given the deaths in the ST44 groups)...
  9. pmc Plasma sterilization of poly lactic acid ultrasound contrast agents: surface modification and implications for drug delivery
    John R Eisenbrey
    School of Biomedical Engineering, Science and Health Systems, Drexel University, Philadelphia, PA 19128, USA
    Ultrasound Med Biol 35:1854-62. 2009
    ..This study not only shows how a highly temperature- and pressure-sensitive agent can be sterilized using plasma, but also that surface modification can be used to increase surface binding of the drug...
  10. ncbi Comparison of in vitro and in vivo acoustic response of a novel 50:50 PLGA contrast agent
    Margaret A Wheatley
    School of Biomedical Engineering, Science and Health Systems, Drexel University, Philadelphia, PA 19104, USA
    Ultrasonics 44:360-7. 2006
    ..Potential causes include increased hydrolysis or polymer softening and increased water uptake by the shell at temperatures closer to the glass transition temperature (T(g))...
  11. ncbi Surfactant-stabilized contrast agent on the nanoscale for diagnostic ultrasound imaging
    Margaret A Wheatley
    School of Biomedical Engineering, Science and Health Systems, Drexel University, Philadelphia, PA 19104, USA
    Ultrasound Med Biol 32:83-93. 2006
    ..025 mL/kg. These results encourage further investigation of the possible diagnostic and therapeutic benefits of using nanoparticles as CA, including passive targeting and accumulation in tumors...