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Accepted (AM)Open Access (License Unspecified), Open
Journal article
Gemcitabine-loaded microbubble system for ultrasound imaging and therapy
Acta biomaterialia, v 130, pp 385-394
Aug 2021
PMID: 34082100
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
Ultrasound imaging presents many positive attributes, including safety, real-time imaging, universal accessibility, and cost. However, inherent difficulties in discrimination between soft tissues and tumors prompted development of stabilized microbubble contrast agents. This presents the opportunity to develop agents in which drug is entrapped in the microbubble shell. We describe preparation and characterization of theranostic poly(lactide) (PLA) and pegylated PLA (PEG-PLA) shelled microbubbles that entrap gemcitabine, a commonly used drug for pancreatic cancer (PDAC). Entrapping 6 wt% gemcitabine did not significantly affect drug activity, microbubble morphology, or ultrasound contrast activity compared with unmodified microbubbles. In vitro microbubble concentrations yielding ≥ 500nM entrapped gemcitabine were needed for complete cell death in MIA PaCa-2 PDAC drug sensitivity assays, compared with 62.5 nM free gemcitabine. In vivo administration of gemcitabine-loaded microbubbles to xenograft MIA PaCa-2 PDAC tumors in athymic mice was well tolerated and provided substantial tumoral image enhancement before and after destructive ultrasound pulses. However, no significant differences in tumor growth were observed among treatment groups, in keeping with the in vitro observation that much higher doses of gemcitabine are required to mirror free gemcitabine activity.
The preliminary results shown here are encouraging and support further investigation into increased gemcitabine loading. Encapsulation of gemcitabine within polylactic acid (PLA) microbubbles does not damage its activity towards pancreatic cancer (pancreatic ductal adenocarcinoma, PDAC) cells. Excellent imaging and evidence of penetration into the highly desmoplastic PDAC tumors is demonstrated. Microbubble destruction was confirmed in vivo, showing that elevated mechanical index shatters the microbubbles for enhanced delivery. The potential to slow PDAC growth in vivo is shown, but higher gemcitabine concentrations are required. Current efforts are directed at increasing drug loading by inclusion of drug-carrying nanoparticles for effective in vivo treatment.
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Details
- Title
- Gemcitabine-loaded microbubble system for ultrasound imaging and therapy
- Creators
- Lauren J. Delaney - School of Biomedical Engineering, Science, and Health Systems, Drexel University, Philadelphia, PA 19104, USAJohn R. Eisenbrey - Thomas Jefferson UniversityDavid Brown - Drexel UniversityJonathan R. Brody - Thomas Jefferson UniversityMasaya Jimbo - Thomas Jefferson UniversityBrian E. Oeffinger - Drexel UniversityMaria Stanczak - Thomas Jefferson UniversityFlemming Forsberg - Thomas Jefferson UniversityJi-Bin Liu - Thomas Jefferson UniversityMargaret A. Wheatley - Drexel University
- Publication Details
- Acta biomaterialia, v 130, pp 385-394
- Publisher
- Elsevier
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- School of Biomedical Engineering, Science, and Health Systems
- Web of Science ID
- WOS:000677504700007
- Scopus ID
- 2-s2.0-85108295121
- Other Identifier
- 991019168897504721
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- Collaboration types
- Domestic collaboration
- Web of Science research areas
- Engineering, Biomedical
- Materials Science, Biomaterials