Intracellular delivery and ultrasonic activation of folate receptor-targeted phase-change contrast agents in breast cancer cells in vitro.
Breast cancer is a diverse and complex disease that remains one of the leading causes of death among women. Novel, outside-of-the-box imaging and treatment methods are needed to supplement currently available technologies. In this study, we present evidence for the intracellular delivery and ultrasound-stimulated activation of folate receptor (FR)-targeted phase-change contrast agents (PCCAs) in MDA-MB-231 and MCF-7 breast cancer cells in vitro. PCCAs are lipid-coated, perfluorocarbon-filled particles formulated as nanoscale liquid droplets capable of vaporization into gaseous microbubbles for imaging or therapy. Cells were incubated with 1:1 decafluorobutane (DFB)/octafluoropropane (OFP) PCCAs for 1h, imaged via confocal microscopy, exposed to ultrasound (9MHz, MI=1.0 or 1.5), and imaged again after insonation. FR-targeted PCCAs were observed intracellularly in both cell lines, but uptake was significantly greater (p<0.001) in MDA-MB-231 cells (93.0% internalization at MI=1.0, 79.5% at MI=1.5) than MCF-7 cells (42.4% internalization at MI=1.0, 35.7% at MI=1.5). Folate incorporation increased the frequency of intracellular PCCA detection 45-fold for MDA-MB-231 cells and 7-fold for MCF-7 cells, relative to untargeted PCCAs. Intracellularly activated PCCAs ranged from 500nm to 6μm (IQR=800nm-1.5μm) with a mean diameter of 1.15±0.59 (SD) microns. The work presented herein demonstrates the feasibility of PCCA intracellular delivery and activation using breast cancer cells, illuminating a new platform toward intracellular imaging or therapeutic delivery with ultrasound.
Department of Medical Imaging, University of Arizona, Tucson, AZ, USA.
Joseph P
JP
Marshalek
Physical Sciences Department, Sunnybrook Research Institute, Toronto, ON, Canada; Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada.
Paul S
PS
Sheeran
Department of Medical Imaging, University of Arizona, Tucson, AZ, USA.
Pier
P
Ingram
Joint Department of Biomedical Engineering, The University of North Carolina and North Carolina State University, Chapel Hill, NC, USA.
Paul A
PA
Dayton
Department of Medical Imaging, University of Arizona, Tucson, AZ, USA.
Russell S
RS
Witte
Department of Medical Imaging, University of Arizona, Tucson, AZ, USA. Electronic address: tmatsunaga@radiology.arizona.edu.
Terry O
TO
Matsunaga
D001943:Breast Neoplasms / Q000000981:diagnostic imaging / Q000378:metabolism*; D045744:Cell Line, Tumor; D003287:Contrast Media / Q000008:administration & dosage*; D016503:Drug Delivery Systems; D005260:Female; D005466:Fluorocarbons / Q000737:chemistry; D058973:Folate Receptors, GPI-Anchored / Q000378:metabolism*; D006801:Humans; D061986:MCF-7 Cells; D018613:Microscopy, Confocal; D010316:Particle Size; D014018:Tissue Distribution; D014465:Ultrasonics / Q000379:methods
D003287:Contrast Media; D005466:Fluorocarbons; D058973:Folate Receptors, GPI-Anchored
Breast cancer; Decafluorobutane; Decafluorobutane (PubChem CID: 9638); Folate (PubChem CID: 6037); Folate receptor; Microbubble; Nanodroplet; Octafluoropropane; Octafluoropropane (PubChem CID: 6432); Perfluorocarbon; Phase-change contrast agent; Ultrasound
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