TY - JOUR
T1 - Deformable gas-filled microbubbles targeted to P-selectin
AU - Rychak, Joshua J.
AU - Lindner, Jonathan R.
AU - Ley, Klaus
AU - Klibanov, Alexander L.
N1 - Funding Information:
This work was supported in part by NIH BRP HL 64381 and a research grant from the Whitaker Foundation to K. Ley. J.J. Rychak was supported via NIH Cardiovascular training grant HL07284 to UVA. Generous donation of laboratory equipment to A.L. Klibanov's laboratory at UVA Cardiovascular Division by Mallinckrodt Inc. (St. Louis, MO) is appreciated. A.L. Klibanov was supported in part via DOE 43-14702, NIH DK63508 and HL64381, and EIF grant to Cardiovascular Division. J.R. Lindner was supported in part via NIH DK63508, HL64381 and Grant-in-Aid GF10013 from the Atlantic Coast Affiliate of American Heart Association, Baltimore, MD. The authors are appreciative to C. Bachmann and M. Smith for their valuable discussion, to Prof. B. Helmke for performing deconvolution microscopy experiments, and to M. Solga for assistance with flow cytometry.
PY - 2006/9/12
Y1 - 2006/9/12
N2 - Ultrasound contrast microbubbles have been successfully targeted to a number of intravascular disease markers. We hypothesized that targeted delivery could be improved further, by making the microbubbles deformable, leading to increased microbubble-endothelium adhesion contact area and stabilized adhesion. Activated leukocytes utilize such strategy; they deform after binding to inflamed endothelium in the vasculature. Lipid-shell microbubbles were targeted to the endothelial inflammatory protein P-selectin with a monoclonal anti-P-selectin antibody attached to the microbubble shell. Deformable microbubbles were created by controlled pressurization with partial gas loss, which generated an average excess shell surface area of ∼ 30% and the formation of outward-projected wrinkles and folds. Targeted microbubble adhesion and deformability were assessed in the parallel plate flow chamber under shear flow. Sustained adhesion of deformable microbubbles at wall shear stresses between 0.4 and 1.35 dyn/cm2 was consistently better than adhesion of wrinkle-free microbubbles. Over this shear range, targeted wrinkled microbubbles were deformed by shear flow, unlike wrinkle-free microbubbles. In a murine cremaster inflammation model, a significant improvement of deformable microbubble targeting was observed by intravital microscopy. Overall, the mechanical aspects of adhesion, such as particle shape, deformability and surface microstructure, are important in engineering efficient site-targeted particle-based agents for medical imaging and therapy.
AB - Ultrasound contrast microbubbles have been successfully targeted to a number of intravascular disease markers. We hypothesized that targeted delivery could be improved further, by making the microbubbles deformable, leading to increased microbubble-endothelium adhesion contact area and stabilized adhesion. Activated leukocytes utilize such strategy; they deform after binding to inflamed endothelium in the vasculature. Lipid-shell microbubbles were targeted to the endothelial inflammatory protein P-selectin with a monoclonal anti-P-selectin antibody attached to the microbubble shell. Deformable microbubbles were created by controlled pressurization with partial gas loss, which generated an average excess shell surface area of ∼ 30% and the formation of outward-projected wrinkles and folds. Targeted microbubble adhesion and deformability were assessed in the parallel plate flow chamber under shear flow. Sustained adhesion of deformable microbubbles at wall shear stresses between 0.4 and 1.35 dyn/cm2 was consistently better than adhesion of wrinkle-free microbubbles. Over this shear range, targeted wrinkled microbubbles were deformed by shear flow, unlike wrinkle-free microbubbles. In a murine cremaster inflammation model, a significant improvement of deformable microbubble targeting was observed by intravital microscopy. Overall, the mechanical aspects of adhesion, such as particle shape, deformability and surface microstructure, are important in engineering efficient site-targeted particle-based agents for medical imaging and therapy.
KW - Adhesion
KW - Microbubbles
KW - Targeted imaging
KW - Targeting
KW - Ultrasound contrast
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U2 - 10.1016/j.jconrel.2006.06.008
DO - 10.1016/j.jconrel.2006.06.008
M3 - Article
C2 - 16887229
AN - SCOPUS:33748201140
SN - 0168-3659
VL - 114
SP - 288
EP - 299
JO - Journal of Controlled Release
JF - Journal of Controlled Release
IS - 3
ER -