Advanced characterization and refinement of poly N-butyl cyanoacrylate microbubbles for ultrasound imaging.

We aimed to develop and characterize poly n-butylcyanoacrylate (PBCA) microbubbles (MBs) with a narrow size distribution. MBs were synthesized by established emulsion polymerization techniques, size-isolated by centrifugation and functionalized for molecular imaging by coating their surface with streptavidin. The physical and acoustic properties of the parent solution, different-size isolated populations and functionalized MBs were measured and compared. As expected from negative zeta potentials at pH 7, cryo scanning electron microscopy showed no aggregates. In phantoms MBs were destructible at high mechanical indices and showed a frequency-dependent attenuation and backscattering. The MBs were stable in solution for more than 14 weeks and could be lyophilized without major damage. However, for injection, small needle diameters and high injection rates are shown to be critical because both lead to MB destruction. In summary, when being handled correctly, size-isolated PBCA MBs are promising candidates for preclinical functional and molecular ultrasound imaging.

[1]  Michel Schneider,et al.  Characteristics of SonoVue™ , 1999 .

[2]  Xiao Zhou,et al.  Preparation and evaluation of poly(L-lactide-co-glycolide) (PLGA) microbubbles as a contrast agent for myocardial contrast echocardiography. , 2005, Journal of biomedical materials research. Part B, Applied biomaterials.

[3]  W N McDicken,et al.  Nanomechanical probing of microbubbles using the atomic force microscope. , 2007, Ultrasonics.

[4]  K. Bjerknes,et al.  Preparation of polymeric microbubbles: formulation studies and product characterisation , 1997 .

[5]  G. Schmitz,et al.  A Statistical Model for the Quantification of Microbubbles in Destructive Imaging , 2010, Investigative radiology.

[6]  Nico de Jong,et al.  Oil-filled polymer microcapsules for ultrasound-mediated delivery of lipophilic drugs. , 2009, Journal of controlled release : official journal of the Controlled Release Society.

[7]  Wolfhard Semmler,et al.  Molecular profiling of angiogenesis with targeted ultrasound imaging: early assessment of antiangiogenic therapy effects , 2008, Molecular Cancer Therapeutics.

[8]  Eckhard Quandt,et al.  Specific targeting of ultrasound contrast agent (USCA) for diagnostic application: an in vitro feasibility study based on SAW biosensor. , 2005, Biosensors & bioelectronics.

[9]  R Gramiak,et al.  Echocardiography of the aortic root. , 1968, Investigative radiology.

[10]  F. Kiessling,et al.  Functional and molecular ultrasound imaging: concepts and contrast agents. , 2009, Current medicinal chemistry.

[11]  M. Stein,et al.  Degradation of polybutyl 2-cyanoacrylate microparticles , 1992 .

[12]  M. Schirner,et al.  The in vitro stability of air-filled polybutylcyanoacrylate microparticles. , 2006, Biomaterials.

[13]  Paul A Dayton,et al.  Maintaining monodispersity in a microbubble population formed by flow-focusing. , 2008, Langmuir : the ACS journal of surfaces and colloids.

[14]  Paul A. Dayton,et al.  Optical observation of lipid- and polymer-shelled ultrasound microbubble contrast agents , 2004 .

[15]  P. Dayton,et al.  Optical and acoustical observations of the effects of ultrasound on contrast agents , 1999, IEEE Transactions on Ultrasonics, Ferroelectrics and Frequency Control.

[16]  S. Homma,et al.  Effect of microbubble size on fundamental mode high frequency ultrasound imaging in mice. , 2010, Ultrasound in medicine & biology.

[17]  L. Hoff,et al.  Oscillations of polymeric microbubbles: effect of the encapsulating shell , 2000, The Journal of the Acoustical Society of America.

[18]  E Stride,et al.  Preparation of suspensions of phospholipid-coated microbubbles by coaxial electrohydrodynamic atomization , 2009, Journal of The Royal Society Interface.

[19]  B. Goldberg,et al.  Experimental investigation of contrast microbubble destruction , 2001, 2001 IEEE Ultrasonics Symposium. Proceedings. An International Symposium (Cat. No.01CH37263).

[20]  J. Pikkemaat,et al.  Preparation of monodisperse polymer particles and capsules by ink-jet printing , 2006 .

[21]  Jameel A Feshitan,et al.  Microbubble size isolation by differential centrifugation. , 2009, Journal of colloid and interface science.

[22]  O. A. Asbjornsen,et al.  Size fractionation of gas-filled microspheres by flotation , 1996 .

[23]  Paul A Dayton,et al.  Tailoring the Size Distribution of Ultrasound Contrast Agents: Possible Method for Improving Sensitivity in Molecular Imaging , 2007, Molecular imaging.

[24]  W. Mcdicken,et al.  Quantification of microbubble destruction of three fluorocarbon-filled ultrasonic contrast agents. , 2000, Ultrasound in medicine & biology.

[25]  Zhanwen Xing,et al.  The fabrication of novel nanobubble ultrasound contrast agent for potential tumor imaging , 2010, Nanotechnology.

[26]  Nico de Jong,et al.  High-speed optical observations of contrast agent destruction. , 2005, Ultrasound in medicine & biology.

[27]  R. Powell,et al.  Needle size and injection rate impact microbubble contrast agent population. , 2008, Ultrasound in medicine & biology.

[28]  M. Schirner,et al.  Sensitive Particle Acoustic Quantification (SPAQ): A New Ultrasound-Based Approach for the Quantification of Ultrasound Contrast Media in High Concentrations , 2005, Investigative Radiology.

[29]  N. Zaffaroni,et al.  Tethering functional ligands onto shell of ultrasound active polymeric microbubbles. , 2006, Biomacromolecules.

[30]  S. Delorme,et al.  Pharmacodynamics of Streptavidin-Coated Cyanoacrylate Microbubbles Designed for Molecular Ultrasound Imaging , 2008, Investigative radiology.

[31]  Eleanor Stride,et al.  Generation of microbubbles for diagnostic and therapeutic applications using a novel device. , 2008, Journal of drug targeting.

[32]  N. Hosten,et al.  Perfusion abnormalities of kidney parenchyma: microvascular imaging with contrast‐enhanced color and power Doppler ultrasonography‐‐preliminary results. , 2000, Journal of ultrasound in medicine : official journal of the American Institute of Ultrasound in Medicine.

[33]  E. Wisner,et al.  The effect of size on the acoustic response of polymer-shelled contrast agents. , 2005, Ultrasound in medicine & biology.

[34]  Michael Reinhardt,et al.  Molecular targeting of lymph nodes with L-selectin ligand-specific US contrast agent: a feasibility study in mice and dogs. , 2004, Radiology.