Abstract
Converting nanoparticles or monomeric compounds into larger supramolecular structures by endogenous1,2 or external3,4 stimuli is increasingly popular because these materials are useful for imaging and treating diseases. However, conversion of microstructures to nanostructures is less common. Here, we show the conversion of microbubbles to nanoparticles using low-frequency ultrasound. The microbubble consists of a bacteriochlorophyll–lipid shell around a perfluoropropane gas. The encapsulated gas provides ultrasound imaging contrast and the porphyrins in the shell confer photoacoustic and fluorescent properties. On exposure to ultrasound, the microbubbles burst and form smaller nanoparticles that possess the same optical properties as the original microbubble. We show that this conversion is possible in tumour-bearing mice and could be validated using photoacoustic imaging. With this conversion, our microbubble can potentially be used to bypass the enhanced permeability and retention effect when delivering drugs to tumours.
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References
Motornov, M. et al. ‘Chemical transformers’ from nanoparticle ensembles operated with logic. Nano Lett. 8, 2993–2997 (2008).
Ng, K. K., Lovell, J. F., Vedadi, A., Hajian, T. & Zheng, G. Self-assembled porphyrin nanodiscs with structure-dependent activation for phototherapy and photodiagnostic applications. ACS Nano 7, 3484–3490 (2013).
Skirtach, A. G., Antipov, A. A., Shchukin, D. G. & Sukhorukov, G. B. Remote activation of capsules containing Ag nanoparticles and IR dye by laser light. Langmuir. 20, 6988–6992 (2004).
Melancon, M. P., Zhou, M. & Li, C. Cancer theranostics with near-infrared light-activatable multimodal nanoparticles. Acc. Chem. Res. 44, 947–956 (2011).
Kripfgans, O. D., Fowlkes, J. B., Miller, D. L., Eldevik, O. P. & Carson, P. L. Acoustic droplet vaporization for therapeutic and diagnostic applications. Ultrasound Med. Biol. 26, 1177–1189 (2000).
Rapoport, N. et al. Ultrasound-mediated tumor imaging and nanotherapy using drug loaded, block copolymer stabilized perfluorocarbon nanoemulsions. J. Control. Rel. 153, 4–15 (2011).
Wei, K. et al. Quantification of myocardial blood flow with ultrasound-induced destruction of microbubbles administered as a constant venous infusion. Circulation 97, 473–483 (1998).
Ferrara, K., Pollard, R. & Borden, M. Ultrasound microbubble contrast agents: fundamentals and application to gene and drug delivery. Annu. Rev. Biomed. Eng. 9, 415–447 (2007).
Chomas, J. E., Dayton, P., Allen, J., Morgan, K. & Ferrara, K. W. Mechanisms of contrast agent destruction. IEEE Trans. Ultrason. Ferroelec. Freq. Control 48, 232–248 (2001).
Sboros, V., Moran, C. M., Pye, S. D. & McDicken, W. N. Contrast agent stability: a continuous B-mode imaging approach. Ultrasound Med. Biol. 27, 1367–1377 (2001).
Huynh, E. & Zheng, G. Engineering multifunctional nanoparticles: all-in-one versus one-for-all. WIREs Nanomed. Nanobiotechnol. 5, 250–265 (2013).
Huynh, E., Jin, C. S., Wilson, B. C. & Zheng, G. Aggregate enhanced trimodal porphyrin shell microbubbles for ultrasound, photoacoustic, and fluorescence imaging. Bioconj. Chem. 25, 796–801 (2014).
Huynh, E. et al. Porphyrin shell microbubbles with intrinsic ultrasound and photoacoustic properties. J. Am. Chem. Soc. 134, 16464–16467 (2012).
Liu, Z. et al. Iron oxide nanoparticle-containing microbubble composites as contrast agents for MR and ultrasound dual-modality imaging. Biomaterials 32, 6155–6163 (2011).
Kabalnov, A. et al. Dissolution of multicomponent microbubbles in the bloodstream: 2. Experiment. Ultrasound Med. Biol. 24, 751–760 (1998).
Luan, Y. et al. Lipid shedding from single oscillating microbubbles. Ultrasound Med. Biol. 40, 1834–1846 (2014).
Cox, D. J. & Thomas, J. L. Rapid shrinkage of lipid-coated bubbles in pulsed ultrasound. Ultrasound Med. Biol. 39, 466–474 (2013).
Sengupta, S. & Wurthner, F. Chlorophyll J-aggregates: from bioinspired dye stacks to nanotubes, liquid crystals, and biosupramolecular electronics. Acc. Chem. Res. 46, 2498–2512 (2013).
Wang, L. V. & Hu, S. Photoacoustic tomography: in vivo imaging from organelles to organs. Science 335, 1458–1462 (2012).
Kopechek, J. A. et al. The impact of bubbles on measurement of drug release from echogenic liposomes. Ultrason. Sonochem. 20, 1121–1130 (2013).
Lovell, J. F. et al. Porphysome nanovesicles generated by porphyrin bilayers for use as multimodal biophotonic contrast agents. Nature Mater. 10, 324–332 (2011).
Liu, T. W. et al. Inherently multimodal nanoparticle-driven tracking and real-time delineation of orthotopic prostate tumors and micrometastases. ACS Nano 7, 4221–4232 (2013).
Liu, T. W., MacDonald, T. D., Shi, J., Wilson, B. C. & Zheng, G. Intrinsically copper-64-labeled organic nanoparticles as radiotracers. Angew. Chem. Int. Ed. 51, 13128–13131 (2012).
MacDonald, T. D., Liu, T. W. & Zheng, G. An MRI-sensitive, non-photobleachable porphysome photothermal agent. Angew. Chem. Int. Ed. 126, 7076–7079 (2014).
Ng, K. K. et al. Stimuli-responsive photoacoustic nanoswitch for in vivo sensing applications. ACS Nano 8, 8363–8373 (2014).
Jin, C. S., Cui, L., Wang, F., Chen, J. & Zheng, G. Targeting-triggered porphysome nanostructure disruption for activatable photodynamic therapy. Adv. Healthcare Mater. 3, 1240–1249 (2014).
Jin, C. S., Lovell, J. F., Chen, J. & Zheng, G. Ablation of hypoxic tumors with dose-equivalent photothermal, but not photodynamic, therapy using a nanostructured porphyrin assembly. ACS Nano 7, 2541–2550 (2013).
Prabhakar, U. et al. Challenges and key considerations of the enhanced permeability and retention effect for nanomedicine drug delivery in oncology. Cancer Res. 73, 2412–2417 (2013).
Wang, Y. H. et al. Synergistic delivery of gold nanorods using multifunctional microbubbles for enhanced plasmonic photothermal therapy. Sci. Rep. 4, 5685 (2014).
Berg, K. et al. Porphyrin-related photosensitizers for cancer imaging and therapeutic applications. J. Microsc. 218, 133–147 (2005).
Feshitan, J. A., Chen, C. C., Kwan, J. J. & Borden, M. A. Microbubble size isolation by differential centrifugation. J. Colloid Interface Sci. 329, 316–324 (2009).
Li, P. et al. Ultrasound triggered drug release from 10-hydroxycamptothecin-loaded phospholipid microbubbles for targeted tumor therapy in mice. J. Control. Rel. 162, 349–354 (2012).
Helfield, B. L., Huo, X., Williams, R. & Goertz, D. E. The effect of preactivation vial temperature on the acoustic properties of definity. Ultrasound Med. Biol. 38, 1298–1305 (2012).
Burlew, M. M., Madsen, E. L., Zagzebski, J. A., Banjavic, R. A. & Sum, S. W. A new ultrasound tissue-equivalent material. Radiology 134, 517–520 (1980).
Huang, S. L. et al. Physical correlates of the ultrasonic reflectivity of lipid dispersions suitable as diagnostic contrast agents. Ultrasound Med. Biol. 28, 339–348 (2002).
Acknowledgements
The authors thank A. Roxin for providing the BChl-lipid, P. McVeigh for technical assistance with the NanoSight LM10, M. Balassu for technical assistance with the animal study and D.M. Charron for help with electron microscopy. The authors also thank R-K. Li for use of his Vevo SoniGene instrument. This work was supported by the Canadian Institutes of Health Research (CIHR) Frederick Banting and Charles Best Canada Graduate Scholarship, the Emerging Team Grant on Regenerative Medicine and Nanomedicine co-funded by the CIHR and the Canadian Space Agency, the Natural Sciences and Engineering Research Council of Canada, the Ontario Institute for Cancer Research, the International Collaborative R&D Project of the Ministry of Knowledge Economy, South Korea, the Joey and Toby Tanenbaum/Brazilian Ball Chair in Prostate Cancer Research, the Canada Foundation for Innovation and the Princess Margaret Cancer Foundation.
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E.H. and G.Z. conceived the idea, interpreted the data and wrote the manuscript. E.H., D.E.G. and G.Z. designed the experiments. E.H. carried out size characterization, light microscopy, optical characterization and imaging studies. B.Y.C.L., B.L.H. and E.H. performed acoustic characterization. M.S. and E.H. carried out electron microscopy. E.H. and C.S.J. carried out animal imaging experiments. J.G. and E.R.M. carried out flow field-flow fractionation. E.H., D.E.G., B.C.W. and G.Z. edited the manuscript.
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Huynh, E., Leung, B., Helfield, B. et al. In situ conversion of porphyrin microbubbles to nanoparticles for multimodality imaging. Nature Nanotech 10, 325–332 (2015). https://doi.org/10.1038/nnano.2015.25
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DOI: https://doi.org/10.1038/nnano.2015.25
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