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Theranostics 2015; 5(2):124-133. doi:10.7150/thno.10014 This issue Cite

Research Paper

α_νβ₃-targeted Copper Nanoparticles Incorporating an Sn 2 Lipase-Labile Fumagillin Prodrug for Photoacoustic Neovascular Imaging and Treatment

Ruiying Zhang^1*, Dipanjan Pan^2,3*, Xin Cai¹, Xiaoxia Yang², Angana Senpan², John S. Allen², Gregory M. Lanza^{1, 2✉}, Lihong V. Wang^1✉

1. Department of Biomedical Engineering, Washington University, St Louis, MO 63130;
2. Department of Medicine, Washington University School of Medicine, St Louis, MO 63108;
3. Current address: Department of Bioengineering and Beckman Institute, University of Illinois, Urbana, IL 61801.
*Authors: equal contribution.

✉ Corresponding authors: Lihong V. Wang, PhD. Department of Biomedical Engineering, Washington University, Whitaker Hall, Room 190D, Campus Box 1097, 1 Brookings Drive, St. Louis, MO 63130. Tel: (314) 935-6152. lhwangedu And Gregory M. Lanza, MD PhD. Professor of Medicine and Bioengineering, Division of Cardiology, Washington University Medical School, CORTEX building, Suite 101, 4320 Forest Park Ave. Saint Louis, MO. Tel: (314) 454-8813 Greg.lanzacom. More

Abstract

Photoacoustic (PA) tomography enables multiscale, multicontrast and high-resolution imaging of biological structures. In particular, contrast-enhanced PA imaging offers high-sensitivity noninvasive imaging of neovessel sprout formation and nascent tubules, which are important biomarkers of malignant tumors and progressive atherosclerotic disease. While gold nanoparticles or nanorods have been used as PA contrast agents, we utilized high-density copper oleate small molecules encapsulated within a phospholipid surfactant (CuNPs) to generate a soft nanoparticle with PA contrast comparable to that from gold. Within the NIR window, the copper nanoparticles provided a 4-fold higher signal than that of blood. α_νβ₃-integrin targeting of CuNPs in a Matrigel^TM angiogenesis mouse model demonstrated prominent (p<0.05) PA contrast enhancement of the neovasculature compared with mice given nontargeted or competitively inhibited CuNPs. Furthermore, incorporation of a Sn 2 lipase-labile fumagillin prodrug into the CuNP outer lipid membrane produced marked antiangiogenesis in the same model when targeted to the α_νβ₃-integrin, providing proof of concept in vivo for the first targeted PA - drug delivery agent.

Keywords: copper, nanoparticle, near-infrared imaging, photoacoustic imaging, angiogenesis imaging, anti-angiogenic therapy.

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