Hyaluronan-modified magnetic nanoclusters for detection of CD44-overexpressing breast cancer by MR imaging Eun-Kyung Lim a , Hyun-Ouk Kim a , Eunji Jang a , Joseph Park a , Kwangyeol Lee e , Jin-Suck Suh b, c, d , Yong-Min Huh b, c, d, ** , Seungjoo Haam a, c, * a Department of Chemical and Biomolecular Engineering, Yonsei University, Seoul 120-749, South Korea b Department of Radiology, College of Medicine, Yonsei University, Seoul 120-752, South Korea c YUHS-KRIBB Medical Convergence Research Institute, Seoul 120-752, South Korea d Severance Biomedical Science Institute(SBSI), Seoul 120-752, South Korea e Department of Chemistry, Korea University, Seoul 136-701, South Korea article info Article history: Received 24 May 2011 Accepted 30 June 2011 Available online xxx Keywords: Hyaluronan Magnetic resonance imaging Magnetic nanoclusters CD44 Breast cancer abstract We fabricated hyaluronan-modified magnetic nanoclusters (HA-MNCs) for detection of CD44- overexpressing breast cancer using magnetic resonance (MR) imaging. CD44 is closely associated with cancer growth, including proliferation, metastasis, invasion, and angiogenesis. Hence, pyrenyl hyalur- onan (PyeHA) conjugates were synthesized as CD44-targetable surfactants with hyaluronan (HA) and 1- pyrenylbutyric acid (Py) to modify hyaluronan on hydrophobic magnetic nanocrystals. Subsequently, HA- MNCs were fabricated using the nano-emulsion method; magnetic nanocrystals were simultaneously self-assembled with PyeHA conjugates, and their physical and magnetic properties depended on the degree of substitution (DS) of Py in PyeHA conjugates. HA-MNCs exhibited superior targeting efficiency with MR sensitivity as well as excellent biocompatibility through in vitro/in vivo studies. This suggests that HA-MNCs can be a potent cancer specific molecular imaging agent via targeted detection of CD44 with MR imaging. Crown Copyright Ó 2011 Published by Elsevier Ltd. All rights reserved. 1. Introduction Molecular imaging has been widely studied for use in precise, non-invasive detection of early-stage cancers, as well as sensitive and specific monitoring of response to drug therapies associated with effective cancer therapy [1e5]. Molecular imaging techniques that depend on efficient nanoprobes have been successful in acquiring highly sensitive images and providing deeper insights into in vivo processes [6,7]. In particular, magnetic resonance (MR) imaging has received substantial attention in cancer detection with the use of magnetic nanocrystals as MR imaging contrast agents, which aid in the acquisition of highly sensitive and tomographic images with excellent spatial resolution [1,8,9]. Recently, magnetic nanocrystals synthesized by thermal decomposition in the organic phase have been greatly attracted because they exhibit a well- defined crystalline structure and high magnetic sensitivity with excellent size and composition control. However, magnetic nano- crystals are insoluble in the aqueous phase due to hydrophobic ligands on their surfaces; thus, they need to attain colloidal stability in the aqueous phase by the use of modifying water-soluble moieties [1,10e14]. Furthermore, these magnetic nanocrystals require modification of specific targeting moieties (such as an antibody or polysaccharide) that can strongly interact with recep- tors expressed on the target cancer to facilitate accurate detection of the specific cancer and enhanced delivery to the target site while reducing unintended side effects, including accumulation in normal tissues [5,15e19]. In particular, CD44, a cell surface glycoprotein that is overex- pressed in breast cancer and gastric cancer stem cells, plays an important role in promoting cancer cell proliferation, migration, invasion, and tumor-associated angiogenesis [20e25]. This receptor is a major surface receptor for hyaluronan (HA), an immune-neutral polysaccharide that is ubiquitous in the human body and critical in many cellular and tissue functions [18,26e34]. Interactions between CD44 and HA inhibit tumor growth and metastatic inflammatory responses by stimulating inflammatory * Corresponding author. Department of Chemical and Biomolecular Engineering, Yonsei University, Seoul 120-749, South Korea. Tel.: þ82 2 2123 2751; fax: þ82 2 312 6401. ** Corresponding author. Department of Radiology, College of Medicine, Yonsei University, Seoul 120-752, South Korea. Tel.: þ82 2 2228 2375; fax: þ82 2 362 8647. E-mail addresses: ymhuh@yuhs.ac (Y.-M. Huh), haam@yonsei.ac.kr (S. Haam). Contents lists available at ScienceDirect Biomaterials journal homepage: www.elsevier.com/locate/biomaterials 0142-9612/$ e see front matter Crown Copyright Ó 2011 Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.biomaterials.2011.06.077 Biomaterials xxx (2011) 1e10 Please cite this article in press as: Lim E-K, et al., Hyaluronan-modified magnetic nanoclusters for detection of CD44-overexpressing breast cancer by MR imaging, Biomaterials (2011), doi:10.1016/j.biomaterials.2011.06.077