Article pubs.acs.org/Biomac
Long-Lasting and Efficient Tumor Imaging Using a High Relaxivity Polysaccharide Nanogel Magnetic Resonance Imaging Contrast Agent Minnie Chan,† Jacques Lux,‡ Tomoki Nishimura,§,⊥ Kazunari Akiyoshi,§,⊥ and Adah Almutairi*,‡ Department of Chemistry and Biochemistry and ‡Skaggs School of Pharmacy and Pharmaceutical Sciences, KACST-UCSD Center of Excellence in Nanomedicine, Laboratory of Bioresponsive Materials, University of California, San Diego, La Jolla, California 92093-0600, United States § Department of Polymer Chemistry, Graduate School of Engineering, Kyoto University, Katsura, Nishikyo-ku, Kyoto 615-8510, Japan ⊥ Japan Science and Technology Agency (JST), The Exploratory Research for Advanced Technology (ERATO), Bionanotransporter Project, Katsura Int’tech Center, Katsura, Nishikyo-ku, Kyoto 615-8530, Japan Downloaded by UNIV OF MANITOBA on August 25, 2015 | http://pubs.acs.org Publication Date (Web): August 25, 2015 | doi: 10.1021/acs.biomac.5b00867
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S Supporting Information *
ABSTRACT: Clinically approved small-molecule magnetic resonance imaging (MRI) contrast agents are all rapidly cleared from the body and offer weak signal enhancement. To avoid repeated administration of contrast agent and improve signal-to-noise ratios, agents with stronger signal enhancement and better retention in tumors are needed. Therefore, we focused on hydrogels because of their excellent water accessibility and biodegradability. Gadolinium (Gd)-chelating cross-linkers were incorporated into self-assembled pullulan nanogels to both impart magnetic properties and to stabilize this material that has been extensively studied for medical applications. We show that these Gd-chelating pullulan nanogels (GdCHPOA) have the highest reported relaxivity for any hydrogel-based particles and accumulate in the 4T1 tumors in mice at high levels 4 h after injection. This combination offers high signal enhancement and lasts up to 7 days to delineate the tumor clearly for longer imaging time scales. Importantly, this long-term accumulation does not cause any damage or toxicity in major organs up to three months after injection. Our work highlights the clinical potential of Gd-CHPOA as a tumor-imaging MRI contrast agent, permitting tumor identification and assessment with a high signal-to-background ratio.
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tissues (e.g., tumors).22−24 An effective tumor-imaging MRI contrast agent must be hydrophilic to increase the water exchange rate and consequently enhance relaxivity. Moreover, they must be nonimmunogenic and highly stable to be clinically relevant. Hydrogel nanoparticles, herein termed nanogels, are crosslinked hydrophilic polymer networks that swell and retain a significant fraction of water within their structure, allowing fast water exchange and thus a high relaxivity.25−28 Despite the advantages of nanogels, only a few nanogel MRI contrast agents have been developed recently29,30 including one developed previously by the Almutairi group.23 Our system was composed of polyacrylamide nanogels with metal chelating cross-linkers making it a versatile system for both positron emission tomography (PET) and MRI.31,32 For genuine translational potential, we seek to improve nanogels biocompatibility, by utilizing nonimmunogenic polysaccharides as the polymer
INTRODUCTION Imaging techniques are critical to identify and monitor cancer by enabling noninvasive assessment of the extent of the disease and treatment feedback.1−3 Among imaging techniques, magnetic resonance imaging (MRI) offers the advantages of high anatomical resolution with unlimited tissue depth and soft tissue contrast, both of which are advantageous for tumor imaging.4−6 Small-molecule gadolinium (Gd) chelates were developed as clinically approved MRI contrast agents; however, they suffer from sensitivity issues and lack of specific disease accumulation. Therefore, their use for oncological imaging is limited.7−10 In addition, their fast clearance confines the imaging window (half-life in blood
