Targeted gadolinium-loaded dendrimer nanoparticles for tumor-specific magnetic resonance contrast enhancement

Original Research

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Authors: Scott D Swanson, Jolanta F Kukowska-Latallo, Anil K Patri, Chunyan Chen, Song Ge, et al

Published Date June 2008 Volume 2008:3(2) Pages 201 - 210

DOI: http://dx.doi.org/10.2147/IJN.S2696

Scott D Swanson¹, Jolanta F Kukowska-Latallo², Anil K Patri⁵, Chunyan Chen⁶, Song Ge⁴, Zhengyi Cao³, Alina Kotlyar³, Andrea T East⁷, James R Baker³

¹Department of Radiology, The University of Michigan Medical School, ²Department of Internal Medicine, The University of Michigan Medical School, ³Michigan Nanotechnology Institute for Medicine and Biological Sciences, The University of Michigan, ⁴Applied Physics, The University of Michigan, MD, USA; ⁵Present address: National Cancer Institute at Frederick (Contractor), MD, USA; ⁶Present address: Intel Corporation, Chandler, AZ, USA; ⁷Present address: Stritch School of Medicine, Chicago, ILL, USA

Abstract: A target-specific MRI contrast agent for tumor cells expressing high affinity folate receptor was synthesized using generation five (G5) of polyamidoamine (PAMAM) dendrimer. Surface modified dendrimer was functionalized for targeting with folic acid (FA) and the remaining terminal primary amines of the dendrimer were conjugated with the bifunctional NCS-DOTA chelator that forms stable complexes with gadolinium (Gd III). Dendrimer-DOTA conjugates were then complexed with GdCl₃, followed by ICP-OES as well as MRI measurement of their longitudinal relaxivity (T1 s⁻¹ mM⁻¹) of water. In xenograft tumors established in immunodeficient (SCID) mice with KB human epithelial cancer cells expressing folate receptor (FAR), the 3D MRI results showed specific and statistically significant signal enhancement in tumors generated with targeted Gd(III)-DOTA-G5-FA compared with signal generated by non-targeted Gd(III)-DOTA-G5 contrast nanoparticle. The targeted dendrimer contrast nanoparticles infiltrated tumor and were retained in tumor cells up to 48 hours post-injection of targeted contrast nanoparticle. The presence of folic acid on the dendrimer resulted in specific delivery of the nanoparticle to tissues and xenograft tumor cells expressing folate receptor in vivo. We present the specificity of the dendrimer nanoparticles for targeted cancer imaging with the prolonged clearance time compared with the current clinically approved gadodiamide (Omniscan^TM) contrast agent. Potential application of this approach may include determination of the folate receptor status of tumors and monitoring of drug therapy.

Keywords: dendrimer, DOTA, gadolinium, MRI, folate receptor