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Enhanced Imaging: MRI and SQUID

We are developing MRI and SQUID imaging using targeted magnetic nanoparticle contrast agents and have proven the concept that functional MRI and SQUID imaging could be accomplished using targeted magnetic nanoparticle contrast agents. The contrast enhancement for the imaging is provided by superparamagnetic nanoparticles approximately 6 nm in diameter. Internalization of the contrast agent is through the high-affinity folate receptor, which is overexpressed in a variety of epithelial cancers. After introduction of the contrast agent, MR imaging is then performed. Similarly, detection of the superparamagnetic particles both in vitro and in vivo is being performed to determine the ultimate limits of the SQUID imaging technique. This approach allows the imagining of pre-clinical lesions and paves the way for intracellular delivery of functional imaging agents.

Clinical applications of magnetic resonance imaging (MRI) require generation of tissue-specific contrast. We have synthesized a target-specific MRI contrast agent for tumor cells expressing high affinity folate receptor 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-1mM-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 (OmniscanTM) contrast agent.  Potential application of this approach may include determination of the folate receptor status of tumors and monitoring of drug therapy.  ( Swanson S.D., Kukowska-Latallo J.F., Patri A.K., Chen C., Ge S., Cao Z., Kotlyar A., East A.T., and Baker Jr. J.R. Targeted Gadolinium-Loaded Dendrimer Nanoparticles for Tumor-Specific Magnetic Resonance Contrast Enhancement, Int J Nanomedicine 3(2), 201-210, 2008. ).

 

Examples of the gradient echo images

Figure 1: Examples of the gradient echo images (A) the mouse injected with FA-G5-Gd to target folic acid receptor-positive tumor cells and (B) of the control mouse. The image of the targeted mouse was obtained 24 hours post-injection of targeted contrast agent. The oval areas drawn on the tumors indicate the regions of interest used to compute the percent signal enhancement. FA=Folic Acid; G5=Generation 5 PAMAM dendrimer; Gd= Gadolinium

 

We have refined two synthetic approaches for the formation of targeted magnetic nanoparticles. The first method uses folic acid for targeting and Gd chelated within DOTA as the magnetic particle. These two components are conjugated to a dendrimer scaffold to form the targeted contrast agent. We have performed initial in vivo NMR studies of this material in murine models. The second synthetic approach involves the formation of a 6-nm FeO nanoparticle and then solubilization by exchange of the surfactant. This process has been completed and concentrated aqueous suspensions of the nanoparticles have been produced and analyzed.

In addition to the NMR, we are developing SQUID techniques for detection of the magnetic particles. In agarose samples, we are able to detect the presence of 10 ng of magnetic particles. We have begun placing the nanoparticles into mice to examine the sensitivity in vivo. We will continue to explore the use of magnetic detection of the contrast agent via SQUID magnetometry.

SQUID Experimental Set-up

Figure 2: SQUID Experimental Set-up

We are conducting toxicity and loading studies in vitro and will be able to determine both loading of the cells and toxicity. in vivo mouse studies and determination of targeting efficacy will follow.
This work has been supported by a grant from the NIH.

Xiangyang Shi, Su He Wang, Scott D. Swanson, Song Ge, Zhengyi Cao,  Mary Van Antwerp, Kevin J Landmark, James R. Baker, Jr. Dendrimer-Functionalized Shell-Crosslinked Iron Oxide Nanoparticles for in vivo Magnetic Resonance Imaging of Tumors.  Accepted by Advanced Materials, 2008

 

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