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					                                              NSF NIRT-0507083: An Optimized Nanosphere Platform for High Resolution Multi-Modality Imaging Applications
                                                                                                                    PIs: H. C. Dorn,1 H. W. Gibson,1 P. Fatouros,2 and C. Wyatt 3
                                                                                  1) Department of Chemistry, Virginia Tech, Blacksburg, VA 24061, 2) Department of Radiology, Virginia Commonwealth
                                                                                      University, Richmond VA, 23298, 3) Department of Electrical Engineering, Virginia Tech, Blacksburg, VA 24061

     Overview:                                                                          Pegylated and Hydroxylated Gd3N@C80                                               Carboxylated and Hydroxylated Gd3N@C80                                               Carboxylated Gd3N@C80@SWNHs
                                The encapsulation of metals and metal
clusters in fullerenes (endohedral metallofullerenes) opens new vistas in                                                                                              Relaxivities in water and PBS                                 (mM-1s-1)
medical research. The carbon cage has inherent advantages because of the
high stability of the carbon cage and expected resistance to any metabolic                                                                                                           0.35 T (15 MHz)      2.4 T (100 MHz)     9.4 T (400 MHz)
cage-opening process. These metallofullerenes were first functionalized                                                                                                               r1         r2        r1         r2        r1        r2
with various groups: poly(ethylene glycol) (PEG), hydroxyls and carboxyls.                                                                                               Water       1547       20422   2079     28231    763     23125
The enhanced water proton relaxivities (r1) for the new trimetallic nitride                                                                                              PBS         291         374     352      627     181      728
template (TNT) endohedral metallofullerenes (EMFs) are significantly
higher than those for commercial agents (e.g., Omniscan). 1H MRI
relaxivity, diffusion, and quantitative concentration distribution for
functionalized Gd3N-TNT EMFs in vitro, agarose gel and in vivo studies
were obtained. The relaxivitives measured are some of highest reported and
allow the use of significantly lower concentrations (10-100-fold) for in vivo
                                                                                Gd3N@C80[DiPEG(OH)x] : r1 and r2 measurements in aqueous solutions
studies. In agarose gel diffusion studies, we find ~25 fold decrease in the
concentration of the functionalized Gd3N-TNT EMF provides equivalent              Mol.
visualization in comparison with commercial MRI agents. Similar results                   r1 (0.35T)   r2 (0.35T)   r1 (2.4T)     r2 (2.4T)   r1 (9.4T)   r2 (9.4T)
                                                                                 Weight
were obtained for direct infusion rat brain in vivo studies. We also                      (mM-1s-1)    (mM-1s-1)    (mM-1s-1)    (mM-1s-1)    (mM-1s-1)   (mM-1s-1)
                                                                                 of PEG                                                                                                                                                                 T1-weighted MRI images of direct infusion of carboxylated
encapsulated the Gd3N-TNT EMFs inside the single-walled carbon
                                                                                                                                                                                                                                                        Gd3N@C80@SWNHs into U87 tumor-bearing mouse brain.
nanohorns (SWNHs) to form a peapod structure. The material was                   5000     107±8        127±36        139±6       221±11       52.5±2.4    186±12
                                                                                                                                                                       T1-weighted images (a) and T2-weighted images (b) of
functionalized with hydrophilic groups by the high speed vibration milling       2000     130±4        148±8         158±6       249±12       41.9±3.0    218±11       Gd3N@C80(OH)26(CH2CH2COOM)16 in pure water and PBS with
method (HSVM) as outlined below for the first time. Cd/ZnS quantum dots
                                                                                 750      152±5        169±20        232±10      398±22       63.3±1.8    274±9        concentrations of 34, 14, and 7 μM [Gd3N] from top to bottom,                    References
(QDs) can be further conjugated. The SWNH-based material provides a                                                                                                    respectively; and Omniscan at [Gd] concentrations of 1.0, 0.5, and 0
multimodality imaging platform.                                                  350      227±31       268±19        237±9       460±23       68.2±3.3    438±5                                                                                    1.    Fatouros, P. P., Corwin, F. D., Chen, Z. J., Broaddus, W. C., Tatum, J. L., Kettenmann,
                                                                                                                                                                       mM (pure water) from top to bottom. Matrix: 192 × 192; slice
                                                                                                                                                                                                                                                         B., Ge, Z., Gibson, H. W., Russ, J. L., Leonard, A. P., Duchamp, J. C., and Dorn, H.
                                                                                Agarose Gel Infusion Studies: T1W
                                                                                                                                                                       thickness = 2 mm.                                                                 C. (2006) In vitro and in vivo imaging studies of a new endohedral metallofullerene
Functionalization of Gd3N@C80 and Gd3N@C80@SWNHs                                images of bilateral infusion into                                                                                                                                        nanoparticle. Radiology 240, 756-764.
                                                                                                                                                                                                           T1 computed map images of bilaterial    2.    Shu, C. Y., Ma, X. Y., Zhang, J. F., Corwin, F. D., Sim, J. H., Zhang, E. Y., Dorn, H.
                                                                                0.6% agarose gel of 0.026 mmol                                                                                                                                           C., Gibson, H. W., Fatouros, P. P., Wang, C. R., and Fang, X. H. (2008) Conjugation
                                                                                                                                                                                                           infusion into 0.6% agarose gel of
Scheme 1                                                                        of Gd3N@C80[DiPEG5000(OH)x]
                                                                                (right side of each image) and 1
                                                                                                                                                                                                           0.005 mM Gd3N@C80
                                                                                                                                                                                                                                                         of a water-soluble gadolinium endohedral fulleride with an antibody as a magnetic
                                                                                                                                                                                                                                                         resonance imaging contrast agent. Bioconjugate Chem. 19, 651-655.
                                                                                                                                                                                                                                                   3.    Shu, C. Y., Corwin, F. D., Zhang, J. F., Chen, Z. J., Reid, J. E., Sun, M. H., Xu, W.,
                                                                                                                                                                                                           (OH)26(CH2CH2COOM)16 (left side               Sim, J. H., Wang, C. R., Fatouros, P. P., Esker, A. R., Gibson, H. W., and Dorn, H. C.
                                                                                mmol gadodiamide (Omniscan) at
                                                                                                                                                                                                           of each image) and 0.25 mM                    (2009) Facile Preparation of a New Gadofullerene-Based Magnetic Resonance
                                                                                0.2 L/min for 120 min.                                                                                                                                                  Imaging Contrast Agent with High H-1 Relaxivity. Bioconjugate Chem. 20, 1186-
                                                                                                                                                                                                           Omniscan (right side of each image).          1193.
                                                                                                                                                                                                           Displayed times are in minutes post-    4.    Zhang, J., Shu, C., Reid, J., Owens, L. S., Cai, T., Gibson, H. W., Long, G. L.,
                                                                                                                                                                                                           beginning of infusion. Infusion was           Corwin, F. D., Chen, Z. J., Fatouros, P. P., Dorn, H. C. High Relaxivity Trimetallic
                                                                                                                                                                                                                                                         Nitride (Gd3N) Metallofullerene MRI Contrast Agents with Optimized Functionality.
                                                                                                                                                                                                           applied for 120 min at 0.2 μL/min. At         (2009) Bioconjugate Chem. (accepted)
                                                                                                                                                                                                           each time point, three contiguous       5.    Shu, C., Zhang, J., Ge, J., Sim, J. H., Burke, B. G., Williams, K. A., Rylander, N. M.,
                                                                                                                                                                                                                                                         Campbell, T., Puretzky, A., Rouleau, C., Geohegan, D. B., More, K., Esker, A. R.,
                                                                                                                                                                                                           slices shown.                                 Gibson, H. W., Dorn, H. C. A Facile High-speed Vibration Milling Method to Water-
                                                                                                                                T1 computed images and T1                                                                                                disperse Single-walled Carbon Nanohorns . (2009) Chem. Mater. (accepted)
                                                                                                                                weighted images of a live rat
Scheme 2                                                                                                                        brain after direct infusion into
                                                                                                                                the tumor of 0.0235 mM                                                                                                  Acknowledgments
            I. 630 oC/air,10 min.               Succinic acyl acid peroxide                                                     Gd3N@C80[DiPEG350(OH)x].
             II. Gd3N@C80450
                                                                                                                                The middle column indicates
                                                       HSVM, 1.5 h                                                              the slice with the tumor, while       T1 weighted images (a) and
             oC/10-6 torr, 24 h
                                                                                                                                                                      T2 weighted images (b) of
                                                                                                                                                                                                                                                    Other Funding:
                                                                                                                                the left and the right columns
TEM image                           HAADF images of                                                                                                                   direct infusion into T9                                                       National Institute of Health(VCU/VT NCI Platform Grant) R01
of SWNHs                                                                                                                        are slices without tumor used as      tumor-bearing rat brain of
                                    Gd3N@C80@SWNHs                                                                                                                                                                                                  CA119371; Virginia Tech Center for Self-Assembled
                                                                                                                                a control.                            0.0475 mM Gd3N@C80
                                                                                                                                                                                                                                                    NanoDevices (CSAND) and VT Institute of Critical Technologies
                                                                                                                                                                      (OH)26(CH2CH2COOm)16.
                                                                                                                                                                      Infusion was applied for 120                                                  (ICTAS)
I Acetone wash                                                                                                                                                        min at 0.2 μL/min.                                                            Collaborators: Dr. Dave Geohegan at Oak Ridge National
 II water wash                                                                                                                                                                                                                                      Laboratory (ORNL) for providing SWNHs samples. Dr. Chunying
                                                                                                                                                                                                                                                    Shu, Jianfei Zhang, Dr. Michael D. Shultz, Lesley Owens, Dr.
                                                                                                                                                                                                                                                    Alan Esker Dr. Gary Long for portions of the study.


                                               V i r g i n i a                   P o l y t e c h n i c                                         I n s t i t u t e                           a n d            S t a t e                U n i v e r s i t y

				
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