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 1547 20422 2079 28231 763 23125
The enhanced water proton relaxivities (r1) for the new trimetallic nitride PBS 291 374 352 627 181 728
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)
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].
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
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
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