| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
Basic Science Investigations |
1 Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, Missouri
2 Department of Chemistry, Washington University, St. Louis, Missouri
3 Department of Radiology, University of Texas Southwestern Medical Center, Dallas, Texas
Long-circulating nanoparticles functionalized with ligands for receptors overexpressed by tumor cells have promising applications for active and passive tumor targeting. The purpose of this study was to evaluate 64Cu-radiolabeled folate-conjugated shell cross-linked nanoparticles (SCKs) as candidate agents to shuttle radionuclides and drugs into tumors overexpressing the folate receptor (FR). Methods: SCKs were obtained by cross-linking the shell of micelles obtained from amphiphilic diblock copolymers. SCKs were then functionalized with folate, fluorescein thiosemicarbazide (FTSC), and 1,4,8,11-tetraazacyclotetradecane-N,N',N'',N'''-tetraacetic acid (TETA). The specific interaction of SCK-folate with the FR was investigated on KB cells. The biodistributions of 64Cu-TETA-SCK and 64Cu-TETA-SCK-folate were evaluated in athymic mice bearing small-size KB cell xenografts (10–100 mg), whereas the intratumor distributions were investigated by autoradiography in 0.3- to 0.6-g KB cell xenografts. Results: A global solution-state functionalization strategy has been introduced for attaching optimum numbers of targeting and imaging agents onto the SCKs for increasing the efficiency of interaction with cell-surface receptors. Epifluorescence microscopy confirmed the specific interaction of FTSC-SCK-folate with the FR in vitro. 64Cu labeling of TETA-SCKs led to the radiolabeled compounds with 15%–20% yield and >95% radiochemical purity. The biodistribution results demonstrated high accumulation of 64Cu-labeled SCKs in organs of the reticuloendothelial system (RES) (56.0 ± 7.1 %ID/g and 45.7 ± 3.5 %ID/g [percentage injected dose per gram] in liver at 10 min after injection for folated and nonfolated SCKs, respectively) and a prolonged blood circulation. No increase of SCK tumor uptake deriving from folate conjugation was observed (5.9 ± 2.8 %ID/g and 6.0 ± 1.9 %ID/g at 4 h after injection for folated and nonfolated SCKs, respectively). However, tumor accumulation was higher in small-size tumors, where competitive block of SCK-folate uptake with excess folate was observed. Autoradiography results confirmed the extravasation of radiolabeled SCKs in vascularized areas of the tumor, whereas no diffusion was observed in necrotic regions. Conclusion: Despite high RES uptake, the evaluated 64Cu-labeled SCKs exhibited long circulation in blood and were able to passively accumulate in tumors. Furthermore, SCK-folate uptake was competitively blocked by excess folate in small-size solid tumors, suggesting interaction with the FR. For these reasons, functionalized SCKs are promising drug-delivery agents for imaging and therapy of early-stage solid tumors.
Key Words: 64Cu • folate-nanoparticles • radiolabeling • folate receptor • enhanced permeability and retention effect
This article has been cited by other articles:
|
|
 |
|
  R. Rossin, S. Muro, M. J. Welch, V. R. Muzykantov, and D. P. Schuster In Vivo Imaging of 64Cu-Labeled Polymer Nanoparticles Targeted to the Lung Endothelium J. Nucl. Med., January 1, 2008; 49(1): 103 - 111. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. L. Ehman, W. R. Hendee, M. J. Welch, N. R. Dunnick, L. B. Bresolin, R. L. Arenson, S. Baum, H. Hricak, and J. H. Thrall Blueprint for Imaging in Biomedical Research Radiology, July 1, 2007; 244(1): 12 - 27. [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| JOURNAL OF NUCLEAR MEDICINE TECHNOLOGY | THE JOURNAL OF NUCLEAR MEDICINE |
