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⁶⁴Cu-Labeled Folate-Conjugated Shell Cross-Linked Nanoparticles for Tumor Imaging and Radiotherapy: Synthesis, Radiolabeling, and Biologic Evaluation

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

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