TY - JOUR
T1 - Imaging taxane-induced tumor apoptosis using PEGylated, 111In-labeled annexin V
AU - Ke, Shi
AU - Wen, Xiaoxia
AU - Wu, Qing Ping
AU - Wallace, Sidney
AU - Charnsangavej, Chusilp
AU - Stachowiak, Anne M.
AU - Stephens, Clifton L.
AU - Abbruzzese, James L.
AU - Podoloff, Donald A
AU - Li, Chun
PY - 2004/1/1
Y1 - 2004/1/1
N2 - 99mTc-Labeled annexin V has been used for the imaging of tumor apoptosis induced by chemotherapy. However, owing to the short half-life of annexin V, multiple injections of the radiotracer are necessary to capture the peak apoptotic activity. In this study, we evaluated the imaging properties of an 111In-labeled, long-circulating annexin V. Methods: Both polyethylene glycol (PEG) and the metal chelator diethylenetriaminepentaacetic acid (DTPA) were simultaneously introduced to annexin V or ovalbumin through the use of a heterofunctional PEG precursor. Imaging studies were performed in mice bearing subcutaneously inoculated human mammary MDA-MB-468 tumors. The mice were treated with poly(L-glutamic acid)-paclitaxel, monoclonal antibody C225, or a combination of poly(L-glutamic acid)-paclitaxel and C225, followed by intravenous injection of 111In-DTPA-PEG-annexin V. Images were acquired 48 h after the injection of the radiotracer. Autoradiography and TUNEL (terminal deoxynucleotidyltransferase-mediated dUTP nick-end labeling) staining were performed on adjacent tumor slices for the localization of apoptotic cells. The imaging properties of unPEGylated annexin V and PEGylated ovalbumin were also determined to permit assessment of the specificity of 111In- DTPA-PEG-annexin V. Results: Tumor apoptotic index increased from 1.67% ± 0.31% at baseline to 7.60% ± 0.72% and 11.07% ± 1.81%, respectively, 4 d after treatment with poly(L-glutamic acid)-paclitaxel or combined poly(L-glutamic acid)-paclitaxel and C225. Tumor uptake (percentage of injected dose per gram of tumor [%ID/g]) of PEGylated 111In-DTPA-PEG- annexin 4 d after treatment was significantly higher in tumors treated with poly(L-glutamic acid)-paclitaxel (10.76 ± 1.38 %ID/g; P = 0.001) and with combined poly(L-glutamic acid)-paclitaxel and C225 (9.84 ± 2.51 %ID/g; P = 0.029) than in nontreated tumors (6.14 ± 0.67 %ID/g), resulting in enhanced visualization of treated tumors. 111In-DTPA-PEG-annexin V distributed into the central zone of tumors, whereas 111In-DTPA- annexin V was largely confined to the tumor periphery. Furthermore, uptake of 111In-DTPA-PEG-annexin V by tumors correlated with apoptotic index (r = 0.87, P = 0.02). Increase in tumor uptake of the nonspecific PEGylated protein 111In-DTPA-PEG-ovalbumin was also observed after poly(L-glutamic acid)-paclitaxel treatment (55.6%), although this increase was less than that observed for 111In-DTPA-PEG-annexin V (96.7%). Conclusion: Increased uptake of and improved visualization with 111In-DTPA-PEG-annexin V in solid tumors after chemotherapy are mediated through both specific binding to apoptotic cells and nonspecific retention of macromolecular contrast agents in the tumors. 111In- Labeled, PEGylated annexin V may be used to assess tumor response to chemotherapy.
AB - 99mTc-Labeled annexin V has been used for the imaging of tumor apoptosis induced by chemotherapy. However, owing to the short half-life of annexin V, multiple injections of the radiotracer are necessary to capture the peak apoptotic activity. In this study, we evaluated the imaging properties of an 111In-labeled, long-circulating annexin V. Methods: Both polyethylene glycol (PEG) and the metal chelator diethylenetriaminepentaacetic acid (DTPA) were simultaneously introduced to annexin V or ovalbumin through the use of a heterofunctional PEG precursor. Imaging studies were performed in mice bearing subcutaneously inoculated human mammary MDA-MB-468 tumors. The mice were treated with poly(L-glutamic acid)-paclitaxel, monoclonal antibody C225, or a combination of poly(L-glutamic acid)-paclitaxel and C225, followed by intravenous injection of 111In-DTPA-PEG-annexin V. Images were acquired 48 h after the injection of the radiotracer. Autoradiography and TUNEL (terminal deoxynucleotidyltransferase-mediated dUTP nick-end labeling) staining were performed on adjacent tumor slices for the localization of apoptotic cells. The imaging properties of unPEGylated annexin V and PEGylated ovalbumin were also determined to permit assessment of the specificity of 111In- DTPA-PEG-annexin V. Results: Tumor apoptotic index increased from 1.67% ± 0.31% at baseline to 7.60% ± 0.72% and 11.07% ± 1.81%, respectively, 4 d after treatment with poly(L-glutamic acid)-paclitaxel or combined poly(L-glutamic acid)-paclitaxel and C225. Tumor uptake (percentage of injected dose per gram of tumor [%ID/g]) of PEGylated 111In-DTPA-PEG- annexin 4 d after treatment was significantly higher in tumors treated with poly(L-glutamic acid)-paclitaxel (10.76 ± 1.38 %ID/g; P = 0.001) and with combined poly(L-glutamic acid)-paclitaxel and C225 (9.84 ± 2.51 %ID/g; P = 0.029) than in nontreated tumors (6.14 ± 0.67 %ID/g), resulting in enhanced visualization of treated tumors. 111In-DTPA-PEG-annexin V distributed into the central zone of tumors, whereas 111In-DTPA- annexin V was largely confined to the tumor periphery. Furthermore, uptake of 111In-DTPA-PEG-annexin V by tumors correlated with apoptotic index (r = 0.87, P = 0.02). Increase in tumor uptake of the nonspecific PEGylated protein 111In-DTPA-PEG-ovalbumin was also observed after poly(L-glutamic acid)-paclitaxel treatment (55.6%), although this increase was less than that observed for 111In-DTPA-PEG-annexin V (96.7%). Conclusion: Increased uptake of and improved visualization with 111In-DTPA-PEG-annexin V in solid tumors after chemotherapy are mediated through both specific binding to apoptotic cells and nonspecific retention of macromolecular contrast agents in the tumors. 111In- Labeled, PEGylated annexin V may be used to assess tumor response to chemotherapy.
KW - Annexin V
KW - Apoptosis
KW - Nuclear imaging
KW - Paclitaxel
KW - Polyethylene glycol
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M3 - Article
C2 - 14734682
AN - SCOPUS:1842592126
SN - 0161-5505
VL - 45
SP - 108
EP - 115
JO - Journal of Nuclear Medicine
JF - Journal of Nuclear Medicine
IS - 1
ER -