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177Lu-AMBA: Synthesis and Characterization of a Selective 177Lu-Labeled GRP-R Agonist for Systemic Radiotherapy of Prostate Cancer

Laura E. Lantry1, Enrico Cappelletti2, Mary Ellen Maddalena1, Jaclyn S. Fox1, Weiwei Feng1, Jianqing Chen1, Regi Thomas1, Stephen M. Eaton1, Nancy J. Bogdan1, Thangavel Arunachalam1, Jean Claude Reubi3, Natarajan Raju1, Edmund C. Metcalfe1, Luciano Lattuada2, Karen E. Linder1, Rolf E. Swenson1, Michael F. Tweedle1 and Adrian D. Nunn1

1 Ernst Felder Laboratories, Bracco Research USA Inc., Princeton, New Jersey; 2 Bracco Imaging S.p.A., Milan, Italy; and 3 Institute of Pathology, University of Bern, Bern, Switzerland


Figure 1
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  		FIGURE 1.  Chemical structure of 177Lu-AMBA shows proposed coordination in lutetium chelate.

 

Figure 2
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  		FIGURE 2.  Recovery of GRP-R after downregulation in human PC-3 cells by pretreatment with 175Lu-AMBA (6 nmol/L) for 1, 4, and 24 h. Half-maximal downregulation occurred in 2–4 min; ~90% of GRP-R was lost from the cell surface by 1 h.

 

Figure 3
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  		FIGURE 3.  In vivo saturation studies in PC-3 tumor mice at 1 h after administration. Graph depicts percentage uptake in human PC-3 tumor, mouse pancreas, and mouse gastrointestinal tract with increasing peptide mass (HPLC-purified [0.0025 µg], 0.08, 0.22, 0.43, and 0.64 µg).

 

Figure 4
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  		FIGURE 4.  Kaplan–Meier plot of 177Lu-AMBA radiotherapy shows that single-dose (27.75 MBq; n = 32) or 2-dose (55.5 MBq; n = 36) treatment significantly increased life span and reduced tumor growth rate over that of control (single dose, n = 15; 2 dose, n = 16) (120 d: single dose, P < 0.001; 2 dose, P < 0.0001). Overall survival at 30, 60, 90, and 120 d from single dose was 100%, 97%, 47%, and 38%; overall survival from 2 doses spaced 14 d apart was 100%, 100%, 78%, and 47%.

 

Figure 5
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  		FIGURE 5.  Average tumor growth over time with 177Lu-AMBA radiotherapy; single-dose (27.75 MBq) or 2-dose (55.5 MBq). Tumor volumes from day 27 to day 80 were significantly different (P < 0.05), with less variability in 2-dose group (day 27 to day 60), most likely due to additional therapeutic effect of second dose.

 

Figure 6
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  		FIGURE 6.  177Lu-AMBA-treated vs. control tumors. (A) Two-dose treated tumor shows necrosis (n) with few residual vimentin-positive (vim+) PC-3 cells (x20). (B) H&E shows deposition of fibrotic tissue and thickening of tumor capsule, with infiltration of phagocytic cells (x100). (C) Vimentin staining of control tumor demonstrates a solid mass of vimentin-positive (vim+) PC-3 cells (x20). (D) H&E shows a thin capsule without fibrosis (x100).

 




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