Mechanism and energetics for complexation of {sup 90}Y with 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA), a model for cancer radioimmunotherapy
A promising cancer therapy involves the use of the macrocyclic polyaminoacetate DOTA (1,4,6,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) attached to a tumor-targeting antibody complexed with the {beta} emitter {sup 90}Y{sup 3+}. However, incorporation of the {sup 90}Y into the DOTA conjugate is too slow. To identify the origins of this problem, ab initio quantum chemistry methods (B3LYP/:ACVP* and HF/LACVP*) were used to predict structures and energetics. The authors find that the initial complex YH{sub 2}(DOTA){sup +} is 4-coodinate (the four equivalent carboxylate oxygens), which transforms to YH(DOTA) (5-coordinate with one ring N and four carboxylate oxygens), and finally to Y(DOTA){sup {minus}}, which is 8-coordinate (four oxygens and four nitrogens). The rate-determining step is the conversion of YH(DOTA) to Y(DOTA){sup {minus}}, which was calculated to have an activation free energy (aqueous phase) of 8.4 kcal/mol, in agreement with experimental results (8.1--9.3 kcal/mol) for various metals to DOTA [Kumar, K.; Tweedle, M.F. Inorg. Chem. 1993, 32, 4193--4199; Wu, S.L.; Horrocks, W.D., Jr., Inorg. Chem. 1995, 34, 3724--2732]. On the basis of this mechanism the authors propose a modified chelate, DO3AlPr, which has calculated at a much faster rate of incorporation.
- Research Organization:
- California Inst. of Tech., Pasadena, CA (US)
- Sponsoring Organization:
- National Science Foundation; National Institutes of Health; US Department of Energy
- OSTI ID:
- 20000114
- Journal Information:
- Journal of the American Chemical Society, Journal Name: Journal of the American Chemical Society Journal Issue: 26 Vol. 121; ISSN JACSAT; ISSN 0002-7863
- Country of Publication:
- United States
- Language:
- English
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