Synthesis and Characterization of a Theranostic Vascular Disrupting Agent for In Vivo MR Imaging

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• 作者：Tammy L. Kalber ; Nazila Kamaly ; Stephanie A. Higham ; John A. Pugh ; Josephine Bunch ; Cameron W. McLeod ; Andrew D. Miller ; Jimmy D. Bell
• 刊名：Bioconjugate Chemistry
• 出版年：2011
• 出版时间：May 18, 2011
• 年：2011
• 卷：22
• 期：5
• 页码：879-886
• 全文大小：1025K
• 年卷期：v.22,no.5(May 18, 2011)
• ISSN：1520-4812

文摘

Colchicine, a known tubulin binding agent and vascular disrupting agent, causes rapid vascular shut down and central necrosis in tumors. The binding of tubulin results in tubulin destabilization, with characteristic cell shape changes and inhibition of cell division, and results in cell death. A gadolinium(III) labeled derivative of colchicine (Gd路DOTA路Colchicinic acid) was synthesized and characterized as a theranostic agent (enabling simultaneous diagnostic/real time MRI contrast imaging). In vitro, Gd路DOTA路Colchicinic acid was shown to initiate cell changes characteristic of tubulin-destabilization in both OVCAR-3 and IGROV-1 ovarian carcinoma cell lines in vitro over a period of 24 h, while maintaining the qualities of the MR imaging tracer. In vivo, Gd路DOTA路Colchicinic acid (200 mg/kg) was shown to induce the formation of central necrosis, which was confirmed ex vivo by histology, in OVCAR-3 subcutaneous tumor xenografts, while simultaneously acting as an imaging agent to promote a significant reduction in the MR relaxation time T₁ (p < 0.05) of tumors 24 h post-administration. Morphological changes within the tumor which corresponded with areas derived from the formation of central necrosis were also present on MR images that were not observed for the same colchicine derivate that was not complexed with gadolinium that also presented with central necrosis ex vivo. However, Gd路DOTA路Colchicinic acid accumulation in the liver, as shown by changes in liver T₁ (p < 0.05), takes place within 2 h. The implication is that Gd路DOTA路Colchicinic acid distributes to tissues, including tumors, within 2 h, but enters tumor cells to lower T₁ times and promotes cell death over a period of up to 24 h. As the biodistribution/pharmacokinetic and pharmacodynamics data provided here is similar to that of conventional colchicines derivatives, such combined data are a potentially powerful way to rapidly characterize the complete behavior of drug candidates in vivo.