In vivo anticancer activity of a rhodium metalloinsertor in the HCT116 xenograft tumor model
Mismatch repair (MMR) deficiencies are a hallmark of various cancers causing accumulation of DNA mutations and mismatches, which often results in chemotherapy resistance. Metalloinsertor complexes, including [Rh(chrysi)(phen)(PPO)]Cl₂ (Rh-PPO), specifically target DNA mismatches and selectively induce cytotoxicity within MMR-deficient cells. Here, we present an in vivo analysis of Rh-PPO, our most potent metalloinsertor. Studies with HCT116 xenograft tumors revealed a 25% reduction in tumor volume and 12% increase in survival with metalloinsertor treatment (1 mg/kg; nine intraperitoneal doses over 20 d). When compared to oxaliplatin, Rh-PPO displays ninefold higher potency at tumor sites. Pharmacokinetic studies revealed rapid absorption of Rh-PPO in plasma with notable accumulation in the liver compared to tumors. Additionally, intratumoral metalloinsertor administration resulted in enhanced anticancer effects, pointing to a need for more selective delivery methods. Overall, these data show that Rh-PPO inhibits xenograft tumor growth, supporting the strategy of using Rh-PPO as a chemotherapeutic targeted to MMR-deficient cancers.
© 2020 the Author(s). Published by PNAS. This open access article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND). Contributed by Jacqueline K. Barton, May 18, 2020 (sent for review April 8, 2020; reviewed by Jonathan L. Sessler and Brian M. Zeglis). PNAS first published July 13, 2020. We are grateful to the NIH for their long-term support of this research (GM33309 to J.K.B.). We thank Dr. Julie Bailis and Dr. Kelsey Boyle for participating in useful discussions that assisted with the design of this study, as well as Dr. Nathan Dalleska from the Environmental Analysis Center at California Institute of Technology for assistance with the ICP-MS analysis. We also thank Yuming Guo for technical assistance. This work was also performed in the City of Hope Analytical Pharmacology Core Facility supported by the National Cancer Institute under Grant P30CA033572. Author contributions: S.D.T., T.W.S., J.W., and J.K.B. designed research; S.D.T. and T.W.S. performed research; S.D.T., T.W.S., and J.W. analyzed data; and S.D.T. and J.K.B. wrote the paper. Reviewers: J.L.S., The University of Texas at Austin; and B.M.Z., Hunter College. The authors declare no competing interest. This article contains supporting information online at https://www.pnas.org/lookup/suppl/doi:10.1073/pnas.2006569117/-/DCSupplemental.
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