Oxaliplatin Pt(IV) prodrugs conjugated to gadolinium-texaphyrin as potential antitumor agents.

Autor:	Thiabaud G; Department of Chemistry, University of Texas at Austin, Austin, TX 78712-1224., He G; Department of Experimental Therapeutics, MD Anderson Cancer Center, Houston, TX 77030., Sen S; Department of Chemistry, University of Texas at Austin, Austin, TX 78712-1224., Shelton KA; Department of Comparative Medicine, MD Anderson Cancer Center, Bastrop, TX 78602., Baze WB; Department of Comparative Medicine, MD Anderson Cancer Center, Bastrop, TX 78602., Segura L; Department of Comparative Medicine, MD Anderson Cancer Center, Bastrop, TX 78602., Alaniz J; Department of Chemistry, University of Texas at Austin, Austin, TX 78712-1224., Munoz Macias R; Department of Chemistry, University of Texas at Austin, Austin, TX 78712-1224., Lyness G; Drug Dynamics Institute, College of Pharmacy, University of Texas at Austin, Austin, TX 78712-1224., Watts AB; Drug Dynamics Institute, College of Pharmacy, University of Texas at Austin, Austin, TX 78712-1224., Kim HM; Research Center for Bioconvergence Analysis, Korea Basic Science Institute, Cheongju 28119, Korea., Lee H; Research Center for Bioconvergence Analysis, Korea Basic Science Institute, Cheongju 28119, Korea., Cho MY; Research Center for Bioconvergence Analysis, Korea Basic Science Institute, Cheongju 28119, Korea., Hong KS; Research Center for Bioconvergence Analysis, Korea Basic Science Institute, Cheongju 28119, Korea., Finch R; Department of Comparative Medicine, MD Anderson Cancer Center, Bastrop, TX 78602; rafinch@mdanderson.org zsiddik@mdanderson.org jfarambula@cm.utexas.edu sessler@cm.utexas.edu., Siddik ZH; Department of Experimental Therapeutics, MD Anderson Cancer Center, Houston, TX 77030; rafinch@mdanderson.org zsiddik@mdanderson.org jfarambula@cm.utexas.edu sessler@cm.utexas.edu., Arambula JF; Department of Chemistry, University of Texas at Austin, Austin, TX 78712-1224; rafinch@mdanderson.org zsiddik@mdanderson.org jfarambula@cm.utexas.edu sessler@cm.utexas.edu.; OncoTEX Inc., Austin, TX 78701., Sessler JL; Department of Chemistry, University of Texas at Austin, Austin, TX 78712-1224; rafinch@mdanderson.org zsiddik@mdanderson.org jfarambula@cm.utexas.edu sessler@cm.utexas.edu.; Research Center for Bioconvergence Analysis, Korea Basic Science Institute, Cheongju 28119, Korea.
Jazyk:	angličtina
Zdroj:	Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2020 Mar 31; Vol. 117 (13), pp. 7021-7029. Date of Electronic Publication: 2020 Mar 16.
DOI:	10.1073/pnas.1914911117
Abstrakt:	Described here is the development of gadolinium(III) texaphyrin-platinum(IV) conjugates capable of overcoming platinum resistance by 1) localizing to solid tumors, 2) promoting enhanced cancer cell uptake, and 3) reactivating p53 in platinum-resistant models. Side by side comparative studies of these Pt(IV) conjugates to clinically approved platinum(II) agents and previously reported platinum(II)-texaphyrin conjugates demonstrate that the present Pt(IV) conjugates are more stable against hydrolysis and nucleophilic attack. Moreover, they display high potent antiproliferative activity in vitro against human and mouse cell cancer lines. Relative to the current platinum clinical standard of care (SOC), a lead Gd(III) texaphyrin-Pt(IV) prodrug conjugate emerging from this development effort was found to be more efficacious in subcutaneous (s.c.) mouse models involving both cell-derived xenografts and platinum-resistant patient-derived xenografts. Comparative pathology studies in mice treated with equimolar doses of the lead Gd texaphyrin-Pt(IV) conjugate or the US Food and Drug Administration (FDA)-approved agent oxaliplatin revealed that the conjugate was better tolerated. Specifically, the lead could be dosed at more than three times (i.e., 70 mg/kg per dose) the tolerable dose of oxaliplatin (i.e., 4 to 6 mg/kg per dose depending on the animal model) with little to no observable adverse effects. A combination of tumor localization, redox cycling, and reversible protein binding is invoked to explain the relatively increased tolerability and enhanced anticancer activity seen in vivo. On the basis of the present studies, we conclude that metallotexaphyrin-Pt conjugates may have substantial clinical potential as antitumor agents. Competing Interests: Competing interest statement: Since the time of the original submission, the texaphyrin conjugates described in this manuscript were licensed by The University of Texas to the IQ Global Group and planned for further development by a new for-profit company, OncoTEX Inc. J.F.A. is now employed by OncoTEX Inc., and J.L.S. now serves as a nonexecutive board member for OncoTEX Inc. The other authors declare no conflict of interest.
Databáze:	MEDLINE
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