Stepwise optimization of tumor-targeted dual-action platinum(iv)-gemcitabine prodrugs
- Author(s)
- Alexander Kastner, Theresa Mendrina, Tomer Babu, Subhendu Karmakar, Isabella Poetsch, Walter Berger, Bernhard K. Keppler, Dan Gibson, Petra Heffeter, Christian R. Kowol
- Abstract
While platinum-based chemotherapeutic agents have established themselves as indispensable components of anticancer therapy, they are accompanied by a variety of side effects and the rapid occurrence of drug resistance. A promising strategy to address these challenges is the use of platinum(iv) prodrugs, which remain inert until they reach the tumor tissue, thereby mitigating detrimental effects on healthy cells. Typically, platinum drugs are part of combination therapy settings. Consequently, a very elegant strategy is the development of platinum(iv) prodrugs bearing a second, clinically relevant therapeutic in axial position. In the present study, we focused on gemcitabine as an approved antimetabolite, which is highly synergistic with platinum drugs. In addition, to increase plasma half-life and facilitate tumor-specific accumulation, an albumin-binding maleimide moiety was attached. Our investigations revealed that maleimide-cisplatin(iv)-gemcitabine complexes cannot carry sufficient amounts of gemcitabine to induce a significant effect in vivo. Consequently, we designed a carboplatin(iv) analog, that can be applied at much higher doses. Remarkably, this novel analog demonstrated impressive in vivo results, characterized by significant improvements in overall survival. Notably, these encouraging results could also be transferred to an in vivo xenograft model with acquired gemcitabine resistance, indicating the high potential of this approach.
- Organisation(s)
- Department of Inorganic Chemistry, Joint Applied Medicinal Radiochemistry Facility
- External organisation(s)
- Medizinische Universität Wien, Hebrew University Jerusalem, Research Cluster Translational Cancer Therapy Research, Vienna Doctoral School in Chemistry (DoSChem)
- Journal
- Inorganic Chemistry Frontiers
- Volume
- 11
- Pages
- 534-548
- No. of pages
- 15
- ISSN
- 2052-1545
- DOI
- https://doi.org/10.1039/d3qi02032k
- Publication date
- 12-2023
- Peer reviewed
- Yes
- Austrian Fields of Science 2012
- 104003 Inorganic chemistry, 301904 Cancer research
- ASJC Scopus subject areas
- Inorganic Chemistry
- Sustainable Development Goals
- SDG 3 - Good Health and Well-being
- Portal url
- https://ucrisportal.univie.ac.at/en/publications/7ac5c447-7d89-452a-9d28-69d32c31677d