1. Structure-Activity Relationships of Triple-Action Platinum(IV) Prodrugs with Albumin-Binding Properties and Immunomodulating Ligands.
- Author
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Fronik P, Poetsch I, Kastner A, Mendrina T, Hager S, Hohenwallner K, Schueffl H, Herndler-Brandstetter D, Koellensperger G, Rampler E, Kopecka J, Riganti C, Berger W, Keppler BK, Heffeter P, and Kowol CR
- Subjects
- Animals, Antineoplastic Agents chemical synthesis, Antineoplastic Agents pharmacology, Cell Line, Tumor, Coordination Complexes chemical synthesis, Coordination Complexes pharmacology, Drug Screening Assays, Antitumor, Female, Humans, Immunologic Factors chemical synthesis, Immunologic Factors pharmacology, Indoleamine-Pyrrole 2,3,-Dioxygenase antagonists & inhibitors, Male, Maleimides chemical synthesis, Maleimides pharmacology, Mice, Inbred BALB C, Mice, SCID, Molecular Structure, Platinum chemistry, Prodrugs chemical synthesis, Prodrugs pharmacology, Structure-Activity Relationship, Succinimides chemical synthesis, Succinimides pharmacology, Succinimides therapeutic use, Mice, Antineoplastic Agents therapeutic use, Coordination Complexes therapeutic use, Immunologic Factors therapeutic use, Maleimides therapeutic use, Neoplasms drug therapy, Prodrugs therapeutic use
- Abstract
Chemotherapy with platinum complexes is essential for clinical anticancer therapy. However, due to side effects and drug resistance, further drug improvement is urgently needed. Herein, we report on triple-action platinum(IV) prodrugs, which, in addition to tumor targeting via maleimide-mediated albumin binding, release the immunomodulatory ligand 1-methyl-d-tryptophan (1-MDT). Unexpectedly, structure-activity relationship analysis showed that the mode of 1-MDT conjugation distinctly impacts the reducibility and thus activation of the prodrugs. This in turn affected ligand release, pharmacokinetic properties, efficiency of immunomodulation, and the anticancer activity in vitro and in a mouse model in vivo . Moreover, we could demonstrate that the design of albumin-targeted multi-modal prodrugs using platinum(IV) is a promising strategy to enhance the cellular uptake of bioactive ligands with low cell permeability (1-MDT) and to improve their selective delivery into the malignant tissue. This will allow tumor-specific anticancer therapy supported by a favorably tuned immune microenvironment.
- Published
- 2021
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