Structure-Activity Relationships of Triple-Action Platinum(IV) Prodrugs with Albumin-Binding Properties and Immunomodulating Ligands.

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.

• Authors: Philipp Fronik, Isabella Poetsch, Alexander Kastner, Theresa Mendrina, Sonja Hager, Katharina Hohenwallner, Hemma Schueffl, Dietmar Herndler-Brandstetter, Gunda Koellensperger, Evelyn Rampler, Joanna Kopecka, Chiara Riganti, Walter Berger, Bernhard K Keppler, Petra Heffeter, Christian R Kowol
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 64 Issue 16 Pg. 12132-12151 (08 26 2021) ISSN: 1520-4804 [Electronic] United States
• PMID: 34403254 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Coordination Complexes
• Immunologic Factors
• Indoleamine-Pyrrole 2,3,-Dioxygenase
• Maleimides
• Prodrugs
• Succinimides
• Platinum

Topics

• Animals
• Antineoplastic Agents (chemical synthesis, pharmacology, therapeutic use)
• Cell Line, Tumor
• Coordination Complexes (chemical synthesis, pharmacology, therapeutic use)
• Drug Screening Assays, Antitumor
• Female
• Humans
• Immunologic Factors (chemical synthesis, pharmacology, therapeutic use)
• Indoleamine-Pyrrole 2,3,-Dioxygenase (antagonists & inhibitors)
• Male
• Maleimides (chemical synthesis, pharmacology, therapeutic use)
• Mice, Inbred BALB C
• Mice, SCID
• Molecular Structure
• Neoplasms (drug therapy)
• Platinum (chemistry)
• Prodrugs (chemical synthesis, pharmacology, therapeutic use)
• Structure-Activity Relationship
• Succinimides (chemical synthesis, pharmacology, therapeutic use)
• Mice