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

• Published in: Journal of medicinal chemistry Vol. 64; no. 16; pp. 12132 - 12151
• Main Authors: Fronik, Philipp, Poetsch, Isabella, Kastner, Alexander, Mendrina, Theresa, Hager, Sonja, Hohenwallner, Katharina, Schueffl, Hemma, Herndler-Brandstetter, Dietmar, Koellensperger, Gunda, Rampler, Evelyn, Kopecka, Joanna, Riganti, Chiara, Berger, Walter, Keppler, Bernhard K, Heffeter, Petra, Kowol, Christian R
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 26.08.2021
• Subjects: Animals; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Cell Line, Tumor; Coordination Complexes - chemical synthesis; Coordination Complexes - pharmacology; Coordination Complexes - therapeutic use; Drug Screening Assays, Antitumor; Female; Humans; Immunologic Factors - chemical synthesis; Immunologic Factors - pharmacology; Immunologic Factors - therapeutic use; Indoleamine-Pyrrole 2,3,-Dioxygenase - antagonists & inhibitors; Male; Maleimides - chemical synthesis; Maleimides - pharmacology; Maleimides - therapeutic use; Mice; Mice, Inbred BALB C; Mice, SCID; Molecular Structure; Neoplasms - drug therapy; Platinum - chemistry; Prodrugs - chemical synthesis; Prodrugs - pharmacology; Prodrugs - therapeutic use; Structure-Activity Relationship; Succinimides - chemical synthesis; Succinimides - pharmacology; Succinimides - therapeutic use
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.1c00770

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 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 and in a mouse model . 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.