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

Authors :
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
Kowol CR
Source :
Journal of medicinal chemistry [J Med Chem] 2021 Aug 26; Vol. 64 (16), pp. 12132-12151. Date of Electronic Publication: 2021 Aug 17.
Publication Year :
2021

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.

Details

Language :
English
ISSN :
1520-4804
Volume :
64
Issue :
16
Database :
MEDLINE
Journal :
Journal of medicinal chemistry
Publication Type :
Academic Journal
Accession number :
34403254
Full Text :
https://doi.org/10.1021/acs.jmedchem.1c00770