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