4.7 Article

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

期刊

JOURNAL OF MEDICINAL CHEMISTRY
卷 64, 期 16, 页码 12132-12151

出版社

AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.1c00770

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资金

  1. Austrian Science Fund (FWF) [P28853]
  2. Fellinger Cancer Research Foundation (Fellinger Krebsforschung)
  3. Italian Association for Cancer Research (AIRC) [IG21408]
  4. Austrian Academy of Sciences
  5. EU [CA17104]
  6. Austrian Science Fund (FWF) [P28853] Funding Source: Austrian Science Fund (FWF)

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The study introduces triple-action platinum(IV) prodrugs that target tumors through maleimide-mediated albumin binding and release the immunomodulatory ligand 1-MDT. The research reveals that the mode of 1-MDT conjugation significantly impacts the reducibility and activation of the prodrugs, affecting ligand release, pharmacokinetic properties, immunomodulation efficiency, and anticancer activity. This innovative strategy shows promise in enhancing the delivery of bioactive ligands and improving tumor-specific anticancer therapy.
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.

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