1 research outputs found
Structure-Activity Relationships of Triple-Action Platinum(IV) Prodrugs with Albumin-Binding Properties and Immunomodulating Ligands
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 platinumÂ(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 platinumÂ(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