Due to their high kinetic inertness and consequently reduced side reactions with biomolecules, PtIV complexes are considered to define the future of anticancer platinum drugs. The aqueous stability of a series of biscarboxylato PtIV complexes was studied under physiologically relevant conditions. Unexpectedly and in contrast to the current chemical understanding, especially oxaliplatin and satraplatin complexes underwent fast hydrolysis in equatorial position (even in cell culture medium and serum). Notably, the resulting hydrolysis products strongly differ in their reduction kinetics, a crucial parameter for the activation of PtIV drugs, which also changes the anticancer potential of the compounds in cell culture. The discovery that intact PtIV complexes can hydrolyze at equatorial position contradicts the dogma on the general kinetic inertness of PtIV compounds and needs to be considered in the screening and design for novel platinum‐based anticancer drugs.
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.
Maleimides are essential compounds for drug conjugation reactions via thiols to antibodies, peptides and other targeting units. However,o ne main drawback is the occurrence of thiol exchange reactions with, for example, glutathione resulting in loss of the targeting ability.A new strategyt oo vercome such retro-Michael exchange processes of maleimide-thiol conjugates by stabilization of the thiosuccinimide via at ranscyclization reactioni s presented. This reaction enablest he straightforward synthesis of stable maleimide-thiol adducts essential in drugconjugation applications.
Clinical efficacy of oxaliplatin is frequently limited by severe adverse effects and therapy resistance. Acquired insensitivity to oxaliplatin is, at least in part, associated with elevated levels of glutathione (GSH). In this study we report on an oxaliplatin-based platinum(IV) prodrug, which releases L-buthionine-S,R-sulfoximine (BSO), an inhibitor of glutamate-cysteine ligase, the rate-limiting enzyme in GSH biosynthesis. Two complexes bearing either acetate (BSO-OxOAc) or an albumin-binding maleimide (BSO-OxMal) as second axial ligand were synthesized and characterized. The in vitro anticancer activity of BSO-OxOAc was massively reduced in comparison to oxaliplatin, proving its prodrug nature. Nevertheless, the markedly lower intracellular oxaliplatin uptake in resistant HCT116/OxR cells was widely overcome by BSO-OxOAc resulting in distinctly reduced resistance levels. Platinum accumulation in organs of a colorectal cancer mouse model revealed higher tumor selectivity of BSO-OxMal as compared to oxaliplatin. This corresponded with increased antitumor activity, resulting in significantly enhanced overall survival. BSO-OxMal-treated tumors exhibited reduced GSH levels, proliferative activity and enhanced DNA damage (pH2AX) compared to oxaliplatin. Conversely, pH2AX staining especially in kidney cells was distinctly increased by oxaliplatin but not by BSO-OxMal. Taken together, our data provide compelling evidence for enhanced tumor specificity of the oxaliplatin(IV)/BSO prodrug.
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