Comparative Evaluation of Thiol- and Amine-Conjugating Moieties for Endogenous Albumin Binding after Intravenous Administration

TL;DR

This study compares new chemical groups for binding to albumin in the body, finding that one (PODS) works better than the commonly used maleimide for drug delivery.

Contribution

The study introduces and evaluates phenyloxadiazolyl methyl sulfone (PODS) as a more stable alternative to maleimide for endogenous albumin binding in drug delivery.

Findings

PODS and DFSA complexes showed higher hydrolytic stability at pH 7.4 compared to maleimide complexes.

PODS-Ox-OAc induced significant tumor regression and prolonged survival in CT26 colon cancer-bearing mice.

PODS complexes exhibited high platinum levels in serum and tumor tissue, outperforming other binders.

Abstract

Maleimides are widely used in anticancer drug development
for linking
small-molecule drugs to macromolecules like antibodies or proteins
via thiol-Michael addition reactions. Despite their widespread use,
even in clinically approved therapeutics, they present significant
drawbacks such as hydrolysis at physiological pH and instability of
the formed thiosuccinimide bond. Hence, there is a growing need for
more stable yet equally efficient binding units. This is particularly
important for drug-delivery systems that bind to endogenous albumin
in vivo, exploiting the ability of the protein to accumulate in tumor
tissue. This study compares phenyloxadiazolyl methyl sulfone (PODS)
and a 2,4-difluorophenyl sulfonamide (DFSA) derivative with maleimide
as endogenous albumin binders. Of note, PODS and maleimide bind to
Cys34, whereas DFSA targets Lys64 of albumin. The albumin binders
were conjugated as axial ligands to oxaliplatin­(IV) complexes (PODS-Ox-OAc and DFSA-Ox-OAc) and studied in comparison
to a maleimide-bearing reference compound (Mal-Ox-OAc). Both PODS- and DFSA-complexes showed higher hydrolytic stability
at pH 7.4 than the maleimide complex. Albumin-binding was highly efficient
for the PODS and maleimide complexes. However, the DFSA derivative
exhibited only slow conjugation. This was also reflected in the serum
pharmacokinetic and organ distribution studies using CT26 colon cancer-bearing
mice. Here, the PODS complex showed the highest platinum levels in
both serum and tumor tissue. Additionally, PODS-Ox-OAc induced the most significant tumor regression and prolonged overall
survival in this model. Together, our data highlight PODS as a promising
alternative to maleimide as an endogenous albumin binder.

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