Striking a Balance between Carbonate/Carbamate Linkage Bond- and Reduction-Sensitive Disulfide Bond-Bearing Linker for Tailored Controlled Release: In Situ Covalent-Albumin-Binding Gemcitabine Prodrugs Promote Bioavailability and Tumor Accumulation

To address the challenges of rapid
enzyme inactivation, poor tumor
targeting, and acquired drug resistance in gemcitabine (GEM) application,
we report two groups of maleimide-functionalized GEM prodrugs conjugating
covalently in situ with Cys-34 of blood-circulating albumin and then
resulting in macromolecular prodrugs after intravenous administration.
Tailored and accurate controlled release was achieved through different
combinations of linkage bonds, relatively stable and labile (carbamate
and carbonate, respectively), and linkers with or without insertion
of a disulfide bond. Interestingly, we found that the overall advantages
or disadvantages brought by a disulfide bond varied with the stability
of the linkage bond. Finally, the carbonate linkage bond-bearing group,
especially the one with a linker lacking a disulfide bond, stood out
with remarkably increased bioavailability (21-fold greater than GEM)
and efficient tumor free-GEM accumulation (8-fold of GEM), which consequently
contributed to excellent in vivo antitumor efficacy.