The novel platinum(IV) prodrug with self-assembly property and structure-transformable character against triple-negative breast cancer

Abstract

Herein, a small library of Pt(IV) prodrugs based on cisplatin and chemosensitizer adjudin (ADD) were explored for efficient cisplatin resistant triple-negative breast cancer (TNBC) treatment. We further elucidated the detail relationship of chemical structure, alkyl chain length (ethyl to dodecyl) and ADD substituted degree, with respect to the self-assembly ability and cytotoxic effect of prodrugs. It demonstrated that all prodrugs could self-assemble into nanomedicine, which was in consist with the molecule structure building and self-assembly simulation. All nanomedicines possessed small particle size, uniform morphology and ultra-high drug loading content (84.0%-86.5%). Moreover, the length of alkyl chain was of great importance for the structure-transformable character and cytotoxicity of nanomedicines. Interestingly, ADD monosubstituted with butyl or hexyl contralateral substituted prodrug (C₄-Pt-ADD or C₆-Pt-ADD) assembled nanomedicine could convert to wire or sheet structure. These transformable nanoparticles showed great potential in improving the sensitivity of cisplatin to TNBC with up to 266-fold lower IC₅₀ value and significantly enhanced in vivo tumor growth inhibition. Therefore, the self-assembled nanomedicine based on Pt(IV)-ADD could be a promising strategy for TNBC therapy.

Keywords: Adjudin; Drug resistance; Platinum(IV) prodrug; Self-assembly; Structure transform; Triple-negative breast cancer.