Doxorubicin-doxorubicin conjugate prodrug as drug self-delivery system for intracellular pH-triggered slow release

[Display omitted] •D-DOXcar with drug content of 86% was designed for pH-triggered slow drug release.•It exhibited particle size- and concentration-dependent slow DOX release.•It showed similar tumor inhibition free from carboxylesterases (CES).•It possessed an enhanced anti-tumor efficacy in comparison with the free DOX. Drug content and releasing rate are the main determining factors for the drug delivery systems (DDSs). Here, doxorubicin dimer (D-DOXcar) was synthesized as drug-drug conjugate prodrug with high drug content of 86%, via an acid-triggered hydrolysable carbamate linker. The prodrug nanoparticles (D-DOXcar-NP) with different diameters were prepared as drug self-delivery system (DSDS) for intracellular pH-triggered slow release. They showed size- and concentration-dependent pH-triggered slow DOX release. For the D-DOXcar-sNP with smaller diameter, the cumulative release ratio reached 25.6% at pH 5.0 within 60 h. The MTT results demonstrated that the proposed DSDS showed similar tumor inhibition regardless of carboxylesterases, and an enhanced anti-tumor efficacy on the HepG2 cells in comparison with the free DOX.