Acid-labile anhydride-linked doxorubicin-doxorubicin dimer nanoparticles as drug self-delivery system with minimized premature drug leakage and enhanced anti-tumor efficacy.

Acid-labile anhydride-linked doxorubicin-doxorubicin dimers (D-DOX) were designed as doxorubicin-doxorubicin conjugate-based drug self-delivery systems (DSDSs) with high drug content for tumor intracellular pH-triggered release, by conjugating doxorubicin (DOX) with various anhydrides, such as maleic anhydride (MAH), succinic anhydride (suc), and 2,3-dimethylmaleic anhydride (DMMAH). With the similar diameter of about 200 nm, the D-DOXMAH showed better pH-triggered DOX release and was thus selected for the further investigation. The D-DOX-5 nanoparticles with desirable average hydrodynamic diameter (Dh) of 162 nm and high drug content of 51.20% were obtained via self-assembly by a facile dialysis technique, with the PEGylated dimer (D-DOXMAH-S-PEG) as surfactant. The cumulative DOX release from the proposed D-DOX nanoparticles reached 40.6% within 36 h in the simulated tumor intracellular acidic micro-environment, while the premature drug leakage was only 4.5% in the simulated normal physiological medium. The MTT results indicated the proposed DSDS possessed an enhanced anti-tumor efficacy for the HepG2 cancer cell than the free DOX.