Drug binding rate regulates the properties of polysaccharide prodrugs

Three intracellular acid-degradable hydroxyethyl starch-doxorubicin (HES=DOX) prodrugs with different drug binding rates (DBRs) were synthesized through the conjugation of oxidized HES and DOX with a pH-responsive Schiff base bond. The DBRs of HES=DOX conjugates were determined to be 1.7, 3.3, and 5.9%, which could be facilely adjusted by the feeding molar amount of DOX. All HES=DOX conjugates could spontaneously self-assemble into spherical micellar nanoparticles in phosphate-buffered saline. The hydrodynamic diameter decreased from 73.4 +/- 5.3, 63.9 +/- 5.5, to 51.9 +/- 8.5 nm with the increase of the DBR from 1.7, 3.3, to 5.9%. The DOX release from HES=DOX could be accelerated by the decrease of pH and the DBR, attributed to the acid-sensitive Schiff base bond and the loose core, respectively. Furthermore, the HES=DOX micelle selectively released DOX in the endosome and/or lysosome after cellular uptake, and exhibited excellent proliferation inhibition toward murine melanoma B16F10 cells in vitro and in vivo. Furthermore, the antitumor efficacy was upregulated by the increase of the DBR, benefiting from the selective acidity-triggered DOX release in tumor cells. These results indicated that HES=DOX exhibited great potential in the precise chemotherapy of malignancy.