Drug binding rate regulates the properties of polysaccharide prodrugs.

Three intracellular acid-degradable hydroxyethyl starch-doxorubicin (HES[double bond, length as m-dash]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[double bond, length as m-dash]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[double bond, length as m-dash]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[double bond, length as m-dash]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[double bond, length as m-dash]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[double bond, length as m-dash]DOX exhibited great potential in the precise chemotherapy of malignancy.