Core-crosslinked polymeric micelles with high doxorubicin loading capacity and intracellular pH- and redox-triggered payload release

• Drug load driven by a combination of ionic bonding and hydrophobic effects.
• High stability upon extensive dilution due to the core-crosslinking.
• High loading capacity and low premature release.
• Rapid release upon entry into the target cells.

Polymeric micelles containing a poly(ethylene glycol) shell and a disulfide-crosslinked core with a hydrophobic moiety and carboxylic acid groups were prepared. The loading of doxorubicin into the core was achieved with a combination of ionic bonding and hydrophobic effects. The cooperativity of these effects enabled doxorubicin to bind tightly to the core, thereby endowing the system with a high loading capacity and a low rate of premature release in the bloodstream. Disulfide crosslinkages prevented the dissociation of the micelles into unimers upon extensive dilution. Under intracellular-like conditions (e.g., pH 5 with the presence of glutathione), the payload was released at a high rate from the micelles. The release was attributed to cleavage of the disulfide crosslinkages by glutathione and disruption of the ionic bonds at a lower pH due to protonation of the carboxylate anions in the core. Intracellular doxorubicin release was found to positively correlate with intracellular glutathione levels.

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