Double security drug delivery system DDS constructed by multi-responsive (pH/redox/US) microgel

In this paper, the multi-responsive core-shell microgels were prepared for constructing a double-locked drug delivery system. The pH- sensitive poly(2-(diisopropylamino ethylmethacry-late)-block-poly(ethyleneimine) diblock copolymers (PDPA-b-PEI) were synthesized and used to prepare micelles through their self-assembly in neutral solution. Redox-responsive gel shells were formed by Michael addition of primary amine group of branched PEI using disulfide as a cross-linker, which was specifically cleaved by glutathione (GSH). Anticancer drug doxorubicin DOX and perfluorohexane (PFH) could be encapsulated in the core of microgel. The DOX was released sustainably only under the condition of pH and GSH were both right. For example, under neutral condition with GSH, DOX could not release swimmingly due to the core of microgels was in hydrophobic state and wrapped the DOX firmly, although the gel shells were collapsed by GSH. When exposed to ultrasound, the drug released abruptly and achieved a complete release instantly. Moreover, it was found that the structure of the microgels was not destroyed after the ultrasound stimulus but had undergone an expansion-recovery process. Finally, it was demonstrated that the microgel had a "double security" effect, ensuring the low drug leakage during the normal blood circulation and efficient drug release under the pH/redox/ultrasound stimulus. The multi-responsive microgels designed here, which combines the usage of both endogenous and exogenous stimuli, has the advantages of low side-effect, high spatiotemporal controllability and complete release.