Many anticancer drugs are hydrophobic and lack tumor selectivity, which reduces their efficacy in cancer therapy. Stimuli-responsive hydrogels are capable of improving the therapeutic function of encapsulated agents because of their ability to achieve on-demand drug release. However, application of these systems to hydrophobic drug delivery has been limited due to the incompatibility between hydrophobic drugs and a hydrophilic hydrogel network. Herein, we present a facile method to prepare a poly(methacrylic acid) (PMAA)-based multilayer hydrogel with controlled nanostructure, cubical shape and redox-responsiveness for the efficient delivery of the hydrophobic anticancer therapeutic 7-(benzylamino)-3,4-dihydro-pyrrolo[4,3,2-de]quinolin-8(1H)-one (BA-TPQ), resulting in a drug delivery platform with enhanced anticancer effect and selective activity to hepatocellular carcinoma cells. The BA-TPQ-loaded hydrogels maintain their cubical shape and pH-sensitivity after lyophilization, which is advantageous for a long-term storage. In contrast, the multilayer hydrogels degrade in the presence of typical intracellular concentrations of glutathione, which ensures fast intracellular drug release. Encapsulating BA-TPQ into hydrogels significantly increases its transport through Caco-2 cell monolayers with a ~2-fold higher permeability coefficient, indicating the potential of our PMAA matrix for oral delivery of BA-TPQ. BA-TPQ-hydrogel cubes exhibit better anticancer activity against HepG2 and Huh7 hepatoma cells with ~40% decrease in the IC<sub>50</sub> value compared to non-encapsulated drug. Remarkably, non-malignant liver cells have a lower sensitivity to BA-TPQ-hydrogel cubes with &gt;2-fold increased IC<sub>50</sub> value compared to those of cancer cells. In addition, the BA-TPQ encapsulation by the hydrogels amplifies the drug potency due to the increased down-regulation of MDM2 oncogenic protein and upregulation of p53 (a tumor suppressor) and p21 (cell proliferation suppressor) expression in HepG2 liver cancer cells. Moreover, enhanced inhibition of MDM2 protein expression by BA-TPQ-hydrogel cubes is independent of p53 status in Huh7 cells. This drug delivery platform of non-spherical shape provides a facile method for encapsulation of hydrophobic drugs and facilitates the enhanced efficacy of BA-TPQ for liver cancer therapy.

Highly efficient delivery of potent anticancer iminoquinone derivative by multilayer hydrogel cubes

254th National Meeting (2017)

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