Peptide-Functionalized Hydrogel Cubes for Active Tumor Cell Targeting

Conjugation of bioactive targeting molecules to nano- or micrometer-sized drug carriers is a pivotal strategy to improve their therapeutic efficiency. Herein, we developed pH- and redox-sensitive hydrogel particles with a surface-conjugated cancer cell targeting ligand for specific tumor-targeting and controlled release of the anticancer drug doxorubicin. The poly(methacrylic acid) (PMAA) hydrogel cubes of 700 nm and 2 μm with a hepsin-targeting (IPLVVPL) surface peptide are produced through multilayer polymer assembly on sacrificial cubical mesoporous cores. The direct peptide conjugation to the disulfide-stabilized hydrogels through a thiol-amine reaction does not compromise the structural integrity, hydrophilicity, stability in serum or the pH/redox sensitivity, but affects the internalization by cancer cells. The cell uptake kinetics and the ultimate extent of internalization is controlled by the cell type and hydrogel size. The peptide modification significantly promotes the uptake of the 700 nm hydr...