Templated Assembly of pH-Labile Covalent Organic Framework Hierarchical Particles for Intracellular Drug Delivery

Covalent organic frameworks (COF), a class of emerging microporous polymers, have been restrained for drug delivery applications due to their limited controllability over particle sizes and degradability. Herein, a dendritic mesoporous silica nanosphere (DMSN)-mediated growth strategy is proposed to fabricate hierarchical DMSN@COF hybrids through in situ growing of 1,3,5-tris(4-aminophenyl)benzene and 2,5-dimethoxyterephthaldehyde connected COF with acid cleavable C=N bonds. After the removal of the DMSN template, COF hierarchical particles (COF HP) with tailored particle sizes and degradability were obtained. Notably, the COF HP could be degraded by 55% after 24 h of incubation at pH 5.5, whereas the counterpart bulk COF only showed 15% of degradation in the same conditions. Due to the improved porosity and surface area, the COF HP can be utilized to load the chemotherapeutic drug, doxorubicin (DOX), with a high loading (46.8 wt%), outperforming the bulk COF (32.1 wt%). Moreover, around 90% of the loaded DOX can be discharged from the COF HP within 8 h of incubation at pH 5.5, whereas, only ~55% of the loaded DOX was released from the bulk COF. Cell experiments demonstrated that the IC(50) value of the DOX loaded in COF HP was 2–3 times lower than that of the DOX loaded in the bulk COF and the hybrid DMSN@COF. Attributed to the high loading capacity and more pH-labile particle deconstruction properties, COF HP shows great potential in the application as vehicles for drug delivery.