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

Abstract

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 IC50 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.

Advances of typical mesoporous materials and the application in drug delivery

“…The COF HP exhibited a pHresponsive drug release behavior, the released rate of DOX up to 90% within the first 8 h in COF HP faster than that in COF (∼55%). Moreover, the biocompatibility of COF HP and COF, and the significantly stronger cytotoxicity of DOX loaded COF HP than that of DOX loaded COF were proved (figure 4) [85]. In conclusion, COFs and the derivatives based drug delivery systems exhibited obvious advantages.…”

“…Das et al proved that the 2D-COF (TRIPTA-COF ) loaded cisplatin displayed superior inhibition against triple negative breast cancer (TNBC) cells and TRIPTA-COF could be internalized by the cancer cells in a time-dependent manner [84]. In order to improve the controllability of particle sizes and degradability, a dendritic mesoporous silica nanosphere (DMSN)-mediated growth strategy was employed to fabricate hierarchical DMSN@COF hybrids [85]. After the removal of the DMSN template, COF hierarchical particles (COF HP) with tailored particle sizes and degradability were obtained.…”

Covalent organic frameworks (COFs) as carrier for improved drug delivery and biosensing applications

“…benzene-associated COF with cleavable C = N linkages. Because of the increased porosity and surface area, DOX can be injected into the COF HP at a larger dosage (46.8 wt%) than bulk COF (32.1 wt%), as presented in Table 2 (Zhou et al, 2022).…”

“…Zhou and his coworkers presented a growth strategy using dendritic mesoporous silica nanospheres (DMSNs) that involves growing in situ 2,5‐dimethoxyterephthaldehyde as well as 1,3,5‐tris(4‐aminophenyl)benzene‐associated COF with cleavable C = N linkages. Because of the increased porosity and surface area, DOX can be injected into the COF HP at a larger dosage (46.8 wt%) than bulk COF (32.1 wt%), as presented in Table 2 (Zhou et al, 2022).…”