Integrating a hydrogen-bonded complex as a secondary building unit to construct a multivariate framework for programmable drug delivery

Abstract

Porous organic frameworks (POFs) consisting of organic building blocks through covalent bonds are novel functional solids. However, the pure covalent bonding pattern leads to the inability to produce strong and selective interactions with organic molecules, restricting applications in biomedical, detection, and sensing fields. Herein, we report a hydrogen-bonded complex (HC) of 5-fluorouracil (5-FU) and p-aminobenzoic acid as a building block to construct a hybrid-bonded framework (F@POF) via a Schiff base reaction, integrating covalent and hydrogen-bonded motifs. The existence of multiple hydrogen bonds enabled 5-FU to exhibit 19-fold enhanced binding affinity versus physical encapsulation. Capitalizing on differential interaction modalities, cyclophosphamide (CTX) and methotrexate (MTX) were sequentially immobilized via van der Waals forces into the F@POF channels and dual hydrogen/π–π interactions on the pore surface, respectively, yielding a triple-drug co-doped multivariate porous framework, CMF@POF. The programmable release (5-FU > MTX > CTX) endowed CMF@POF with remarkable antitumor activity in in vivo mouse experiments, outperforming the classical CMF chemotherapy. This hydrogen-bond-guided engineering paradigm redefines multifunctional POFs for intelligent multidrug delivery, offering a transformative approach to optimize combination chemotherapy.