Photoactivated Multivariate Metal–Organic Frameworks for On-Demand Drug Release: The Role of Host–Guest Interactions

The development of smart drug delivery vehicles capable of controlled release upon application of an external stimulus is of paramount interest for the next generation of personalized medicine. Herein, we report a series of six multivariate (MTV) MOFs capable of visible light-activated drug delivery. The drug loading capacity and release rates were systematically tuned through variation of the linker ratio between 4,4′-azobenzene dicarboxylic acid (H2ABDA) and 4,4′-(diazene-1,2-diyl)bis(3,5-difluorobenzoic acid) (H2ABDA(3,5-F)). The drug loading capacity, dictated by host–guest interactions, was thoroughly explored via a combined experimental and computational approach using two model drug or drug-like molecules, 5-fluorouracil (5-FU) and Nile Red. Notably, the loading capacity for 5-FU follows a "Goldilocks" profile with a maximum loading at 33% H2ABDA(3,5-F) content. Computational results confirm the existence of a cooperative ligand environment that promotes strong, preferential binding at the tetrahedral/octahedral pore window formed between two H2ABDA and one H2ABDA(3,5-F). Thus, the MTV approach enhanced capacity over the native 100% H2ABDA(3,5-F) and 0% H2ABDA(3,5-F) MOFs. In addition to increased loading, the rate of cargo release upon green light excitation also increased as the percentage of H2ABDA(3,5-F) in the MOF was raised, reaching a maximum release rate of 0.9 ± 0.1% of total cargo per minute for the MOF containing 100% H2ABDA(3,5-F) MOF. The results highlight the promise of MTV MOF design for optimizing drug delivery vehicles with relevant payloads and patient-dictated dosing.