Evaluation of the potential application of RAPA-based delivery: Structural evolution and biocompatibility of monodispersed nano-ZIF-8@RAPA

Rapamycin (RAPA) is widely used in biomedical applications due to its antitumor, autoimmune disease and neuroprotective effects. However, direct administration of RAPA may lead to side effects such as excessive suppression of the immune system, severe infections and increased risk of tumors. Zeolitic imidazolate framework-8 (ZIF-8) is one of the most promising MOFs that shows great potential in the field of drug delivery. In this study, we successfully prepared nano-ZIF-8 particles of uniform size and monodispersity by optimizing the reaction time, stirring time, and reactant concentration. ZIF-8 was used as a carrier loaded with RAPA (ZIF-8@RAPA), which was characterized by XRD, FTIR, UV vis, TGA, and zeta potential, and the results revealed that ZIF-8@RAPA with a dodecahedral morphology, a particle size of 82 nm ± 4.7 nm, and a drug-loading rate of up to 11.53 % was successfully synthesized and that the loaded RAPA could achieve long-lasting slow release. Furthermore, we monitored the structural evolution of ZIF-8@RAPA in PBS. We found that the structural stability of ZIF-8@RAPA could be maintained for up to 6 weeks, followed by the gradual cleavage and disintegration of the crystal structure, and the reformation of micro-crystals (dia(Zn)) at 8 weeks, which is presumed to be affected by the [HPO 4 ] 2- in the PBS solution. In addition, the biocompatibility of the ZIF-8@RAPA delivery system was comprehensively evaluated using macrophage RAW 264.7 and the zebrafish embryo model. The results revealed that the biotoxicity of ZIF-8@RAPA was concentration dependent and that it had good biocompatibility when it was applied at concentrations lower than 100 μg/mL. In summary, our study preliminarily elucidated the in vitro disintegration and reconstruction mechanisms of nano-ZIF-8@RAPA crystals and demonstrated their feasibility for application in biomedical fields.