Efficient oral insulin delivery with sustained release by folate-conjugated metal-organic framework nanoparticles
Jun-Jie Zou, Qing Chen, Joshua Phipps, Yu Zhao, Xudong Qin, Wanyi Tai, Shengqian Ma*, Jian Tian*
Matter 2024
https://doi.org/10.1016/j.matt.2024.101948
Highlights
•Sustained-release oral insulin delivery by folate-conjugated MOF nanoparticles
•Overcoming intestinal epithelial barriers via PCFT-mediated epithelial transport
•Selectively hypoglycemic effect in diabetics with reduced hypoglycemia risk
•Extraordinary oral bioavailability and extended duration of action of insulin
Progress and potential
Long-acting oral delivery of therapeutic proteins/peptides poses one of the biggest challenges in drug delivery. This study reports a simple yet highly efficient oral formulation based on folate-conjugated Zr-MOF nanoparticles, which realizes sustained insulin release selectively in diabetics and extraordinary bioavailability. The acid-resistant Zr-MOF nanocarriers protect insulin from acid and enzymatic degradation in the harsh gastrointestinal environment. By utilizing functional folate molecules to occupy the vacant coordination sites of metal clusters in Zr-MOF, MOF nanocarriers can not only achieve specific intestinal transport but also realize highly controlled insulin release behaviors in vivo with reduced hypoglycemia risk, avoiding rapid disintegration and burst drug release. The extended drug duration and improved efficacy of MOF-based oral protein/peptide delivery nanosystems offer translational opportunities for effective glycemic management in the long term.
Summary
Oral protein/peptide delivery systems have garnered global interest due to their potential to provide substantial benefits to patients. However, their clinical translation has been impeded by challenges pertinent to poor intestinal permeability, acid instability, and the short half-life of proteins/peptides. Here, we report a simple, efficient, and sustained-release oral insulin delivery system based on folic acid (FA)-conjugated acid-resistant metal-organic framework (MOF) nanoparticles with high drug-loading capacity. The FA conjugation on MOF (PCN-777) nanoparticles not only selectively augmented intestinal transportation efficiency in diabetic animals via upregulated intestinal FA transporter-mediated endocytosis but they also tuned PCN-777 disintegration in the phosphate-rich bloodstream environment to sustain long-acting basal insulin release kinetics within a narrow therapeutic range. In diabetic animal models, the FA-PCN-777 oral insulin delivery nanosystem exhibited a smooth hypoglycemic effect for up to 48 h and a markedly high bioavailability of 35.5%, representing a potential long-acting oral formulation with reduced hypoglycemia risk.
