Piperazine‐Functionalized Nanoparticles Enable Oral Insulin Delivery in Obese Mice

Biologics have gained prominence as a rapidly advancing therapeutic modality for a diverse spectrum of medical conditions. Nonetheless, they are predominantly administered parenterally due to poor absorption through the gastrointestinal tract. Additionally, repeated injections of biologics such as insulin cause injection pain, leading to dose-skipping and poor medication adherence. Recently, our group and others have shown that nanoparticle-based drug delivery systems enhance intestinal permeation and oral delivery of biologics such as insulin and exenatide. However, their effectiveness is not on par with chemical permeation enhancers (PEs) including fatty acids, lipids, and 1-phenylpiperazine (PPZ), which are toxic at their effective doses. In this work, we report successful PPZ grafting onto silica nanoparticles with no apparent toxicity and significantly increased permeation of macromolecules such as insulin in an in vitro Caco-2 monolayer model and a co-culture model. In vivo experiments, with silica-PPZ-based novel PE improves the permeation of FITC-dextran-4 kDa in healthy mice compared to bare silica nanoparticles and macromolecule alone. In a high-fat diet mouse model, the use of silica-PPZ significantly enhances insulin absorption in the intestine. This led to markedly lower and more sustained blood glucose levels compared to controls without any associated toxicity to mice. Overall, we have shown, for the first time, that PPZ-grafted silica nanoparticles can serve as a safe and effective permeation enhancer for the oral administration of insulin and potentially other biologics.