Oral nano-formulation improves pancreatic islets dysfunction via lymphatic transport for antidiabetic treatment

Type 2 diabetes mellitus (T2DM) therapy is facing the challenges of long-term medication and gradual destruction of pancreatic islet b-cells. Therefore, it is timely to develop oral prolonged action formu-lations to improve compliance, while restoring b-cells survival and function. Herein, we designed a simple na-noparticle with enhanced oral absorption and pancreas accumulation property, which combined apical sodium -dependent bile acid transporter-mediated intestinal uptake and lymphatic transportation. In this system, tauro-cholic acid (TCA) modified poly(lactic-co-glycolic acid) (PLGA) was employed to achieve pancreas location, hydroxychloroquine (HCQ) was loaded to execute therapeutic efficacy, and 1,2-dilauroyl-sn-glycero-3-phosphocholine (DLPC) was introduced as stabilizer together with synergist (PLGA-TCA/DLPC/HCQ). In vitro and in vivo results have proven that PLGA-TCA/DLPC/HCQ reversed the pancreatic islets damage and dysfunction, thus impeding hyperglycemia progression and restoring systemic glucose homeostasis via only once administration every day. In terms of mechanism PLGA-TCA/DLPC/HCQ ameliorated oxidative stress, remodeled the inflammatory pancreas microenvironment, and activated PI3K/AKT signaling pathway without obvious toxicity. This strategy not only provides an oral delivery platform for increasing absorption and pancreas targetability but also opens a new avenue for thorough T2DM treatment.

Automated summary

To improve compliance and restore the survival and function of pancreatic islet b-cells in type 2 diabetes mellitus (T2DM) therapy, we designed a simple nanoparticle with enhanced oral absorption and pancreas accumulation property. This nanoparticle combined intestinal uptake mediated by apical sodium-dependent bile acid transporter and lymphatic transportation. In vitro and in vivo results have shown that this nanoparticle reversed pancreatic islets damage and dysfunction, improved hyperglycemia progression, and restored systemic glucose homeostasis with once daily administration. The mechanism of action involves amelioration of oxidative stress, remodeling of the inflammatory pancreas microenvironment, and activation of the PI3K/AKT signaling pathway without obvious toxicity.