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

Lin Hou; Xueyuan Peng; Ruiting Wang; Yifei Wang; Hong Li; Huijuan Zhang; Yun Zhang; Zhenzhong Zhang

doi:10.1016/j.apsb.2022.12.014

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

Acta Pharm Sin B. 2023 Jul;13(7):3137-3152. doi: 10.1016/j.apsb.2022.12.014. Epub 2022 Dec 22.

Authors

Lin Hou^{1

2

3}, Xueyuan Peng^{1

2}, Ruiting Wang^{1

2}, Yifei Wang^{1

2}, Hong Li^{1

2}, Huijuan Zhang^{1

2

3}, Yun Zhang^{1

2

3}, Zhenzhong Zhang^{1

2

3}

Affiliations

¹ School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, China.
² Key Laboratory of Targeting Therapy and Diagnosis for Critical Diseases, Zhengzhou University, Zhengzhou 450001, China.
³ Collaborative Innovation Center of New Drug Research and Safety Evaluation, Zhengzhou University, Zhengzhou 450001, China.

Abstract

Type 2 diabetes mellitus (T2DM) therapy is facing the challenges of long-term medication and gradual destruction of pancreatic islet β-cells. Therefore, it is timely to develop oral prolonged action formulations to improve compliance, while restoring β-cells survival and function. Herein, we designed a simple nanoparticle 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, taurocholic 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.

Keywords: Hydroxychloroquine; Lymphatic transportation; Oral drug delivery; PLGA nanoparticles; Pancreas microenvironment; Pancreatic islet β-cells; Taurocholic acid; Type 2 diabetes mellitus.