International Journal of Nanomedicine (Nov 2018)
Mechanisms of deformable nanovesicles based on insulin-phospholipid complex for enhancing buccal delivery of insulin
Abstract
You Xu,1,2 Xing Zhang,1,2 Yun Zhang,1,2 Jun Ye,1,2 Hong-Liang Wang,1,2 Xuejun Xia,1,2 Yuling Liu1,2 1State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China; 2Beijing Key laboratory of Drug Delivery Technology and Novel Formulation, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China Background: Non-injectable delivery of peptides and proteins are not feasible due to its large molecular, high hydrophilic and gastrointestinal degradation. Therefore, proposing a new method to solve this problem is a burning issue. Purpose: The objective of this study was to propose a novel protein delivery strategy to vanquish the poor efficacy of buccal mucosa delivery systems for protein delivery and then investigate the detailed mechanisms of the enhanced buccal delivery of protein, using insulin as a model drug. Materials and methods: Insulin-phospholipid complex combined with deformable nanovesicles (IPC-DNVs) were prepared, using deformable nanovesicles based on insulin (INS-DNVs) and conventional nanovesicles based on insulin-phospholipid complex (IPC-NVs) as references. Besides, their physicochemical characterization, in vitro transport behavior, in vivo bioactivity and hypoglycemic effect were systematically characterized and compared. Finally, we evaluated the in vivo safety of IPC-DNVs. Results: First, IPC-DNVs increased insulin permeability through deposition of the IPC and deformability of the DNVs, which was revealed by an in vitro mucosal permeation study. Second, DNVs could act as a drug carrier and penetrate the mucosa to reach the receiver medium as intact nanovesicles, which was supported by the observation of intact nanovesicles in the receiver medium through transmission electron microscopy (TEM). Third, IPC-DNVs exhibited both transcellular and paracellular transport in the form of IPC and DNVs, respectively, which was proved by confocal laser scanning microscopy (CLSM). Unlike the other two formulations, IPC-DNVs exhibited a sustained mild hypoglycemic effect, with a relative bioavailability (Fp) of 15.53% (3.09% and 1.96% for INS-DNVs and IPC-NVs, respectively). Furthermore, buccal administration of IPC-DNVs resulted in no visible mucosal irritation to the buccal mucosa. Conclusion: Our work reveals the mechanisms underlying the enhanced buccal delivery of IPC-DNVs: the DNVs facilitate penetration through the main barrier, and the deposition of IPC enhances buccal absorption. Our results and proposed mechanisms could be an important reference to understand other nanocarriers based on protein (peptide)-phospholipid complexes that penetrate the mucosa and provide a theoretical basis for the future development of buccal delivery systems for insulin. Keywords: diabetes, hypoglycemic effect, mucosal permeation, absorption, safety
