Overcoming the Diffusion Barrier of Mucus and Absorption Barrier of Epithelium by Self-Assembled Nanoparticles for Oral Delivery of Insulin

• Published in: ACS nano Vol. 9; no. 3; pp. 2345 - 2356
• Main Authors: Shan, Wei, Zhu, Xi, Liu, Min, Li, Lian, Zhong, Jiaju, Sun, Wei, Zhang, Zhirong, Huang, Yuan
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 24.03.2015
• Subjects: Absorption, Physicochemical; Administration, Oral; Amino Acid Sequence; Animals; Biological Transport; Cell-Penetrating Peptides - chemistry; Coating; Diffusion; Drug Carriers - chemical synthesis; Drug Carriers - chemistry; Drug Carriers - pharmacokinetics; Epithelium; Epithelium - metabolism; HT29 Cells; Humans; Hydrophobic and Hydrophilic Interactions; Hypoglycemic Agents - administration & dosage; Hypoglycemic Agents - chemistry; Hypoglycemic Agents - pharmacokinetics; Hypoglycemic Agents - pharmacology; Insulin; Insulin - administration & dosage; Insulin - chemistry; Insulin - pharmacokinetics; Insulin - pharmacology; Intracellular Space - metabolism; Male; Molecular Sequence Data; Mouth Mucosa - metabolism; Mucus; Nanoparticles; Nanoparticles - chemistry; Nanostructure; Penetration; Permeability; Permeation; Polymethacrylic Acids - chemistry; Rats; Rats, Sprague-Dawley; epithelium; nanoparticles; insulin; cell penetrating peptide; oral delivery; mucus
• ISSN: 1936-0851; 1936-086X
• DOI: 10.1021/acsnano.5b00028

Nanoparticles (NPs) have demonstrated great potential for the oral delivery of protein drugs that have very limited oral bioavailability. Orally administered NPs could be absorbed by the epithelial tissue only if they successfully permeate through the mucus that covers the epithelium. However, efficient epithelial absorption and mucus permeation require very different surface properties of a nanocarrier. We herein report self-assembled NPs for efficient oral delivery of insulin by facilitating both of these two processes. The NPs possess a nanocomplex core composed of insulin and cell penetrating peptide (CPP), and a dissociable hydrophilic coating of N-(2-hydroxypropyl) methacrylamide copolymer (pHPMA) derivatives. After systematic screening using mucus-secreting epithelial cells, NPs exhibit excellent permeation in mucus due to the “mucus-inert” pHPMA coating, as well as high epithelial absorption mediated by CPP. The investigation of NP behavior shows that the pHPMA molecules gradually dissociate from the NP surface as it permeates through mucus, and the CPP-rich core is revealed in time for subsequent transepithelial transport through the secretory endoplasmic reticulum/Golgi pathway and endocytic recycling pathway. The NPs exhibit 20-fold higher absorption than free insulin on mucus-secreting epithelium cells, and orally administered NPs generate a prominent hypoglycemic response and an increase of the serum insulin concentration in diabetic rats. Our study provides the evidence of using pHPMA as dissociable “mucus-inert” agent to enhance mucus permeation of NPs, and validates a strategy to overcome the multiple absorption barriers using NP platform with dissociable hydrophilic coating and drug-loaded CPP-rich core.