pH and Reactive Oxygen Species‐Sequential Responsive Nano‐in‐Micro Composite for Targeted Therapy of Inflammatory Bowel Disease

• Published in: Advanced functional materials Vol. 28; no. 50
• Main Authors: Bertoni, Serena, Liu, Zehua, Correia, Alexandra, Martins, João Pedro, Rahikkala, Antti, Fontana, Flavia, Kemell, Marianna, Liu, Dongfei, Albertini, Beatrice, Passerini, Nadia, Li, Wei, Santos, Hélder A.
• Format: Journal Article
• Language: English
• Published: Hoboken Wiley Subscription Services, Inc 12-12-2018
• Subjects: Chitosan; Esters; Hydrogen peroxide; Inflammatory bowel disease; Materials science; microfluidics; Microparticles; Nanoparticles; Oxidation; oxidation‐responsive; Pathogenesis; Polymer matrix composites; ROS‐responsive delivery; Side effects; Surface stability; Therapy
• ISSN: 1616-301X; 1616-3028
• DOI: 10.1002/adfm.201806175

Oxidative stress and abnormally high levels of reactive oxygen species (ROS) play an essential role in the pathogenesis and progression of inflammatory bowel disease (IBD). Oxidation‐responsive nanoparticles (NPs) are formulated from a phenylboronic esters‐modified dextran (OxiDEX) that degrades selectively in response to hydrogen peroxide (H2O2). OxiDEX NPs are coated with chitosan and encapsulated in a pH‐sensitive polymer to produce nano‐in‐micro composites. The microparticles are spherical with homogeneous particle size (53 ± 3 µm) and maintain integrity at acidic pH, preventing the premature release of the NPs in gastric conditions. The degradation of NPs is highly responsive to the level of H2O2, and the release of the drug is sustained in the presence of physiologically relevant H2O2 concentrations. The presence of chitosan on the particles surface significantly enhances NPs stability in intestinal pH and their adhesion on the intestinal mucosa. Compared to a traditional enteric formulation, this formulation shows tenfold decreased drug permeability across C2BBe1/HT29‐MTX cell monolayer, implying that lower amount of drug would be absorbed to the blood stream and, therefore, limiting the undesired systemic side effects. Based on these results, a successful nano‐in‐micro composite for targeted therapy of IBD is obtained by combination of the responsiveness to pH and ROS.
An advanced nano‐in‐micro composite is successfully prepared with a phenylboronic esters‐modified dextran (OxiDEX) to achieve an oxidation‐responsive drug delivery for the therapy of inflammatory bowel disease. H2O2‐selective OxiDEX degradation and consequent drug release are demonstrated. The composite limits the drug permeation through intestinal epithelium providing a promising approach to limit unspecific absorption and systemic side effects.