Ultra-stable dextran conjugated prodrug micelles for oxidative stress and glycometabolic abnormality combination treatment of Alzheimer's disease.

Abstract

Sophisticated nanomedicines are continually being developed, but big obstacles remain before they finish the drug release mission. The first challenge is rupture possibility of structure when infinite dilution, competitive reaction of electrolytes and protein in blood circulation. In addition, low responsive drug release efficiency in the lesion site remains the major challenge for clinical application of nanomedicine combination treatment. In this study, we discussed the opportunities for Alzheimer's disease (AD) combination therapy based on the thermodynamically ultra-stable dextran conjugated prodrug micelles. Dextran-nateglinide conjugated prodrug micelles (NA) and dextran-vitamin E succinate conjugated prodrug micelles (VES) presented ultra-low critical micelle concentration of ~10-5 mM and high physiological stability when challenged by NaCl, sodium dodecyl sulphate (SDS), dodecyl dimethyl benzyl ammonium chloride (DDBAC) and no rupture of structure happened. The NA/insulin polymer-drug conjugate micelles (NA/INS PDC) and VES/insulin polymer-drug conjugate micelles (VES/INS PDC) efficiently cleaved by reactive oxygen species (ROS), leading to over 80% release of the encapsulated and conjugated drugs. The combination of nateglinide and insulin, vitamin E succinate and insulin improved the glucose metabolism, reduced oxidative stress, improved the mitochondrial function and recovered the cognitive capacity of mice. This work demonstrated a paradigm for specific and high efficacy AD combination therapy.

• Authors: Bo Zhang, Yachai Gao, Xiaolei Zhang, Jicheng Jiang, Jian Ren, Shaoteng Wang, Haodong Hu, Yiping Zhao, Li Chen, Kongyin Zhao, Fengying Dai
• Journal: International journal of biological macromolecules (Int J Biol Macromol) Vol. 203 Pg. 430-444 (Apr 01 2022) ISSN: 1879-0003 [Electronic] Netherlands
• PMID: 35093435 (Publication Type: Journal Article)
• Copyright: Copyright © 2022. Published by Elsevier B.V.

Chemical References

• Dextrans
• Micelles
• Prodrugs

Topics

• Alzheimer Disease (drug therapy)
• Animals
• Cell Line, Tumor
• Dextrans
• Mice
• Micelles
• Oxidative Stress
• Prodrugs (chemistry, pharmacology, therapeutic use)