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

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.

Legumain-induced intracerebrally crosslinked vesicles for suppressing efflux transport of Alzheimer's disease multi-drug nanosystem.

Brain barrier is both a protective permeability hurdle and a limitation site where therapeutic agents are excluded to enter the target region. Designing drug vehicle to overcome this notorious barrier bottle is challenging. Herein, we construct a stimuli-responsive self-assembled nanovesicle that delivers water-soluble drugs to prevent the efflux transport of brain barriers by responding to the endogenously occurring signals in Alzheimer's disease (AD) brain microenvironment. Once stimuli-responsive vesicles are accumulated in intracerebrally, the intrinsically occurring legumain endopeptidase cleaves the Ac-Ala-Ala-Asn-Cys-Asp (AK) short peptide on the drug vesicles to expose the 1,2 thiol amino group to cyclize with the cyano groups on 2-cyano-6-aminobenzothiazole (CABT) of the chaperone vesicles, thus triggering the formation of cross-linked micrometre-scale vesicles. Such a structural alteration completely prevents further brain barriers efflux. The superior neuroprotective capacity of cross-linked vesicles is validated in senescence accelerated mouse prone 8 (SAMP8). This smart multi-drug delivery vesicle is promising to serve as a powerful system for AD treatment and can be adapted for the therapy of other central nervous system (CNS) disorders.