Shell-crosslinked micelles with neighborhood effect and pH/GSH sensitivity for co-loading of protein and polyphenol drugs

Abstract

Herein, tri-block copolymer polyethyleneimine-poly(2-(diisopropylamino)ethyl methacrylate)-poly(3-acrylamido phenylboronic acid (PEI42-PDPA50-PAPBA15) and di-block copolymer PEI42-PAPBA15 were synthesized and used to prepare micelles for constructing a double-drug delivery system. Firstly, polyphenol drugs were coupled to PAPBA block of copolymer by ester bonds, which were verified to be enhanced by the neighborhood effect of tertiary amines on PDPA. And, a mixed micelle composed of PEI42-PDPA50-PAPBA15 and PEI42-PAPBA15 (denoted as Mixed-micelle) was prepared for comparing the drug release behavior with those micelles composed of single copolymer. Afterwards, a shell-crosslinked Mixed-micelle (denoted as Mixed-micelleGEL) was obtained through crosslinking PEI layer using a disulfide bond-contained crosslinker. The gel shell effectively improved the stability of the micelles and realized co-loading of protein and polyphenol drugs into independent space. The Mixed-micelleGEL had a good "bilayer blocking" effect on drug leakage. Their single- and double- drug releases under pH/GSH stimulus were studied. Furtherly, cell experiments explored the functions of Mixed-micelleGEL, such as the biocompatibility, the tumor targeting and intracellular transport of biomacromolecular drugs. In short, the drug delivery system prepared here showed excellent independently partitioned encapsulation and intracellular transport of two drugs including small molecule and biological macromolecule drugs.