Research progress of self-assembled nanogel and hybrid hydrogel systems based on pullulan derivatives

Abstract

Polymer nano-sized hydrogels (nanogels) as drug delivery carriers have been investigated over the last few decades. Pullulan, a nontoxic and nonimmunogenic hydrophilic polysaccharide derived from fermentation of black yeast like Aureobasidium pullulans with great biocompatibility and biodegradability, is one of the most attractive carriers for drug delivery systems. In this review, we describe the preparation, characterization, and 'switch-on/off' mechanism of typical pullulan self-assembled nanogels (self-nanogels), and then introduce the development of hybrid hydrogels that are numerous resources applied for regenerative medicine. A major section is used for biomedical applications of different nanogel systems based on modified pullulan, which exert smart stimuli-responses at ambient conditions such as charge, pH, temperature, light, and redox. Pullulan self-nanogels have found increasingly extensive application in protein delivery, tissue engineering, vaccine development, cancer therapy, and biological imaging. Functional groups are incorporated into self-nanogels and contribute to expressing desirable results such as targeting and modified release. Various molecules, especially insoluble or unstable drugs and encapsulated proteins, present improved solubility and bioavailability as well as reduced side effects when incorporated into self-nanogels. Finally, the advantages and disadvantages of pullulan self-nanogels will be analyzed accordingly, and the development of pullulan nanogel systems will be reviewed.

Keywords: Carrier; hybrid hydrogel; pullulan; research progress; self-assembled nanogel.

Figure 1.

Chemical structures of (A) pullulan, (A) cholesterol-bearing pullulan (CHP), (B) CHPNH2, and (C) CHPOA-PEGSH; (D) Pullulan-based nanogels and hybrid hydrogels; and (E, F) schematic representation of chaperone-assisted refolding.

Figure 2.

(A) Schematic illustration showing the composition of the degradable deep penetrating cationic nanoparticle (HA/DpNG-PTX, Table 3), and how it can be used to penetrate into tissue; (B) temperature-induced changes in the morphology and association of CHPMA-PNIPAM nanogels and SPL complexes; swollen nanogels formed by the association of a few CHPMA nanogels, shrunken nanogels, and botryoidal nanogels are shown; (C) aqueous condition at 4 °C but hydrogel condition at 37.5 °C is shown; (D) schematic illustration of SpS nanogel under UV–Vis light. HA/DpNG-PTX: hyaluronic acid-coated degradable cationic nanogel–paclitaxel; CHPMA-PNIPAM: methacryloyl-substituted CHP-poly-N-isopropylacrylamide; SPL: succinated pullulan-poly(l-lactide).