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

DRUG DELIVERY, 2018 VOL. 25, NO. 1, 278–292 https://doi.org/10.1080/10717544.2018.1425776 REVIEW ARTICLE Research progress of self-assembled nanogel and hybrid hydrogel systems based on pullulan derivatives Tao Zhanga, Ruyi Yanga, Shengnan Yanga, Jibin Guana, Dong Zhanga, Yan Mab and Hongzhuo Liua a School of Pharmacy, Shenyang Pharmaceutical University, Shenyang, China; bSchool of Chinese Materia Medica, Guangzhou University of Chinese Medicine, Guangzhou, China ABSTRACT ARTICLE HISTORY 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. Received 9 November 2017 Revised 2 January 2018 Accepted 5 January 2018 Introduction The use of nanodrug delivery systems has resulted in significant advances in reduced toxicity, modified release, and enhanced treatment efficiency (Mura et al., 2013). The development of nanocarriers, including nanoparticles, liposomes, vesicles, carbon nanotubes, polymeric micelles, nanoemulsions, microspheres, nanogels, and prodrug-nanosystems has provided alternative options for the prevention, treatment, and diagnosis of diseases (Pehlivan, 2013). Nanogels are endowed with unique physicochemical and biological properties that enable them to encapsulate and protect many payload drugs, confer high stability for prolonged circulation, and participate in versatile drug release protocols; additionally, they possess stimuli-responsive behavior potential, tunable size, and can assist with facile removal of empty devices (Maya et al., 2013). Hence, there has been enormous interest in nanogel systems (Varshosaz et al., 2017). Nanogel is a gel with a nonfluid colloidal/polymer network but a diameter less than 100 nm (Tahara & Akiyoshi, 2015). Because of their hydrophilic three-dimensional macromolecular networks, polymer nanogels have been extensively studied as functional materials in biotechnological and biomedical fields (Zhang et al., 2015; Yahyaei et al., 2017). Similar to other polysaccharides such as chitosan (Huang & KEYWORDS Carrier; pullulan; selfassembled nanogel; hybrid hydrogel; research progress Lapitsky, 2017), hyaluronic acid (Wei et al., 2013), mannan (Ferreira et al., 2010), cycloamylose (Tahara et al., 2015), dextrin (Molinos et al., 2012), and enzymatically synthesized glucogen (Takeda et al., 2013), pullulan also has played a critical role in nanogel systems in recent years (Sasaki & Akiyoshi, 2010; Chacko et al., 2012). Pullulan is one of the commercially emerging aqueous polysaccharides synthesized by the yeast-like fungus Aureobasidium pullulans. It consists of hundreds of repeated units of the maltotriose trimer a-D-glucopyranosyl-(1 ! 6)-a-D-glucopyranosyl-(1 ! 4)-a-D-glucopyranosyl-(1 ! 4)- (Figure 1(A)). The relative molecular mass can reach more than 1  104 Da (1  105 Da and 2  105 Da are most frequently used). Although many active sites of pullulan may be modified and grafted, some evidence has revealed that extrinsic groups preferably introduce at the C-6 hydroxyl groups of pullulan (Bruneel & Schacht, 1994). Innumerable examples demonstrate that partial modification of water-soluble polymers affects the solution properties (Zhu et al., 2017). Furthermore, chemical derivatization can control pullulan’s solubility with reactive groups accordingly (Jung et al., 2003; Singh et al., 2008). If modified by a hydrophobe such as cholesterol, pullulan becomes an amphiphilic molecule in the form of cholesterol-bearing pullulan (CHP, Figure 1(A)), which could act as an excellent nanogel carrier CONTACT Hongzhuo Liu School of Pharmacy, Shenyang Pharmaceutical University, Shenyang 110016, China Supplemental data for this article can be accessed here. ß 2018 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. DRUG DELIVERY 279 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. (Akiyoshi et al., 1993). CHP nanogels present great biocompatibility and biodegradability, nontoxicity, ease of preparation, reversible connections, thermal stability, and suppression of massive aggregation of proteins (Ayame et al., 2008; Boridy et al., 2009; Sawada & Akiyoshi, 2010; Yuki et al., 2013; Wang et al., 2014). Additionally, pullulan or CHP can be modified by other pharmaceutical agents to achieve superior applications in the biomedical field (Ferreira et al., 2011; 280 T. ZHANG ET AL. Nakahashi-Ouchida et al., 2017). The text below mainly introduces the origin, concept, mechanism, and application of major pullulan nanogels and related hybrid hydrogels and will assist researchers in understanding the development of the nanogel field and other relevant delivery systems. Concept and mechanism of typical pullulan nanogels Synthesis, preparation, and characterization of typical pullulan nanogels The nanogel system based on CHP backbone is the most popular object of study, and accordingly, an introduction explaining cholesterol-modified pullulan is below. Other pullulan nanogels or reactive group-modified pullulan nanogels will be explained and analyzed in the specific chapter of this article w (...truncated)