Chondroitin sulfate-based nanocarriers for drug/gene delivery

Highlights

• The structure and the physiological functions of chondroitin sulfate were presented.

• The application of chondroitin sulfate in drug/gene delivery systems was discussed.

• Future perspectives on chondroitin sulfate development were summarized.

Abstract

In recent years, the naturally occurring polysaccharides captured an increasing amount of attention in the field of drug/gene delivery systems owing to their outstanding propensities, including biocompatibility, biodegradability, non-immunogenicity, extremely low toxicity, and so on. Chondroitin sulfate (ChS), a member of glycosaminoglycan family, consists of repeating disaccharide units of b-1,3-linked N-acetyl galactosamine (GalNAc) and b-1,4-linked d-glucuronic acid (GlcA) with certain position(s) sulfated, which has been widely applied in nano-sized carriers. This review will focus on shared and unique properties of ChS and its latest development in drug/gene delivery systems. In detail, the application of ChS as nanocarriers will be discussed in three dimensions: self-assembly of hydrophobically modified ChS, ChS decorated nanocarriers, and some other nanocarriers based on ChS. A discussion relating to the future perspectives of ChS-based nanocarriers for drug/gene delivery is also included.

Introduction

Nano-sized drug/gene carriers captured the attention of investigators since last several decades. In general, nano-sized carriers consist of various sub-micro particles possessing diameters below 1000 nm and drugs can be adsorbed, encapsulated or/and dispersed in them (Letchford & Burt, 2007), or conjugated to carrier materials. A wide variety of nano-sized carriers with distinct architectures, sizes and surface merits have been fabricated, including micelles, nanoparticles, nanoemulsions, nanocapsules, nanospheres, nanogels, nanocrystals, polymersomes, liposomes, niosomes, carbon nanotubes and nanodrugs, etc. (Jung et al., 2000, Wang et al., 2012). These novel nanocarriers possess a number of advantages and some of them are listed below:

• Direct injection into blood circulation system without the risk of blocking blood vessels (Gref et al., 2012). A nanometric diameter endows nanocarriers the feasibility of direct injections, such as intravenous injection and arterial injection.

• An increased water solubility of payloads with low solubility (Park, Kim, Tran, Huh, & Lee, 2010). Nanocarriers are capable of incorporating bioactives with different water solubilities. An enhanced drug concentration in the pharmaceutical preparations may decrease the dose applied to patients and thereby improve the patient compliance in the treatment.

• A prolonged circulation time. The longevity in blood circulation of nanocarriers can be increased through various ways, like prepared with materials possessing mocoadhesiveness (for instance, mucopolysaccharides) (Letchford & Burt, 2007) or modification by hydrophilic molecules such as polyethylene glycol (Klibanov, Maruyama, Torchilin, & Huang, 1990).

• An enhanced stability in vivo, especially during blood circulation (Jhaveri, Deshpande, & Torchilin, 2014). Nanocarriers are able to protect the payloads from deactivation, which might be caused by enzymes, pH values, etc.

• Designed distribution of payloads in the body (Torchilin, 2012, Kamaly et al., 2012). Bioactives can be delivered, and released in specific sites in the body with the aid of specially fabricated nanocarriers. Drugs can passively accumulate in tumor tissues by the enhanced permeability and retention (EPR) effect (Wang et al., 2011) and actively with the direction of specific ligand–receptor binding, like folate acid–folate receptors (Liu et al., 2011). In this way, an effective therapy and reduced side effects can be achieved at the same time.

Besides the advantages mentioned above, plenty of alternative merits have also attracted an increasing interest in the development of nanocarriers. In the early stage, investigators designed and created various types of nanocarriers composed of a range of materials including lipids, conventional surfactants, and inorganic materials (Klumpp et al., 2006, Liggins and Burt, 2002). Up to date, a wide variety of nanocarriers comprised of novel biodegradable polymers have been developed. Among them, numerous amphiphilic block copolymers comprised of both hydrophilic and hydrophobic regions have been synthesized and applied in the preparation of nanocarriers. Moreover, many advances revealed that the naturally occurring polysaccharides and their derivatives have attracted a great deal of attention (Khatun et al., 2012, Lemarchand et al., 2004). For instance, polysaccharides, have been demonstrated to possess a large amount of positive merits which render them excellent candidates in the application of drug/gene delivery systems, such as high stability, low toxicity, non-immunogenicity, biodegradability, and biocompatibility, etc. (Bhattarai et al., 2010, Liu et al., 2008). In addition, the naturally occurring polysaccharides have various reactive groups like carboxyl, hydroxyl and amino groups, which render the possibility of multiple modifications to polysaccharides (Lee, Park, & Robinson, 2000). More importantly, polysaccharides are extremely abundant in nature, for example, synovial fluid and extracellular matrix (ECM) are particularly rich in hyaluronic acid and chondroitin sulfate (Caterson et al., 1990, Fajardo et al., 2012, Oh et al., 2010). Therefore, the application of polysaccharides and their derivatives with a wide range of molecular weight, varying chemical structures and properties has been widely spread. In this present review, we focus on merits of chondroitin sulfate and its derivatives, especially the design and fabrication of chondroitin sulfate and its derivatives based nanocarriers for drug/gene delivery.