Preparation and characterization of pectin/chitosan beads containing porous starch embedded with doxorubicin hydrochloride: A novel and simple colon targeted drug delivery system

Highlights

• A simple colon targeted drug delivery system was designed.

• The sustained release effect of the beads was enhanced by adding porous starch.

• The encapsulation efficiency of DOX was increased by porous starch addition.

• 86.20% of the loaded doxorubicin could reach the colon.

Abstract

The objective of this study was to design a simple, colon targeted drug delivery system by using porous starch (PS), pectin and chitosan. Porous maize starch was prepared by hydrolysis with a combination of α-amylase and amyloglucosidase, and it was characterized by scanning electron microscopy, revealing the formation of porous structures in the starch granules. A Brunauer-Emmett-Teller (BET) specific surface area analysis indicated that the specific surface area of the PS (0.8768–0.9448 m²/g) was 19.88–21.42 times larger than that of native maize starch (0.0441 m²/g). The average pore diameter of the PS granules, as calculated by the Barrett-Joiner-Halenda (BJH) method, was 40.52–62.42 nm. A favorable adsorptive potential of the PS granules was verified by water and soybean oil tests. Doxorubicin was loaded into PS granules, which were then coated with a pectin/chitosan complex solution. The results of confocal laser scanning microscopy (CLSM) demonstrated that doxorubicin was successfully absorbed into the PS granules. In addition, an in vitro simulated digestion method demonstrated the effectiveness of this delivery design, as only a 13.80% release rate of doxorubicin was observed in the upper gastrointestinal tract, whereas release rates of 17.56% and 67.04% were observed for pectin/PS/doxorubicin and pectin/doxorubicin beads, respectively. It was concluded that the use of PS and a pectin/chitosan coating is an effective method for colon targeted drug delivery compared with the simple polysaccharide system.

Introduction

Colon cancer is one of the most pervasive cancers worldwide, causing high mortality. This type of cancer is considered to be the fourth most frequent cause of cancer-related death (Al-Rajab, Lu, & Xu, 2017). With the increasing incidence rate of colon cancer and the problems associated with traditional chemotherapy (Huang et al., 2013), oral colon drug delivery systems (OCDDSs) have been widely studied. OCDDSs can be generally classified into the following five types based on various mechanisms of action: time-lag, pH-dependent, enzyme-dependent, microbiota-triggered and pressure-controlled. Local targeted and sustained-release drug delivery systems can expose tumor cells to a suitable concentration of a drug for a long period (Feng et al., 2017). OCDDSs allow drugs that are barely soluble in water or unstable in the presence of gastric acid to be delivered and protected from degradation in the stomach or small intestine before being released in a specific part of the small intestine or colon, thus greatly increasing the treatment efficacy.

Polysaccharide polymers have been used as coating materials because of their excellent colloid-forming ability, high mechanical strength and low chemical permeability (Du, Chen, Zheng, Meng, & Zhong, 2012). Pectin is predominantly an acidic hetero-polysaccharide composed of D-galacturonic acids linked by α-1,4-glycosidic bonds and coupled with neutral monosaccharides, such as l-rhamnose, d-galactose and d-arabinose. Pectin has been widely used in drug delivery systems. However, pectin readily swells in aqueous environments due to the presence of many hydroxyl groups in its structure. To minimize drug leakage in the stomach and small intestine, other hydrophobic natural polymers, such as chitosan and hydroxypropylmethylcellulose, have been used to modify pectin (Rampino et al., 2016, Tung et al., 2016). Hydrophobically modified pectin exhibits a lower drug release in the gastrointestinal (GI) tract. Many studies have reported colon targeted drugs that have utilized pectin (Chang et al., 2017, Ferrari et al., 2013, Huang et al., 2013). Chang et al. (2017) used pectin to coat caseinate/zein nanoparticles for the delivery of curcumin. The results indicated that the pectin coating effectively increased the encapsulation rate of curcumin, which was highly stable in the gastrointestinal tract, suggesting that pectin has potential in oral delivery systems. Khurana, Singh, Sapra, Tiwary, and Rana (2014) coated mesalamine with Tamarindus indica pectin and chitosan. The protective film with its water-resistant properties was shown to have a stronger adhesive strength than that of Eudragit-coated tablets. Combined with chitosan, silica and enoxaparin sodium, nano-materials have also been widely studied to deliver doxorubicin to the colon (Wang et al., 2017a, Wang et al., 2017b, Zuo et al., 2017). Despite these achievements, once the pectin coating is decomposed, the drug exhibits a pulsed release, decreasing its sustained effect (Tung et al., 2016).

Porous starch (PS) is a typical modified starch that has been studied for a long time. PS can be prepared by an enzymatic hydrolysis method or a solvent exchange method (Chang et al., 2012, Chang et al., 2011). PS has many applications in foods (Belingheri, Ferrillo, & Vittadini, 2015), pharmaceuticals (Li, Thuy Ho, Turner, & Dhital, 2016), environment management (Xu et al., 2017) and other industries (Chang et al., 2011) due to its high adsorption capacity, specific surface area and biodegradability (Du et al., 2013, Li et al., 2013, Qian et al., 2011). Interestingly, PS has been utilized to encapsulate many substances such as bioactive compounds (Jiang et al., 2017), drugs (Jiang et al., 2014), microorganisms (Li et al., 2016) and preservatives (Wang, Shao, Wang, & Lu, 2012) that have the characteristics of low hydrophilicity, unpleasant odor, low pH resistance or tendency to be readily oxidized. However, PS is almost completely hydrolyzed in the GI tract, so it is difficult for the carried drugs to reach the colon. Pectin and chitosan can traverse the upper GI tract where pectinase is absent (Andishmand et al., 2017, Chang et al., 2017), and these compounds are decomposed by the pectinases secreted from the abundant bacteria present in the colon. As the decomposition proceeds, the drugs are continuously released from the PS granules, realizing local targeted drug delivery.

In this study, doxorubicin-loaded PS granules were coated with pectin or pectin/chitosan. The stability and release of the microspheres were studied in an enzyme-dependent OCDDS (Fig. 1). With this carrier system, a lasting drug release can be realized, clinically reducing the required medication times. This system has a great potential application in colon-specific drug delivery for colitis and colon cancer.