pH-Sensitive Hydrogels in Drug Delivery Systems

pH-sensitive hydrogels are another class of stimuli-sensitive hydrogels with considerable attractiveness for biomedical applications (Gao et al. 2014). The main feature of these hydrogels is their functional groups that undergo reversible ionization/deion- ization processes when the environmental pH changes and, implicitly, cause a swell- ing/collapse behaviour of the hydrogel network (Fajardo et al. 2015). The pH- responsive hydrogels are of particular interest for biomedical applications, especially for developing a wide variety of drug delivery systems, because substantial pH changes are found in various organs or locations in the body (gastrointestinal tract, blood vessels, intracellular vesicles) (Chatterjee and Hui 2018).

Chitosan-based pH-responsive hydrogels. Chitosan is an excellent example of pH-responsive natural polymer; its pH-responsiveness comes from primary amino groups which can be protonated or deprotonated depending on the pH of external environment (Lee et al. 2004). It forms cationic hydrogel network in water which swells in acidic pH and remains collapsed in basic pH (Sharpe et al. 2014). Chitosan- based systems are used for the delivery of proteins/peptides (Amidi et al. 2010), growth factors (Li et al. 2014), anti-inflammatory drugs (Badawi et al. 2008), antibiotics (Saha et al. 2010; Sevostyanov et al. 2015), as well as in gene therapy (Mao et al. 2010). Chitosan-based pH-sensitive hydrogels are performed via physical or chemical interactions (Delmarand Bianco-Peled 2016).

pH-sensitive xanthan-chitosan hydrogels, performed by ionic interactions between the free carboxyl group of xanthan and the free amino group of chitosan, were used for the encapsulation of neomycin sulfate drug. The hydrogels can sustain the release of neomycin sulfate for about 24 hours, as demonstrated by in vitro tests. The antimicrobial tests confirmed the prolonged drug release and effective bacterial inhibition when exposed to Escherichia coli and Staphylococcus aureus (Merlusca et al. 2018). Physically cross-linked pH-responsive hydrogel based on chitosan was developed via in situ free radical polymerization, using chitosan. acrylic acid (AA), and (2-dimethylaminoethyl) methacrylate (DMAEMA). These hydrogels proved to have very good mechanical strength and be suitable for controlled drug delivery of bovine serum albumin, and 5-fluorouracil (5-FU) in cancer therapy (Chatterjee and Hui 2018). Covalently cross-linked chitosan hydrogels with dialdehydes, such as glyoxal and glutaraldehyde (GA), lead to mechanical and chemical reinforced matrix, which are more stable and more suitable for intestinal protein delivery (Sharpe et al.

2014).

Interpenetrating polymeric network (IPN) gels based on chitosan and PVA were prepared and cross-linked either chemically with glutaraldehyde or by y-irradiation. The obtained IPNs were characterized, and equilibrium swelling and the in vitro cumulated release of 5-fluorouracil (5-FU), as a model drug, in different buffer solutions were studied. The release percent of 5-FU depends directly on the content of PVA and more significantly on the pH of the releasing medium, where it was faster in an acidic medium than in a neutral or w'eakly alkaline one (Abdelaal et al. 2007).

Hollow silica nanoparticles (HNPs) covered with a chitosan layer have been investigated as drug delivery carriers to control the release of loaded anticancer drugs to the acidic local environment in tumour tissues. With mesoporous structures, silica nanoparticles are particularly attractive due to their large surface area, highly accessible pores, bio-inertness, and compatibility. The resulting nanocarriers exhibit good performance in gradually releasing tumour necrosis factor alpha (TNF-a) to breast cancer cells, both in vitro and in vivo, inducing apoptosis of targeted cells (Deng et al. 2011).

Cationic chitosan hydrogel N-(2-hydroxyl) propyl-3-trimethyl ammonium chito- san chloride (HTCC), prepared with different degree of substitution (DS) by a relatively easy chemical reaction of chitosan and epoxypropyl trimethyl ammonium chloride (EPTMAC), and the effect of DS on the pH- and glucose-sensitivity was discussed. With increasing DS, the cross-linking density decreased, and in the meantime the swelling ratio and pH-sensitivity of the hydrogel increased. HTCC hydrogels showed glucose concentration-dependent response release behaviour, and the step like release behaviour for incremental doses of glucose clearly showed the versatility of the system to respond to the sequential addition of glucose (Zou et al.

2015).

Starch-based pH-responsive hydrogels. Starch-based biodegradable polymers, in the form of microsphere or hydrogel, are suitable for drug delivery (Lu et al. 2009). Modified starch film can also act as a carrier for drug release. For instance, starch- based hydrogels have been reported for colon-targeted drug delivery. Starch- methacrylic acid (MAA) copolymer hydrogels was prepared and the release behaviour of ketoprofen as model drug was investigated. The starch-based hydrogels could retain the loaded drug (ketoprofen) at pH 1 and release it at pH 7. Thus, the hydrogel has good pH-sensitivity and can be a good candidate for colon drug delivery systems (Ismail et al. 2013).

Blending lignin with corn starch improves significantly the mechanical and water absorption properties of the starch films; and in addition, this film can also control the release of the load drug ciprofloxacin in response to the pH of the medium. Only 75% of ciprofloxacin was released in a medium with pH of 7.5, while almost 100% was released in a medium of pH 1 (Zhang 2015).

Alginate-based pH-responsive hydrogels. Alginate has been extensively used in preparing drug carriers due to its biocompatibility, good morphological and mechanical properties. It has the property of gelation in an aqueous solution with aid of divalent cations such as Ca²⁺ and Mg²⁺. Park et al. studied the release profile of dual- stimuli-responsive hydrogel beads composed of calcium alginate and PNIPAM. The results showed that at 25°C the release rate from the beads was slower than that from the homo-PNIPAM beads due to the presence of the Ca-alginate chain network (Prabaharan and Mano 2006). Drug release from alginate hydrogels cross-linked with Ca²⁺ depends on the pH of the medium and the solubility of the drug. Generally, poorly water-soluble drugs are not released in acid pH due to the poor swelling by the hydrogels. In contrast, in phosphate buffer and simulated intestinal fluid the swelling and the release are promoted as phosphate ions extract the calcium from the hydrogels (Alvarez-Lorenzo et al. 2013).

Hyaluronic acid-based pH-responsive hydrogels. Another natural polymer commonly used in drug delivery formulations is hyaluronic acid (HA), which is an anionic glucosaminoglycan. The presence of one carboxylic group per repeat unit imparts a pH-responsiveness, and such behaviour is enhanced in cross-linked hydrogel network. Recent research found pH-responsive HA nanoparticles as a viable option for oral insulin delivery systems, showing enhanced delivery via transcellular pathway found in both in vitro and in vivo studies (Sharpe et al. 2014). Fiorica et al. developed a novel derivative of HA with increased carboxylic groups to optimize the system for delivery to the colon and demonstrated pH-sensitive release using a-chymotrypsin (Fiorica et al. 2013).

Cellulose-based pH-responsive hydrogels. Carboxymethyl cellulose (CMC), obtained by substitution of some of the hydroxyl groups of cellulose with carboxymethyl groups, displays pH-sensitivity due to the incorporation of carboxyl groups, making this material interesting for oral delivery systems (Gao et al. 2014).