**2.1 Types of stimuli-responsive microgels**

### *2.1.1 Microgels responsive to temperature*

Several classes of polymers, including poly(N-isopropylacrylamide) and poly(ethylene glycol), demonstrate swelling/deswelling changes in response to temperature [19, 20]. With increase in temperature, these systems have reduced solvency and pronounced deswelling. Nolan et al. [21] demonstrated higher insulin release from poly (N-isopropyl acrylamide), with increasing temperature. Temperaturedependent aggregation property of such thermosensitive microgel systems may also be utilized in drug delivery, e.g., at elevated temperature; due to aggregation of PNIPAM microgels particle inside the cancerous cell, toxicity was observed [22].

## *2.1.2 Microgels responsive to particular compounds*

Microgels can be designed to be triggered by the concentration of particular compounds, like insulin [23, 24]. For example, insulin containing poly (diethyl aminoethyl methacrylate) microgels conjugated with glucose oxidase [25]. The enzymatic conversion of glucose to gluconic acid causes pH-responsive swelling of the polymer network leading to release of insulin. In another study Sui et al. [26] reported trifluoperazine triggered volume transition in calmodulin-based hydrogels.

### *2.1.3 Microgels responsive to external fields*

Microgel systems may also respond to external fields (ultrasound, light, and magnetic fields). Patnaik et al. [27] investigated photoresponsive drug release in azo-dextran nanogels based on (trans-cis) photoisomerization of an azobenzene present in the cross-linker. For this system, the release of drug was slower for transconfiguration while faster for cis-configuration.

Metal nanoparticles may be used for optical or magnetic heating. When temperature-responsive microgels are combined with metals, heat induced by the external fields may result in deswelling, leading to release of the absorbed drugs. Using this perspective, Wong et al. [28] explored Fe-containing PNIPAM microgels. The microgels showed ability to manifest local heating attributed to an oscillating magnetic field. With increasing temperature microgels deswelled. Similar kind of triggering was also manifested in other studies, where light-originated heating of absorbed metal nanoparticles was used to induce local heat, provoking permeability variations in temperature-responsive polymers [29–31].

#### *2.1.4 Microgels responsive to degradation*

Microgel degradation in response to stimuli offers another way of controlled drug delivery [32, 33]. Such systems are commonly based on biodegradable microgels, occasionally surrounded by a shell impermeable to the drug. In later case, microgel degradation causes increased osmotic pressure, finally breaking the

**87**

*pH-Responsive Microgels: Promising Carriers for Controlled Drug Delivery*

shell and drug release. Examples include dextran microgels coated by different polyelectrolyte multilayer systems [34] and lipid-coated microgels for the release of

Biodegradable acrylamide/bisacrylamide microgels containing acetal linkers were investigated by Murthy et al. [36]. Biodegradation stimulated by low pH, resulting from acid-catalyzed hydrolysis of acetal linkage, was responsible for drug release. Similarly, Bromberg et al. [37] investigated poly (acrylic acid)-containing microgels cross-linked with disulfide groups. The chemical reduction of the disul-

pH-responsive microgels represent one of the major approaches for microgel-based delivery of biomacromolecular drugs. Of the many stimuli, alteration in pH is markedly fascinating because of the availability of pH gradients admissible for drug targeting. For example, pH gradients between normal tissues and some pathological sites, between the extracellular environment and some cellular compartments, and along the gastrointestinal (GI) tract are well characterized [38]. Orally administered drug encounters a pH gradient as it move from the stomach (pH 1–2, fasted state) to the duodenum (pH of about 6) and along the jejunum and ileum (pH 6–7.5) [39, 40]; therefore, attempts to avoid deterioration of drug and/or to promote intestinal absorption by exploiting this pH gradient is promising. pH-responsive polymeric networks, hence, have been

pH-responsive polymers are generally fabricated by inserting pendant acidic or basic functional groups to the backbone of the polymer. These functional groups either accept or release protons in response to appropriate pH and changes in the ionic strength of the surrounding aqueous media [42]. Polymers with acidic groups are unexpanded at low pH values, since the acidic groups are protonated and unionized. While increasing pH acidic groups are ionized, the resulting negatively charged polymer expands. The opposite behavior will be observed in the case of polybasic polymers [43, 44]. These systems can form polyelectrolytes with water, and microgels fabricated from weak polyelectrolytes demonstrate a pHresponsive volume phase changes. On the basis of the framework of polyelectrolyte, pH-responsive microgels can be classified as cationic, basic, or amphoteric. For instance, poly(acrylic acid) and polyethylenimine are weak polyacid and a poly-

Methods used for the synthesis of microgels can be divided into two major ideas:

The first approach is based on the investigations of Staudinger [45], who prepared

inter- and intramolecularly cross-linked microgels by free radical cross-linking copolymerization of monomers in dilute solutions. However, the resulting internal structure of microgels was not well established, but investigations performed on these systems were key step to understand the process of gel formation [46].

(a) The synthesis of microgels in homogeneous phase

(b) The synthesis of microgels in heterophase

**3.1 Synthesis of microgels in homogeneous phase**

extensively studied for the design of efficient carriers for drug delivery [41].

*DOI: http://dx.doi.org/10.5772/intechopen.82972*

fide bonds manifested the swelling of these systems.

doxorubicin [35].

base, respectively.

**3. Synthesis of microgels**

*2.1.5 Microgels responsive to pH*

#### *pH-Responsive Microgels: Promising Carriers for Controlled Drug Delivery DOI: http://dx.doi.org/10.5772/intechopen.82972*

shell and drug release. Examples include dextran microgels coated by different polyelectrolyte multilayer systems [34] and lipid-coated microgels for the release of doxorubicin [35].

Biodegradable acrylamide/bisacrylamide microgels containing acetal linkers were investigated by Murthy et al. [36]. Biodegradation stimulated by low pH, resulting from acid-catalyzed hydrolysis of acetal linkage, was responsible for drug release. Similarly, Bromberg et al. [37] investigated poly (acrylic acid)-containing microgels cross-linked with disulfide groups. The chemical reduction of the disulfide bonds manifested the swelling of these systems.
