Stimuli-Responsive Nanogels in Drug Delivery Systems

Hydrogels with dimensions in submicron range, known as nanogels, have received considerable attention as drug delivery systems, mainly because they combine the advantages resulting from their small dimensions (improved bioavailability, large surface area for multivalent bioconjugation, targeted delivery of drug, easier intracellular permeation, high stability, adjustable particle size) with the hydrogels properties like hydrophilicity and biocompatibility (Oh et al. 2008; Daniel-da-Silva et al. 2011; Hajebi et al. 2019).

Naturally derived nanogels can be prepared from polysaccharides, such as chito- san. hyaluronic acid, heparin, chondroitin sulfate, agarose, and alginate. For instance, hyaluronic acid-based nanogels (Yang et al. 2015; Pedrosa et al. 2017), chitosan- based nanogels (Duan et al. 2011; Wang et al. 2013; Feng et al. 2015), or hybrid microgels based on chitosan chemically cross-linked with hyaluronic acid (Schmitt et al. 2010) were prepared for delivery of different drugs. Different techniques have been applied to get small gel particles, as indicated in Figure 9.9.

Nanogels prepared from external stimuli-responsive polymers are of particular interest, being promising materials for the development of more effective disease treatments based on intelligent drug delivery systems, which can sense and respond directly to pathophysiological conditions (Daniel-da-Silva et al. 2011).

pH-responsive drug delivery> systems based on nanogels are well explored by numerous researchers. Because of the different pH values observed in healthy tissues (pH 7.4), and tumour tissues (pH 6.5-7.0), nanogels have been designed to be sensitive to the particular pH range of interest allowing drug release only in the tissue to be targeted (Hajebi et al. 2019). For example, nanogels containing pH-responsive functional

Different preparation methods for obtaining micro/nanogel particles. (Reprinted with permission from del Valle et al. 2017)

FIGURE 9.9 Different preparation methods for obtaining micro/nanogel particles. (Reprinted with permission from del Valle et al. 2017).

linkages in structures have been developed for the attachment of pH-triggered drug delivery for cancer therapy using the facts that tumour extracellular environment is more acidic than blood (Debele et al. 2016).

Nanogels composed of chitosan (CS) and carboxymethyl chitosan (CMCS) were generated via electrostatic interaction between positively charged CS and negatively charged CMCS in the presence of sodium tripolyphosphate (TPP) as ionic crosslinker. The doxorubicin hydrochloride (DOX) loading capacity of these nanogels has been greatly improved by incorporation of CMCS compared with CS only, mainly due to better interaction between positive charged DOX and negatively charged CMCS. The drug release rate of DOX:CS/CMCS nanogels was much low'er in simulating gastric acid environment (< 18%) than that in simulating intestinal environment, which was in favour of targeted delivery of drug to the colon (Debele et al.


Duan and co-workers synthesized chitosan grafted poly(N-isopropyl acrylamide) (PNIPAM) nanogels using N.N’-methylene-bis-acrylamide (MBA) as the cross-linking agent, and a potent anticancer agent for variety of tumours and cancer cell types (Oridonin, ORI) was successfully encapsulated. In vitro drug release result indicated that. ORI-loaded nanogels could enhance the antitumor activity under an acidic environment, because these nanogels exhibited a pH-triggered fast drug release under a slightly acidic condition: the release rates drastically increased from about 50% at pH 7.4 to more than 80% at pH 6.5, 6.0 and 5.0, owing in part to the ionization of chitosan (Duan et al. 2011).

Hyaluronic acid nanogels with enzyme-sensitiveness were prepared for doxorubicin (DOX) delivery (Yang et al. 2015) The DOX-loaded nanogels showed superior antitumour efficacy compared with the free DOX, demonstrated by great tumour penetrating capacity, enhanced DOX accumulation in the tumour site, and prolonged DOX circulation time. Therefore, these targeting, biocompatible, and multi-enzymatic degradable HA nanogels have great potential in drug delivery for cancer therapy.

Redox-sensitive dextran nanogels, for intracellular delivery of antigens (ovalbumin. OVA) were synthesized (Li et al. 2015). Disulfide bonds of dextran nanogels are stable in the extracellular environment, but are reduced in the cytosol of dendritic cells (DCs), due to the presence of glutathione (GSH). OVA-conjugated nanogels show intracellular release of the antigen in DCs and boost the major histocompatibility complex class I (MHC-I) antigen presentation, demonstrating the feasibility of this concept for the aimed intracellular antigen delivery.

Redox-sensitive nanogels based on carboxymethyl cellulose with a diameter of about 192 ± 2 nm were synthesized from methacrylated carboxymethyl cellulose (MACMC) and disulfide containing cystamine bisacrylamide (CBA). In vitro cytotoxicity, indicated that the relatively faster release of DOX from MACMC-CBA nanogels in the reductive environment of the cytoplasm can induce more inhibition of cell proliferation, leading to an improved antitumour efficiency. In vivo antitumour evaluation also showed that DOX loaded nanogels exhibited a significantly superior antitumour effect than the free DOX by combining the tumor volume measurement and the examination of cell apoptosis and proliferation in tumour tissues (Qian et al. 2014).

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