**4. Alginate-Based Nanoparticles**

Alginates are a group of the most important biopolymers, also known as sodium-alginates, which are unbranched polysaccharide anionic polymers (Figure 5). Alginate demonstrates a wide range of potential applications in a polymeric drug delivery system, in the food industry in the form of additives based on electrostatic interaction. A modified form of alginates has introduced a greater level of properties in the biomedical and pharmaceutical industries [74]. Alginate is made up of unbranched polysaccharides extracted from brown seaweeds and soil bacteria. Alginic acid is the resulting product extracted from seaweed which is converted into sodium alginate, currently used in the pharmaceutical industry as an effective drug carrier. Alginic acid is a linear polymer consisting of L-guluronic acid and D-mannuronic acid; these are linearly arranged in the polymer chain. Alginates from various sources differ in their extents of blocks. Hydration of alginic acid leads to the synthesis of a high-viscosity "acid gel" due to intermolecular binding. Due to gelation, water molecules are enclosed inside the alginate matrix but are still free to migrate, which has a great application in drug encapsulation and cell immobilization [74].

**Figure 5.** Types of alginate blocs: M = mannuronic acid; G = guluronic acid [75].

Alginate is a perfect polymer for chemical functionalization, due to its free carboxyl and hydroxyl groups among the backbone. Properties such as hydrophobicity and solubility, and physicochemical and biological characteristics are enhanced due to the formation of alginate derivatives based on hydroxyl and carboxylic groups. Many physical and chemical methods, such as polymer blending, grafting copolymerization with hydrophilic vinyl monomers, and compounding with other functional components, can be used to modify sodium alginate [76]. Divalent cations act as cross-linkers between the functional groups of alginate chains. Polyvalent cations such as Ca2<sup>+</sup>, Sr2<sup>+</sup>, or Ba2<sup>+</sup> are responsible for intrachain and interchain cross-linking of alginate, forming insoluble alginate with the anionic polymer. Calcium is the main cation used because it is considered to be simply accessible, clinically safe, and cost-effective. The reaction of sodium alginate and calcium ion consists of a simple cross-linking process in which sodium-alginate is converted into calcium alginate [77].

$$\text{2Na(Algirate)} + \text{Ca}^{2+} \rightarrow \text{Ca(Algirate)}\_2 + \text{2Na}^+$$

Wandrey et al. [77] reported that, in the development of high mechanical strength and greater permeability, G alginate showed advantageous properties, and for additional properties, M alginate was suggested. Amphiphilic alginate is a current choice for drug delivery systems, and it shows properties such as low toxicity, good biocompatibility, mechanical stiffness, binding and release of drugs upon modification; it also reduces side effects and increases affinity with drugs [78,79]. Alginate-based smart polymers respond to pH [80], temperature [81], light [82], enzymes and magnetic

field [81,83]. Most of the drug carriers are synthesized on the basis of an ionic complexes of alginate or its sulfate derivatives with a cationic macromolecule such as peptides or proteins. Wu et al. [84] reported on a nano-sized drug carrier for chemotherapeutic applications based on inorganic/organic hybrid alginate/CaCO3 using the co-precipitation method under optimal conditions in the presence of an aqueous solution. A hydrophobic drug (paclitaxel, PTX) and hydrophilic drug (doxorubicin hydrochloride, DOX) were co-encapsulated in the alginate/CaCO3 hybrid nanoparticles. Different characterization techniques were used to observe the behavior of a simple nanoparticle-encapsulated drug and a co-encapsulated one. The drug-loaded with modified nanoparticles showed greater cellular uptake and an enhanced inhibitory effect. These results showed that alginate/CaCO3 hybrid nanoparticles have beneficial applications for the co-delivery of drugs with altered physicochemical properties. In another study, Jahanban-Esfahlan et al. [84] reported on an effective and drug release system for tumor treatment. They developed magnetic natural hydrogel based on alginate (Alg), Fe3O4 magnetic, and gelatin (Gel), nanoparticles (MNPs). Firstly, alginate was partially oxidized, then a shift-base condensation reaction was used to develop alginate-gel. Secondly, using a co-precipitation method, Fe3O4 nanoparticles were introduced in prepared alginate-gel. Characterization showed that this method synthesized hydrogel without any micro-phase separation. The attained Alg-Gel/Fe3O4 was loaded with doxorubicin hydrochloride (DOX), its drug loading, encapsulation properties and anticancer movement, were examined against Hela cells. The presence of carboxylic acid in the drug delivery system (synthesized Alg-Gel/Fe3O4-DOX) showed pH-dependent drug release. This modified form of alginate with magnetic nanoparticles showed promising results for a smart drug delivery system.

Moreover, Gao et al. [79] presented hydrophobic drug-based self-assembled micelles, a dual-stimuli responsive drug delivery system for hydrophobic drugs. Alginate was modified with dodecyl glycidyl as a hydrophobic group and was able to form self-assembled micelles in the aqueous solution above the critical micelle concentration. Doxorubicin (DOX) was used as an exemplary drug and successfully loaded in HMA (hydrophobic modified alginate) micelles. The enzyme and pH-stimuli release behavior of DOX from DOX-HMA micelles was such that the release of DOX was enhanced in an acidic medium. The release of drugs in the presence of a catalyst named an Alpha-Lfucosidase was effectively increased. Zhang et al. [85] synthesized graphene functionalized alginate (GO-ALG) for colon cancer treatment. This modification opened the way for many other therapeutic applications. The main issue linked with colon cancer is liver metastasis. Conventional drug delivery systems have many problems, such as failure to control the drug release ratio, poor stability, wrong targeting, and exposure to the microenvironment. This study reports the synthesis of graphene oxide (GO)-functionalized, sodium alginate (ALG) colon-targeting drug delivery system, with 5-fluorouracil (5-FU) used as the sample anticancer drug. The results showed that modified GOALG/5-FU expressively stopped tumor growth and liver metastasis and increased the life span of mice. This research opened a new route for the treatment of colon cancer liver metastasis. Nazemi et al. [86] investigated the ionic complexation of various configurations of alginate and its sulfated derivative with tetracycline hydrochloride (TCH). Remarkably, the functionalization of alginate with sulfate groups resulted in drug-polymer complex formation. Mannuronate-enriched alginate complex with TCH trapped the greater quantity of the drug. The results showed that this modification of alginate with TCH comes out as a favorable biomaterial for a cationic drug delivery system. Hügl et al. [87] entrapped the neurotrophic factor producing cell in an alginate polymer matrix. The application processes were tested for their potential in an artificial human cochlea model. Since the methods potentially affect the electrode implant capacity, the coating stability and insertion forces were analyzed on custom-made electrode arrays. Both inoculation of the alginate-cell solution into the model and a manual dip coating of electrode arrays with successive insertion into the model were promising. The filling of the model with a non-cross-linked alginate-cell solution improved the insertion forces. A good stability of the coating was examined after the first supplement. Both application schemes are a promising choice for cell-induced drug delivery to the inner ear, but an alginate-cell coating of electrodes has great potential with a reduction of insertion forces.
