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Sources, Structures, and Properties of Alginate

Alginate, also known as alginic acid, is a kind of natural linear anionic polysaccharide widely used in the field of biomedicine. Alginate is mainly distributed in the cell wall of brown algae and extracted in the form of acidification and sodium salt. In recent years, some researchers have extracted alginate through microbial fermentation of Pseudomonas aeruginosa [1].

Alginate is a straight-chain polymer composed of 1-4-linked ß-D-mannuronic acid (M) or a-L-guluronic acid (G), which is interspersed with regions containing alternating M-G sequence [2]. The chemical structure of alginate from different sources is also quite different. Alginate from algae has high content of Poly G and excellent antibacterial activity, while alginate from microorganism has high content of Poly M, which can induce monocytes to produce inflammatory mediators such as interleukin-1, interleukin-6, and tumor necrosis factor. Na+ in alginate guluronic acid (Poly G) can be exchanged with divalent cations to form physically cross-linked hydrogels, in which the cross-linking model with Ca2+ is called "eggs-box model" (side-by-side Poly G can form a pore conducive to Ca2+ cross-linking, and each Poly G binds to the corresponding two Poly G in an orderly manner) [3]. During the cross-linking process, the alginate droplets containing the required protein will be extruded from the gel frame to form alginate microspheres. Due to the mild cross-linking conditions and excellent mechanical properties, alginate hydrogel has become a research hotspot in the field of cell encapsulation and tissue engineering. Owing to the free hydroxyl and carboxyl groups, alginate also has excellent bio-adhesion. In addition, the pH sensitivity of alginate (which shrinks under low pH conditions) also has a great prospect in targeted drug delivery.

At present, the modification of alginate is mainly based on the following two aspects: Firstly, the alginate materials with different properties were obtained by adjusting the content of Poly M and Poly G in alginate. Secondly, the active sites of alginate (carboxyl group, hydroxyl group, 1-4 glycosidic, internal glycolic bonds) were modified to improve the properties of the derived materials.

1.1 Alginate-Based Hydrogel for Biomedical Application

1.1.1 Drug and Cell Delivery

Systematic administration of antibiotics is the main cause of widespread drug resistance throughout the body, and the development of a local targeted administration system is an effective way to solve this clinical problem. In order to solve many side effects of intravenous application of antibiotics, Czuban et al. [4] prepared tetrazine-modified alginate hydrogel. Based on the principle of the inverse electron-demand Diels-Alder chemistry, vancomycin and daptomycin loaded with hydrogel can be released at the site of infection, and this hydrogel can repeatedly achieve drug loading and local release, significantly reducing adverse reactions caused by the use of antibiotics.

Autologous tumor cell vaccine is an individualized therapeutic strategy to activate tumor-specific immune response. However, it has limited efficacy in "cold" solid tumors that lack tumor-infiltrating T cells and are insensitive to immunotherapy. Ke et al. constructed a dendritic cell (DC)-activated hydrogel system using bifunctional fusion membrane nanoparticles (FM-NPs) composed of autologous tumor cell membranes and Mycobacterium leprae membrane extract to provide tumor antigenic signals and to interact with granulocyte-macrophage colony-stimulating factor (GM-CSF). Nanoparticles (NPs) composed of autologous tumor cell membranes and Mycobacterium leucocephala membrane extracts were used to provide tumor antigen signaling and were co-loaded with GM-CSF in an alginate hydrogel. Rapid release of GM-CSF recruited DCs; FM-NPs continuously activated the maturation of DCs and provided tumor antigens. The hydrogel system could increase the infiltration of effector memory T cells and activate "cold" tumors to exert significant anti-tumor effects. This study provides a feasible strategy to overcome the bottleneck of the efficacy of autologous tumor vaccines in "cold" tumors and points out a new direction to improve the clinical efficacy [5] (Figure 1.1).

The adenosinergic axis limits the effectiveness of current tumor immunotherapy by inhibiting the activity of effector T cells. How to effectively remodel the adenosinergic axis has become a key target to improve the effect of anti-tumor immunotherapy. Zhao et al. constructed an injectable hydrogel system based on alginic acid, and used the synergistic effects of adenosine deaminase, docetaxel, and benzotricarboxylic acid to realize the conversion from immunosuppressive adenosine to immuno-strengthening inosine to remodel the adenosinergic axis and exert anti-tumor effects. Docetaxel and benzotricarboxylic acid synergistically induced a large release of ATP, which triggered a strong immune response; adenosine deaminase catalyzed the conversion of adenosine to inosine, which further enhanced the immune effect; and ultimately achieved the reversal of the negative feedback from adenosine to positive feedback from inosine. The hydrogel strategy reshaped the adenosinergic axis through cascade amplification of ATP-mediated anti-tumor immune response, which provided a new idea and means to enhance the effect of tumor immunotherapy [6].

Figure 1.1 (a) Fusion membrane nanoparticles (FM-NPs) were prepared from autologous tumor cell membranes and Bacillus membrane extracts. (b) Sodium alginate solution was cross-linked with cationic solution to form hydrogels at room temperature. (c) FM-NPs and sodium alginate solution were used to form a hydrogel in vivo, which attracted dendritic cells and were activated by FM-NPs. Mature dendritic cells carrying tumor antigens stimulated the increase of effector memory T-cells, which exerted anti-tumor effects.

Source: Ref. [5]/John Wiley & Sons.

In the postoperative treatment of breast cancer, high local recurrence rates and potential wound infections pose significant risks to patient survival. To overcome these challenges, Wu et al. conducted a study on a nanocomposite dual-network (NDN) hydrogel. The hydrogel was constructed using polyethylene glycol acrylate (PEGDA) and alginate, embedded with 125i-labeled RGDY peptide-modified gold nanorods (125I-GNR-RGDY). This study formed hydrogels with a dual-network structure by near infrared (NIR) light-induced polymerization of PEGDA and endogenous Ca2+ cross-linking of alginate to construct a second network. This design enabled the hydrogel to exhibit stable photothermal effects and radiolabeling under NIR light irradiation. Photothermal therapy synergizes with brachytherapy by inhibiting DNA self-repair, promoting blood circulation, and improving the hypoxic microenvironment to enhance the therapeutic effect. This study provides a novel therapeutic approach by in situ injection of a precursor solution into the lumen of excised mouse cancerous breasts to form a rapidly gelatinizing hydrogel. By combining photothermal therapy and radiation therapy, this approach is expected to reduce the risk of local recurrence and decrease the likelihood of wound infection in postoperative breast cancer patients. This targeted therapeutic strategy offers new prospects for improving the outcome and survival of breast cancer patients [7].

The presence of immunosuppressive cells in the tumor microenvironment, especially tumor-associated macrophages (TAMs), poses a limitation on T-cell infiltration and activation, which in turn constrains the anticancer effect of immune checkpoint blockade. Li et al. developed a biocompatible alginate-based hydrogel that carries encapsulated nanoparticles loaded with pessitinib (PLX). The hydrogel gradually released PLX at the tumor site by blocking the colony-stimulating factor 1 receptor (CSF1R) in order to reduce the presence of TAMs. This strategy not only creates an environment conducive to promoting local and systemic delivery of anti-PD-1 antibodies (aPD-1), thereby inhibiting postoperative tumor recurrence, but also further contributes to T-cell infiltration of tumor tissue by reprogramming the tumor immunosuppressive microenvironment. In addition, the postoperative inflammatory environment triggers platelet activation, which promotes the release of aPD-1 and reactivates T cells by binding to the PD-1 receptor. It was noted that hydrogels can act as local reservoirs for sustained release of PLX-NP and P-aPD-1 to enhance the efficacy of tumor immunotherapy. The immunotherapeutic effect of systemic injection of P-aPD-1 could also be further enhanced by the hydrogel strategy of local depletion of TAMs, broadening the route of administration...