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Putri, A.P. Alginate Application in Drug Delivery. Encyclopedia. Available online: (accessed on 11 December 2023).
Putri AP. Alginate Application in Drug Delivery. Encyclopedia. Available at: Accessed December 11, 2023.
Putri, Arlina Prima. "Alginate Application in Drug Delivery" Encyclopedia, (accessed December 11, 2023).
Putri, A.P.(2021, December 22). Alginate Application in Drug Delivery. In Encyclopedia.
Putri, Arlina Prima. "Alginate Application in Drug Delivery." Encyclopedia. Web. 22 December, 2021.
Alginate Application in Drug Delivery

Alginates are generally used in the food, beverage, cosmetic, paper, textile printing, and pharmaceutical industries. They have been utilized as stabilizers, thickeners, emulsifiers, and hydration and gelling agents. The main use of alginate in the biomedical industry is mainly focused on hydrogels used in wound healing, drug delivery, and tissue regeneration. The broad range of applications is due to its biocompatibility, low toxicity and relatively low-cost consumption, and structural similarity to the extracellular matrices of living tissue.

alginate drug delivery

1. Alginate Hydrogel

Alginate hydrogels are biocompatible and structurally identical to the macromolecular-based component of the biological body. Hydrogels are defined as three-dimensional networks in which hydrophobic polymers chains are crosslinked together [1]. The crosslinking of alginates, specifically, can be conducted via ionic, covalent, and cell pathways as well as by free radical polymerization [2][3]. However, ionic crosslinking is the typical way to synthesize alginate gels, and calcium has been traditionally used to establish crosslinking. The tendency to use ionic crosslinking is supported by the fact that it offers an adequate method for active substance entrapment without affecting their bioactivity [4].
A critical factor in controlling the gelation process using divalent cations is the gelation rate. Gel uniformity and greater mechanical integrity are expected from a slower gelation system [5]. When crosslinking alginates, calcium carbonate and calcium sulfate have shown different gelation rates [6]. With a rapid gelation rate, the calcium chloride is suitable for ionic crosslinker for a bioencapsulation scheme, whereas others are more favored in tissue engineering scaffolds. The gelation rate also depends on the temperature; low temperature reduces the Ca2+ reactivity, leading to low gelation rates, well-ordered network structures, and improved mechanical properties [2].
On the other hand, the alginates’ M/G ratio and molecular weight contribute to the variation of the physicochemical properties of their ionic-crosslinked gel. The geometries of the G-block, M-block, and alternating regions are different due to particular shapes and modes of linkage in the alginate sequence. Thus, their intermolecular crosslinking with divalent ions is dissimilar and gives other gel characteristics. A higher content of G-block results in higher tensile strength and modulus and more extensibility than for alginates richer in M-blocks [7]. In addition, a rheological study of high molecular weight alginate fluid gels showed rapid gelation kinetics and higher viscosities than lower molecular weight [8]. The alginate source and the gelling ion conditions (type and concentration) affect the gel stability and permeability. A study on calcium, barium, and strontium ions has been conducted, forming alginate microbeads [9]. These three different cations reacted differently with the G- and M-blocks of alginate, resulting in diverse stability, permeability, gel strength, and distribution of alginates in the gel beads.
Besides ionic crosslinking, many alternative approaches to produce alginate gels have been investigated. Alginate can be covalently crosslinked using carbodiimide chemistry, and one study found that the crosslinker type and the crosslinking density adequately affect hydrogel properties [10]. The crosslinking density affected the mechanical properties of hydrogels, and the type of crosslinking molecules influenced the swelling properties. Another representative strategy prompting the covalent crosslinking in alginate is free radical polymerization. Alginate-methacrylate hydrogels can be prepared through photopolymerization, obtaining mechanical properties that are dominated by the molecular conformation and electron density of the methacrylate reactive groups [11]. Nevertheless, if the alginate polymer chain’s surface is decorated with cell adhesion ligands, cell cross linking most likely also produces alginate gels [12].
The properties of alginate hydrogels, such as high-water content, nontoxicity, soft consistency, biocompatibility, and biodegradability, make them sufficient candidates as drug carriers. As reported previously, alginate hydrogel could synthesize into nanogel, and it has good stability in biological fluid because of the low deriving for aggregation [13]. An alginate nanogel loaded with gold nanoparticles creates a thermos-responsive platform suitable for chemo-photothermal therapy for breast cancer [14]. Another study also developed a pressure trigger controlled drug released from alginate-cyclodextrin nanogel [15]. This carrier manages to enhance the apoptosis mechanism for colon cancer drug delivery. An improved drug loading efficiency of alginate nanogel for cancer therapy can be achieved using additional keratin to create a composite platform [16].

2. Alginate Ester

Alginate ester is synthesized through esterification. Esterification is the earliest functionalization of alginate, and it is generally carried out in non-aqueous systems. This functionalization could perform to both available functional groups, either carbonyl or hydroxyl. An additional catalyst is needed for esterification of the hydroxyl groups for a more selective reaction [17].
A full chemoselective carbonyl alginate ester was introduced with the use of tetrabutylammonium (TBA) salt of alginate [18]. This amphiphilic alginate is suggested for use as an amorphous solid dispersions (ASDs) matrix. The presence of alginate esters, ethyl, butyl, and benzyl are aimed at enhancing drug solubility. The introduction of butyl groups to alginate through esterification forms hydrophilic alginate without losing their gelation ability in the presence of calcium chloride [19]. By using the same functionalization method, a methyl alginate ester was synthesized and used as an excipient for direct compression in immediate drug-release tablet production [20]. Another study created a nanoparticle platform based on oleate alginate ester for curcumin delivery [21]. Alginate is active with formamide so it can actively react with methyl oleate; alginate ester is formed after 48 h of reaction, and the excess formamide can be removed with soxhlet apparatus.
The attachment of the hydrophobic moieties on the alginate backbone creates a micelle carrier system. Such a system is one way to enhance the solubility of poorly water-soluble drugs and drug loading encapsulation, and is a controlled release mechanism [22]. However, further investigation is necessary to improve the solubility enhancement factor and to find a compatible way to facilitate ASD formation. Moreover, the development of a specific esterification method is needed to create a tunable hydrophobicity–hydrophilicity balance characteristic [18].

3. Alginate Dialdehyde

Alginate cannot degrade in mammals due to a lack of alginate-degrading enzymes [23]. Ionically crosslinked alginate hydrogels, on the other hand, can be dissolved by ionic exchange reaction, but the high molecular weights (>50 kDa) of the parent alginate restrain the renal clearance. To address the limitation, alginate dialdehyde (ADA), which Malaprade first reported, has been widely investigated [24][25][26]. This alginate derives from partial oxidation of alginate chains, involving C2-C3 bond cleavage and transforming into an open ring containing two aldehyde groups. This functionalization is selective modification of the hydroxyl moieties. ADA has a lower molecular weight and is more soluble in aqueous media. Its stiffness and persistence length decreases with an increase in the degree of oxidation [27].
ADA consists of multiple aldehyde groups, a reactive group that can form covalent bonds with free amino groups in gelatin, and chitosan. The development of Schiff’s base crosslinking hydrogels between ADA and polymer containing free amino groups has been investigated [28][29]. A study found that the degree of crosslinking of ADA/PEG(polyethylene glycol)-gelatin hydrogels are higher than ADA/PEG-chitosan hydrogels [30]. This degree of crosslinking is defined as the number of groups that interconnect two materials, generally expressed in mole percent. This can be determined by trinitrobenzene sulfonic acid (TNBS) assay or ninhydrin assay [29][31]. Furthermore, the rheological, degradation, and comprehensive properties of the ADA/PEG-chitosan hydrogel are suggested to be more suitable for the self-crosslinking injectable scaffold.
The synthesis of hydrogels derived from ADA and gelatin has been reported; the crosslinking between ADA and gelatin was increased by increasing the degree of oxidation of ADA [32]. Such in situ forming hydrogel is used as wound dressing material; it is molded in accordance with the wound shape to enable conformability of the dressing for their application [33]. The advantage of alginates as a wound dressing is the ability to absorb excess wound fluid and maintain physiological moisture and an aseptic environment [34]. Another study successfully performed bone regeneration with RGD-alginate and found that the alginate’s system showed an excellent bone formation ability [35]. The application of injectable hydrogel from ADA and gelatin for meniscal injury treatment has also been investigated [36]. Moreover, the same hydrogel could serve as a drug delivery vehicle in the formed nanogel and successfully delivered curcumin as an active ingredient [37].


  1. Chai, Q.; Jiao, Y.; Yu, X. Hydrogels for Biomedical Applications: Their Characteristics and the Mechanisms behind Them. Gels 2017, 3, 6.
  2. Augst, A.D.; Kong, H.J.; Mooney, D.J. Alginate hydrogels as biomaterials. Macromol. Biosci. 2006, 6, 623–633.
  3. Abasalizadeh, F.; Moghaddam, S.V.; Alizadeh, E.; Akbari, E.; Kashani, E.; Fazljou, S.M.B.; Torbati, M.; Akbarzadeh, A. Alginate-based hydrogels as drug delivery vehicles in cancer treatment and their applications in wound dressing and 3D bioprinting. J. Biol. Eng. 2020, 14, 8.
  4. Dianawati, D.; Mishra, V.; Shah, N.P. Role of calcium alginate and mannitol in protecting Bifidobacterium. Appl. Environ. Microbiol. 2012, 78, 6914–6921.
  5. Kuo, C.K.; Ma, P.X. Ionically crosslinked alginate hydrogels as scaffolds for tissue engineering: Part 1. Structure, gelation rate and mechanical properties. Biomaterials 2001, 22, 511–521.
  6. Aguero, L.; Zaldivar-Silva, D.; Pena, L.; Dias, M.L. Alginate microparticles as oral colon drug delivery device: A review. Carbohydr. Polym. 2017, 168, 32–43.
  7. Drury, J.L.; Dennis, R.G.; Mooney, D.J. The tensile properties of alginate hydrogels. Biomaterials 2004, 25, 3187–3199.
  8. Fernández Farrés, I.; Norton, I.T. Formation kinetics and rheology of alginate fluid gels produced by in-situ calcium release. Food Hydrocoll. 2014, 40, 76–84.
  9. Mørch, Ý.A.; Donati, I.; Strand, B.L.; Skjåk-Bræk, G. Effect of Ca2+, Ba2+, and Sr2+ on Alginate Microbeads. Biomacromolecules 2006, 7, 1471–1480.
  10. Eiselt, P.; Lee, K.Y.; Mooney, D.J. Rigidity of Two-Component Hydrogels Prepared from Alginate and Poly(ethylene glycol)−Diamines. Macromolecules 1999, 32, 5561–5566.
  11. Araiza-Verduzco, F.; Rodríguez-Velázquez, E.; Cruz, H.; Rivero, I.A.; Acosta-Martínez, D.R.; Pina-Luis, G.; Alatorre-Meda, M. Photocrosslinked Alginate-Methacrylate Hydrogels with Modulable Mechanical Properties: Effect of the Molecular Conformation and Electron Density of the Methacrylate Reactive Group. Materials 2020, 13, 534.
  12. Drury, J.L.; Boontheekul, T.; Mooney, D.J. Cellular Cross-linking of Peptide Modified Hydrogels. J. Biomech. Eng. 2004, 127, 220–228.
  13. Yallapu, M.M.; Jaggi, M.; Chauhan, S.C. Design and engineering of nanogels for cancer treatment. Drug Discov. 2011, 16, 457–463.
  14. Mirrahimi, M.; Abed, Z.; Beik, J.; Shiri, I.; Shiralizadeh Dezfuli, A.; Mahabadi, V.P.; Kamran Kamrava, S.; Ghaznavi, H.; Shakeri-Zadeh, A. A thermo-responsive alginate nanogel platform co-loaded with gold nanoparticles and cisplatin for combined cancer chemo-photothermal therapy. Pharmacol. Res. 2019, 143, 178–185.
  15. Hosseinifar, T.; Sheybani, S.; Abdouss, M.; Hassani Najafabadi, S.A.; Shafiee Ardestani, M. Pressure responsive nanogel base on Alginate-Cyclodextrin with enhanced apoptosis mechanism for colon cancer delivery. J. Biomed. Mater. Res. A 2018, 106, 349–359.
  16. Sun, Z.; Yi, Z.; Zhang, H.; Ma, X.; Su, W.; Sun, X.; Li, X. Bio-responsive alginate-keratin composite nanogels with enhanced drug loading efficiency for cancer therapy. Carbohydr. Polym. 2017, 175, 159–169.
  17. Suzuki, S.; Kurachi, S.; Wada, N.; Takahashi, K. Selective Modification of Aliphatic Hydroxy Groups in Lignin Using Ionic Liquid. Catalysts 2021, 11, 120.
  18. Pawar, S.N.; Edgar, K.J. Alginate esters via chemoselective carboxyl group modification. Carbohydr. Polym. 2013, 98, 1288–1296.
  19. Broderick, E.; Lyons, H.; Pembroke, T.; Byrne, H.; Murray, B.; Hall, M. The characterisation of a novel, covalently modified, amphiphilic alginate derivative, which retains gelling and non-toxic properties. J. Colloid. Interface Sci. 2006, 298, 154–161.
  20. Sanchez-Ballester, N.M.; Bataille, B.; Benabbas, R.; Alonso, B.; Soulairol, I. Development of alginate esters as novel multifunctional excipients for direct compression. Carbohydr. Polym. 2020, 240, 116280.
  21. Raja, M.; Liu, C.; Huang, Z. Nanoparticles Based on Oleate Alginate Ester as Curcumin Delivery Aystem. Curr. Drug Deliv. 2015, 12, 613–627.
  22. Zhang, N.; Wardwell, P.R.; Bader, R.A. Polysaccharide-based micelles for drug delivery. Pharmaceutics 2013, 5, 329–352.
  23. Lee, K.Y.; Mooney, D.J. Alginate: Properties and biomedical applications. Prog. Polym. Sci. 2012, 37, 106–126.
  24. Gomez, C.G.; Rinaudo, M.; Villar, M.A. Oxidation of sodium alginate and characterization of the oxidized derivatives. Carbohydr. Polym. 2007, 67, 296–304.
  25. Jejurikar, A.; Seow, X.T.; Lawrie, G.; Martin, D.; Jayakrishnan, A.; Grøndahl, L. Degradable alginate hydrogels crosslinked by the macromolecular crosslinker alginate dialdehyde. J. Mater. Chem. 2012, 22, 9751–9758.
  26. Bouhadir, K.H.; Hausman, D.S.; Mooney, D.J. Synthesis of cross-linked poly(aldehyde guluronate) hydrogels. Polymer 1999, 40, 3575–3584.
  27. Omtvedt, L.A.; Dalheim, M.O.; Nielsen, T.T.; Larsen, K.L.; Strand, B.L.; Aachmann, F.L. Efficient Grafting of Cyclodextrin to Alginate and Performance of the Hydrogel for Release of Model Drug. Sci. Rep. 2019, 9, 9325.
  28. Fan, L.-H.; Pan, X.-R.; Zhou, Y.; Chen, L.-Y.; Xie, W.-G.; Long, Z.-H.; Zheng, H. Preparation and characterization of crosslinked carboxymethyl chitosan–oxidized sodium alginate hydrogels. J. Appl. Polym. Sci. 2011, 122, 2331–2337.
  29. Balakrishnan, B.; Joshi, N.; Jayakrishnan, A.; Banerjee, R. Self-crosslinked oxidized alginate/gelatin hydrogel as injectable, adhesive biomimetic scaffolds for cartilage regeneration. Acta Biomater. 2014, 10, 3650–3663.
  30. Naghizadeh, Z.; Karkhaneh, A.; Khojasteh, A. Self-crosslinking effect of chitosan and gelatin on alginate based hydrogels: Injectable in situ forming scaffolds. Mater. Sci. Eng. C 2018, 89, 256–264.
  31. Friedman, M. Applications of the Ninhydrin Reaction for Analysis of Amino Acids, Peptides, and Proteins to Agricultural and Biomedical Sciences. J. Agric. Food Chem. 2004, 52, 385–406.
  32. Balakrishnan, B.; Jayakrishnan, A. Self-cross-linking biopolymers as injectable in situ forming biodegradable scaffolds. Biomaterials 2005, 26, 3941–3951.
  33. Balakrishnan, B.; Mohanty, M.; Umashankar, P.R.; Jayakrishnan, A. Evaluation of an in situ forming hydrogel wound dressing based on oxidized alginate and gelatin. Biomaterials 2005, 26, 6335–6342.
  34. Aderibigbe, B.A.; Buyana, B. Alginate in Wound Dressings. Pharmaceutics 2018, 10, 42.
  35. Krishnan, L.; Priddy, L.B.; Esancy, C.; Li, M.-T.A.; Stevens, H.Y.; Jiang, X.; Tran, L.; Rowe, D.W.; Guldberg, R.E. Hydrogel-based Delivery of rhBMP-2 Improves Healing of Large Bone Defects Compared with Autograft. Clin. Orthop. Relat. Res. 2015, 473, 2885–2897.
  36. Resmi, R.; Parvathy, J.; John, A.; Joseph, R. Injectable self-crosslinking hydrogels for meniscal repair: A study with oxidized alginate and gelatin. Carbohydr. Polym. 2020, 234, 115902.
  37. Chettri, D.; Boro, M.; Sarkar, L.; Verma, A.K. Lectins: Biological significance to biotechnological application. Carbohydr. Res. 2021, 506, 108367.
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