Agarose Background
Because agarose is a natural polysaccharide, which is highly biocompatible, it makes a good drug carrier/controlled release compound in biomedicine. Currently, agarose molecular structure is changeable using biological/physical/chemical modification techniques to get good performance expansion. Drug delivery, tissue engineering, separation and coating dressings are just a few applications for agarose biomaterials.
Agarose is a linear natural polysaccharide obtained from red algae that has a molecular weight between 80-140kDa. When the temperature is greater than 90°C, hydrogen bonds between the molecular chains of agarose rupture, and agarose diffuses in water to make a clear solution; at 30-40°C, agarose's molecular chains are joined by hydrogen bonds into a double helix that is tightly packed together to make a gel.
Drug delivery carriers based on natural matrices, such as chitosan, cellulose and starch, have attracted widespread attention. Chitosan has problems such as needing to be dissolved in an acidic medium and difficulty in controlling pore size uniformity.
Cellulose has problems with poor water solubility and thermoplasticity. Starch is highly water soluble and difficult to use in drug sustained release, and has problems with poor mechanical properties. Agar has considerable viscoelasticity and thermoplasticity, making it very suitable for controlling drug release.
Figure 1. Agarose-based biomaterials for advanced drug delivery. (Khodadadi Yazdi M, et al.; 2020)
Agarose for Drug Delivery
Take cancer applications as an illustration. Tumor is not a lump, it's made of tumor cells, then enclosed by a matrix of immune cells and tumour stem cells. Chemotherapy, radiotherapy and surgery are all popular treatments that have the downsides of being high-dose, big-side-effect and largely lack of specificity. The polymer targeted drug delivery agent (hydrogel, nanoparticles, etc.) can give the best possible answer to the problems above. Agarose hydrogels are normally very hydrophilic and many chemotherapy drugs can be hydrophobic, how do you overcome that? Add Amphiphilic surfactants (Tween 80, poloxamer, sodium dodecyl sulfate) to make the drug evenly distributed within the hydrogel.
Agarose for Nucleic Acid Drug Delivery
Nucleic acid drugs are DNA drugs based on DNA manipulation (eg, in vivo gene therapy viruses-based gene therapy medicines, in vitro gene therapy virus-based gene therapy medicines, naked plasmid drugs etc.) and RNA therapeutics (antisense oligonucleotide drug (ASO), siRNA drugs, mRNA gene therapy, etc.). These drugs' in vivo degradation, mistargeting and cellular absorption are all concerns. Current syringes that are mature delivery systems include GalNAC (N-acetylgalactosamine) delivery system and LNP. GalNAc is a highly specific binding ligand of asialoglycoprotein receptor (ASGPR), an endocytic receptor very specifically localised on the membrane of hepatocytes. Both ASGPR and clathrin endocytosis can carry GalNAc from the cell surface to the cytoplasm.Although no gel excipients are found in the nucleic acid drugs and their delivery systems currently approved by the FDA. So, are gels or agarose-based biomaterials really not suitable for nucleic acid drugs? Studies have shown that agarose nanocarriers can be used to deliver nucleic acids (DNA). A pH-sensitive amino acid-modified agarose nanocarrier was used to deliver DNA. The system binds the drug under acidic conditions and releases it under alkaline conditions.
Agarose Protein Drug Delivery
Protein-based drugs are still a big topic of study from the past decades. The first protein drug to be cleared by the US FDA was the mouse monoclonal antibody Orthoclone OKT3 (for prevention of host rejection after kidney transplantation). Some 200 protein therapies (monoclonal antibodies, polyclonal antibodies and ADCs) have already been developed. Currently, these above protein drugs are mostly injected. Protein therapies are very high doses that you have to do again and again for a very long time. Proteins are unstable, and that's a major barrier to their controlled, sustained release. Many systems (liposomes, micelles, etc.) supposedly deliver protein drugs in body but end up trapped by the reticuloendothelial cell system. In-situ gel formulation excipients are typically polymeric. When polymers like PLGA are broken down they can release acidic waste products (lactic acid and glycolic acid) which can lead to inflammation and lower product performance. For protein drugs, the presence of PLGA carboxylic acid end groups can interact with the positive charge of the encapsulated protein, changing or even preventing its release; and exposure of therapeutic proteins to acidic pH can induce their aggregation or affect their activity. In fact, drug loading systems for protein-based injectable drugs in agarose hydrogels have been developed and characterized a long time ago. Fibroblast growth factor (bFGF) is one of the growth factors commonly used for tissue regeneration or angiogenesis. Researchers prepared agarose gel particles through emulsification/gelation method as a sustained-release carrier or storage of bFGF. library, and the agarose hydrogel particles of bFGF enhanced the angiogenic effect. Although agarose-based materials have the problem of initial burst release rather than sustained controlled release in drug delivery, their application in sustained-release/controlled systems can be solved restricted problem through the functionalized drug delivery system of agarose-based materials.
Agarose Cell-Based Drug Delivery
Agarose is rarely used for cell transplantation, but they have the potential benefit of protecting cells from harsh physiological conditions. 3D culture containing agar-based biomaterials provides a simulation of various physiologically relevant situations and can minimize the use of animal models in preclinical trials.
Judging from the number of studies, the research on agarose-based gel delivery is decreasing, but agarose-based biomaterials show great application potential due to their unique physicochemical properties, especially in drug delivery research. However, it is undeniable that agarose-based biomaterials have problems such as slow degradation rate, high dissolution temperature, and slow adsorption/desorption rate of certain drugs. Of course, similar to other natural matrices, modified agar will have better drug delivery applications, and the practical application of agarose-based biomaterials and improved agarose-based biomaterials still has a long way to go.
References
- Khodadadi Yazdi M, et al.; Agarose-based biomaterials for advanced drug delivery. J Control Release. 2020, 326:523-543.
- Jiang F, et al.; Extraction, Modification and Biomedical Application of Agarose Hydrogels: A Review. Mar Drugs. 2023, 21(5):299.
