Introduction
Alginate comes from brown algae and kelp mostly, found in the ocean. Sodium alginate can be extracted by the method of sodium carbonate/sodium hydroxide neutralisation and calcium chloride precipitation. It is very viscous, water-soluble and highly charge-density; thus, being used in food, medicine and industry. Alginate is also widely used in medicine and biotechnology because of its high biocompatibility and biodegradability. Its breakdown is largely hydrolytic and enzymatic, so it gradually breaks down into molecules in the body and won't get poisoned with the possibility of long-term residues.
Why Alginate is Crucial for the Delivery of Medicines?
The use of alginate for drug delivery has been widely studied because of its specific physicochemical features: high biocompatibility, controllable physicochemical features and controllable biodegradability. This is what makes it the perfect drug carrier compound. Alginate is low toxicity and biodegradable with variable physicochemical stability. For instance, its ability to deliver drugs can be tuned by modifying its molecular weight or mixing it with other molecules (chitosan, gelatin). Alginate can also increase drug bioavailability by altering release behavior, and good bioadhesion contributes to localisation of drugs at the target location.
Figure 1. Alginate based chemotherapeutic drug delivery system. (Lakkakula JR, et al.; 2021)
Structure and Properties of Alginate
Alginate molecular pattern is divided into homogeneous patterns and heterogeneous patterns. Where in the homogeneous patterns, M or G residues are repeating whereas in the heterogeneous patterns, M and G residues are spaced on opposite sides. This structural difference shapes the physical and chemical characteristics of alginate (gellling force, viscosity, molecular selectivity). Depending on the extent of polymerization and molecular weight, alginate's use in drug delivery systems can vary a great deal. The higher the molecular weight, the better the hydrogel's physical stiffness is likely to be, reducing the tendency to release the drug. Furthermore, depending on the degree of polymerization can also be controlled to give long or fast release of drugs.
Alginate is very water soluble and dissolution forms a liquid solution in water. Alginate will become gummy if divalent cations (eg, Ca2+) are added and the hydrogel will harden. This gelation is a function of M/G residue ratio and divalent cation type. Chemical changes can change the degradation rate of alginate (by adding new functional groups through esterification or oxidation) and modify its degradation rate and in vivo drug release pattern.
Alginate derivatives can also be greatly enhanced by adding other functional groups or copolymerising with another element. By copolymerizing with chitosan, for instance, it becomes better for colon and gastric drug delivery. In addition, derivatives can be shaped for a biomedical purpose by adding hydrophobic tags or cell adhesion molecules like RGD sequences. Alginate can be copolymerised with other monomers into functional composites. Copolymerisation with polyacrylamide or liquid metals for instance, for example, can yield electrically conducting hydrogels or filter membrane materials. To broaden alginate's uses, researchers have come up with a series of functional modification techniques. For instance, the conversion of chitin acid into glucuronic acid through enzymatic reaction, or chemical cross-linking to make them mechanically better. Such techniques not only optimize the activity of alginate, they open new applications for the compound in biomedicine, sensing monitoring and chemical analyses.
Alginate Applications in Drug Delivery
Alginate has multiple drug delivery uses and is already being demonstrated for oral drug delivery, targeted drug delivery, controlled release, local delivery/wound healing and gene delivery.
- Oral Drug Delivery System
Alginate is also popular in oral drug delivery systems because it is both biocompatible and biodegradable. For instance, microparticles of alginate are employed to improve drug bioavailability for the delivery of drugs like nonsteroidal anti-inflammatory drugs (NSAIDs) by manipulating the mechanism of drug release. Alginate hydrogel microcapsules are pH sensitive, too, and ideal for targeted delivery of drugs into the small intestine. They are stable in non-active gastric fluid and fast or slow release in non-active intestinal fluid. Alginate is often used to manufacture a pharmaceutical capsule and microparticle to enhance the stability and bioavailability of drugs. For instance, dental implant rings from alginate and chitosan to prevent the absorption of metronidazole were employed. Additionally, calcium alginate microcapsules made by the combination of spray and high-voltage electrostatic field have small particles and even distribution, and thus can protect protein drugs from stomach acid harm. - Targeted Drug Delivery
Alginate nanoparticles are the ideal targeted drug carrier because they are biocompatible and low toxic. Combining with targeting molecules like antibodies and peptides allow drug delivery to target site and therefore increase the effectiveness of therapy while minimizing the adverse effects. For instance, sodium alginate nanoparticles can bind to receptors by surface modification to deliver selectively. - Controlled Release System
Alginate-based microcapsules and nanoparticles are the champions of controlled release. Alginate hydrogel microcapsules, for instance, provide exact drug release rate control based on pH level and particle size. Also controlled release of bioactive compounds have been attempted with alginate nanocarriers. - Local Delivery and Wound Healing
Alginate is widely used in dressing wounds, in hydrogel for wound repair, and as a cell capsule for tissue engineering. For instance, alginate hydrogels are used to deliver cancer drug locally, and in wound dressings to speed up wound healing. - Gene Delivery System
Alginate can be used as a gene therapy vector, or as a vector for RNA or DNA. Alginate nanocarriers, for instance, are encapsulated in genes for delivery of genes.
Design and Optimization of Alginate Drug Delivery Systems
It is the preparation process, factors that affect drug loading and release properties, assessment of effects on drug delivery, or synthesis with another component that are all part of alginate drug delivery systems design and optimization.
Alginate drug delivery systems are mostly prepared through ion crosslinking and solvent evaporation. The ion crosslinking procedure is to create a network of crosslinking between divalent or trivalent cations (Ca2+, Zn2+) and -COO groups between molecules of alginate in order to form stable hydrogel particles or beads. This approach is often applied to drug carriers. A second widely applied preparation method is solvent evaporation, where alginate is dissolved in a suitable solvent and then evaporated into nanoparticles or microspheres.
- Variables of Drug Loading and Release Properties
There are a lot of parameters that influence loading and release characteristics such as alginate molecular weight, crosslinking density, pH value, temperature and other conditions of stimulation. For instance, the amount of crosslinking or pH level can be altered and the drug rate-controlled release. Moreover, composites can be used in other ways to optimize the drug loading capacity and drug release. Alginate combined with, for instance, chitosan or nanoparticles can help stabilize and target drugs.
- Drug Delivery Effect Evaluation
Drug delivery effect assessment is usually conducted by the calculation of drug release curve and drug loading efficiency. A drug release curve is the percentage of the drug released at a certain time, and the drug loading efficiency is the ratio of the drug into the carrier. By way of instance, we can observe the release of alginate-based hydrogel microcapsules at varying pH conditions using in vitro simulated release experiments. Then there are also in vitro and in vivo pharmacodynamic and toxicological considerations that become relevant connections in the assessment of drug delivery platforms to guarantee their safety and efficacy.
- Alginate Composite Materials
The hybridization of alginate with other components can add a great deal of stability and delivery. This combination of alginate, for instance, with chitosan, nanoparticles, polyvinyl alcohol and others can increase the mechanical, mucosal adhesion and controlled release properties of drugs. More specifically, alginate/chitosan composites have been used extensively in colon-targeted and eye-based drug delivery systems, where they have been shown to increase the stability and bioavailability of drugs.
- Enhanced Stability and Dispense Impact of Drugs
To add a bit more stability and delivery efficiency, scientists have tried out several other approaches too. For instance, if you add stimulus-responsive group (like a temperature- or pH-sensitive group), you can control the release of drug delivery. pH-sensitive alginate hydrogel microcapsules manufactured by microfluidic equipment were stable and apt for release. Alginate drug delivery systems must be conceived and optimised at every step of the process, from preparation, to material selection, release profile control and safety analysis. By being improved and innovated constantly, alginate-based materials will become more and more relevant to drug delivery in the future.
References
- Lakkakula JR, et al.; A comprehensive review on alginate-based delivery systems for the delivery of chemotherapeutic agent: Doxorubicin. Carbohydr Polym. 2021, 259:117696.
- Severino P, et al.; Alginate Nanoparticles for Drug Delivery and Targeting. Curr Pharm Des. 2019, 25(11):1312-1334.
