Background
Cancer is currently one of the major killers of human health, characterised by high morbidity, high mortality, poor prognosis and younger age. Among these, cutaneous melanoma is one of the most threatening tumour types. It can arise from a variety of melanocytes. The incidence rate is increasing every year and it has become the most lethal type of skin cancer. In addition, melanoma cells are highly invasive and metastatic, and tend to metastasise to the lungs, which increases the difficulty of treating melanoma. Traditional treatment methods include surgery, cryotherapy and chemotherapy, but patients are not optimistic about the response to treatment methods, especially chemotherapy drugs. Among them, chemotherapy drugs face the problem of low drug concentration at the tumour site, and the use of high doses is prone to multidrug resistance (MDR) and high toxic side effects. Therefore, finding new treatment methods, especially more effective drug formulations, to improve the treatment effect of melanoma is still a major challenge.
The application of nanotechnology is providing technical support for the development of modern medicine, especially promoting the huge development of nano drug delivery systems. Nano drug delivery systems use nanoparticles as carriers, with particle sizes in the range of tens to hundreds of nanometres, and internal drug preparations that provide a good reservoir for chemotherapy drugs, genetic drugs, etc. The nano-drug delivery system can significantly improve the solubility and stability of poorly soluble drugs. Various targeting molecules can be functionally modified externally, allowing the nano-drug delivery system to enter tumours through the enhanced penetration and retention (EPR) effect to achieve passive targeting or through ligands - receptor binding to achieve active targeting. Nano drug delivery system aims to achieve tumour targeting and controlled drug release. It has become a hot spot in tumour treatment due to its advantages of high efficiency, low toxicity, tumour localisation and sustained and controlled drug release.
Nanocarriers Based on Polysaccharide Skeleton
Polysaccharide polymers can be used as ideal drug carrier matrices. Currently, commonly used polysaccharide carriers include grapes, chitosan, hyaluronic acid, chondroitin sulfate, etc. Compared with synthetic polymers, such polysaccharides have the advantages of low toxicity, biocompatibility, degradability and bioadhesion. Polysaccharides are sugar chains composed of multiple monosaccharide units (aldose or ketose) connected by glycosidic bonds, in which the number of monosaccharides is not less than ten. Polysaccharide polymers are natural polymers with a wide range of sources and are widely present in organisms. For example, hyaluronic acid and chondroitin sulfate are abundant in synovial fluid and extracellular matrix. The main chain of polysaccharides has abundant functional groups, such as amino, carboxyl, hydroxyl, etc., which are easy to modify to form different polysaccharide derivatives as drug carriers. For example, polysaccharides are modified by free radical polymerization to prepare cross-linked hydrogels, which is a common modification method for preparing polysaccharide hydrogels. In addition, polysaccharides are hydrophobically modified to obtain amphiphilic polymers, which can self-assemble in water to form nanoaggregates. Among them, the substances used for modification include small molecules, oligomers and high molecular polymers with reactive functional groups. Among them, hydrophobic small molecules such as stearic acid and bile acid can react with the active groups of the polysaccharide side chains to obtain hydrophobically modified amphiphilic comb polymers. Polysaccharides can also form grafted polymers with high molecular polymers such as polylactic acid (PLA), polycaprolactone (PCL), polyglycolide (PGA), etc.
Characteristics of Chondroitin Sulphate Nanocarriers
Chondroitin sulphate is a sulphated linear mucopolysaccharide composed of repeated disaccharide units consisting of glucuronic acid and N-acetylgalactosamine linked by glycosidic bonds. Chondroitin sulphate is widely distributed in animal tissues such as synovial fluid and cartilage, bone and the nervous system, with an average molecular weight of approximately 2X104 Daltons. It has multiple physiological activities such as antioxidant, anti-atherosclerotic and anticoagulant. It is widely used in the treatment of bone diseases, brain injury complex and other diseases.
Figure 1. Chondroitin sulfate-based redox-responsive nanoparticles for melanoma-targeted drug delivery. (Abdur Rauf Khan, et al.; 2020)
Chondroitin sulfate is non-toxic, has good biocompatibility and excellent water solubility. The skeleton contains a large number of active groups, which makes it easy to achieve hydrophobic chemical modification and polymer grafting. One of the major advantages of hyaluronic acid as a drug carrier is that it can bind to the CD44 receptor highly expressed on the surface of tumor cells. Related studies have reported that chondroitin sulfate also has the characteristics of specific recognition and binding with CD44 due to its structural similarity with hyaluronic acid. Therefore, without the need for surface modification, the nanocarrier with hydrophilic chondroitin sulfate as the skeleton itself has a certain active targeting of tumor cells with high expression of CD44 receptors. At the same time, chondroitin sulfate can be degraded by hyaluronidase (Hyal-1) overexpressed in tumor cells, which helps the rapid cleavage of nanocarriers with chondroitin sulfate as the skeleton in tumor cells and the rapid release of drugs. Based on these advantages of chondroitin sulfate, the research on nanocarriers using chondroitin sulfate as a new carrier framework for tumor treatment is increasing.
Chondroitin Sulfate to Construct Nanocarriers
Chondroitin sulfate is usually used to construct nanocarriers in the following ways: (1) As a surface material, it can be used to modify the surface of other particles to improve the stability and biocompatibility of nanocarriers, as well as to improve tumor targeting. For example, chondroitin sulfate can be modified on the surface of gold nanoparticles, iron oxide nanoparticles, magnetic nanoparticles, etc. (2) As the skeleton of nanocarriers, it can be grafted with other macromolecular polymers. Currently, the research on chondroitin sulfate-chitosan is more extensive. In addition, chondroitin sulfate-polyethyleneimine (PEI) polymer can also be used as a gene carrier to achieve drug delivery. (3) As the skeleton of nanocarriers, it can be connected with small molecule drugs and hydrophobic groups through functional groups to form amphiphilic polymers to construct different types of nanocarriers, such as chondroitin sulfate-drug polymers, amphiphilic polymer nanoparticles, etc. Chondroitin sulfate-drug polymers significantly increase the solubility and stability of drugs in water, but drugs chemically bonded to the backbone face the disadvantage of being relatively difficult to release. At present, the formation of self-assembled nanoparticles by constructing amphiphilic polymers has received great attention. Unlike chondroitin sulfate-drug polymers, the drug is encapsulated in the hydrophobic core of the nanoparticles by physical encapsulation, and the drug is easy to release. Interestingly, some researchers have synthesized chondroitin sulfate-paclitaxel (PTX) amphiphilic polymers, and physically encapsulated two drugs, PTX and sunitinib, in the hydrophobic core at the same time, and prepared dual-drug nanoparticles by physical encapsulation and chemical combination. The construction of such amphiphilic polymers has multiple advantages. In addition to the protection provided by amphiphilic nanoparticles for drugs, the preparation method is simple and avoids organic solvents to a certain extent, thus reducing the toxicity of nanoparticles. In addition, the selectivity of hydrophobic groups is relatively wide, and multiple anti-tumor properties can be given to nanoparticles by introducing functional hydrophobic groups, such as introducing environmental stimulus-responsive groups.
Reference
- Abdur Rauf Khan, et al.; Chondroitin sulfate-based redox-responsive nanoparticles for melanoma-targeted drug delivery. Journal of Drug Delivery Science and Technology. 2020, Volume 60, 102033.
