Cancer is one of the malignant diseases that threaten human survival. It starts with the abnormal differentiation and proliferation of cells, then infiltrates normal tissues and spreads to other parts of the body, causing organ dysfunction and endangering human life and health. Cancer not only affects the quality of life of patients, but also imposes a heavy economic burden on families and society. Currently, the main methods of cancer treatment include surgery, radiotherapy, chemotherapy, targeted therapy, immunotherapy, etc. Chemotherapy often becomes an essential treatment when a patient cannot undergo surgery or when surgery cannot completely remove the tumor. However, traditional chemotherapeutic drugs have problems such as poor selectivity for tumor tissue, insignificant efficacy, multidrug resistance and toxic side effects on normal tissues, which limit the clinical application of chemotherapeutic drugs.
In recent years, the rise of nanotechnology has brought new hope for cancer treatment. The use of nanotechnology to construct drug delivery systems can effectively improve drug solubility, stability, and tumor targeting while reducing its toxic and side effects. At present, a variety of nanomedicines such as liposomes, albumin nanoparticles, polymers and nanocrystals have been commercialized, such as paclitaxel and albumin nanoparticles Abraxane. Researchers have adopted a variety of strategies to improve the cancer treatment effect of nanomedicines, such as passive targeted drug delivery based on enhanced permeability and retention effect (EPR), active targeted drug delivery based on receptor-ligand interaction, Stimulus-responsive drug delivery system of tumor microenvironment, etc.
Figure 1. Chitosan-based nanoparticles of targeted drug delivery system in breast cancer treatment.(Herdiana Y, et al.; 2021)
Chitosan (CS) is a natural cationic polymer that is abundant in nature. There are multiple active functional groups in its structure that can be modified, making it easy to make a variety of drug delivery systems and tissue engineering scaffolds, and it has wide applications in the field of biomedicine.
Chitosan and Its Derivatives
The chemical name of chitosan is (1-4)-2-amino-2-deoxy-β-glucose, which was first discovered by Frenchman Rouget in 1859. Chitosan is the product of deacetylation of chitin, which is widely distributed in the shells of shrimps and crabs, as well as algae, fungi and other animals and plants. It is the second largest biological resource on earth after cellulose. The molecular weight of chitosan ranges from tens of thousands to millions, and the degree of deacetylation is usually greater than 80%. Due to the presence of primary amino groups, chitosan has a positive charge and is the only alkaline polysaccharide that exists in nature. Chitosan not only has good biocompatibility, biodegradability and low immunogenicity, but also has bioadhesion, antibacterial, hemostatic and other functions. Therefore, chitosan has a wide range of applications in the field of biomedicine and is often used in drug carriers, tissue engineering, etc.
Because chitosan has a large molecular weight and strong hydrogen bonds within and between molecules, chitosan can only be dissolved in acidic solutions, but not in neutral and alkaline aqueous solutions and most organic solvents, which limits its application. In view of this, researchers have modified the C2 amino group and C3 and C6 hydroxyl groups of chitosan through cross-linking, grafting, acylation, sulfonation, carboxymethylation, phosphorylation, alkylation, nitration, halogenation, oxidation, reduction, and complexation, and prepared a series of chitosan derivatives. These derivatives give chitosan different characteristics depending on the modified added groups. In addition, by introducing special groups, chitosan can be given targeting, pH responsiveness, temperature responsiveness, adhesion and other properties. This greatly enriches the application of chitosan in the field of biomedicine.
Chitosan Nanoparticle Cancer Treatment Strategy
After the drug is coated with chitosan nanoparticles, it is also necessary to transport it specifically to the tumor tissue to improve the anti-tumor effect and reduce the side effects of other sites. Generally speaking, cancer treatment strategies of chitosan nanoparticles include passive targeted drug delivery strategies, active targeted drug delivery strategies and stimulus-response drug delivery strategies.
- Passive Targeted Drug Delivery Strategies
Due to the damaged blood vessels of solid tumor tissues, wide gaps between blood vessel walls, poor structural integrity, and lack of lymphatic return, nanoparticles that cannot penetrate normal vascular tissues can pass through tumor blood vessels and selectively accumulate in tumor tissues. This characteristic of tumor tissue can improve the efficacy of anti-tumor drugs and reduce the occurrence of adverse reactions. This phenomenon is called the EPR effect. In general, factors such as the particle size, shape, and surface properties of chitosan nanoparticles will affect their passive targeting effect. Studies have found that nanoparticles smaller than 5 nanometers can pass through the glomerular membrane and be cleared by the kidneys, while nanoparticles larger than 200 nanometers are easily cleared by the reticuloendothelial system. Therefore, chitosan nanoparticles with a particle size between 5 and 200 nm can stay in the circulatory system for a long time and have a good passive targeting effect.
It is worth noting that the ERP effect has been controversial in recent years, because it has better effects in animal experiments, but its effects in human experiments are not significant. Therefore, it is an inevitable trend to develop new targeted delivery strategies based on passive targeting.
- Active Targeted Drug Delivery Strategies
The principle of active targeting is that there are specifically expressed or overexpressed antigens or receptors on the surface of cancer cells. By modifying the corresponding antigens or ligands on the surface of nanoparticles, they can achieve the specificity of antigen-antibody and ligand-receptor. Actively identify tumor cells under combination and deliver drugs to tumor tissues. Compared with passive targeting, active targeting can specifically recognize and bind to tumor cells, and the targeting effect is better. There have been a large number of research reports on active targeting of chitosan nanoparticles, and the targeting groups modified on their surface usually include small molecules, peptides, polysaccharides, antibodies or nucleic acid aptamers. Currently, the most commonly used tumor-targeting chitosan is folate receptor-targeting chitosan nanoparticles, biotin receptor-targeting chitosan nanoparticles, and asialoglycoprotein receptor-targeting chitosan nanoparticles, hyaluronic acid receptor-targeting chitosan nanoparticles, and transferrin receptor-targeting chitosan nanoparticles.
- Stimulus-responsive Drug Delivery Strategies
After nanomedicines are targeted to tumor cells, they have to face multiple steps such as cell entry, lysosomal escape, drug release, and avoidance of metabolism before reaching the site of action. With the deepening of research, researchers have discovered that there are many differences between the microenvironment of tumor tissue and normal tissue, such as low pH, high temperature, reactive oxygen species, etc. Stimulus-responsive drug delivery systems take advantage of these differences to control the specific release of drugs at the tumor site under endogenous stimulation or external stimulation of the tumor microenvironment, or promote them to overcome multiple barriers such as cellular entry and lysosomal degradation, and are becoming increasingly popular. Common stimulus-responsive drug delivery includes single, dual or multiple stimulus-responsive drug delivery systems such as pH, temperature, magnetic field, light, enzyme, electric field, ultrasound, etc. Due to its many reaction sites, chitosan can be made into a variety of the above stimulus-responsive drug delivery systems, and it has great potential in this regard.
References
- Herdiana Y, et al.; Chitosan-Based Nanoparticles of Targeted Drug Delivery System in Breast Cancer Treatment. Polymers (Basel). 2021, 13(11):1717.
- Li S, et al.; Application of chitosan/alginate nanoparticle in oral drug delivery systems: prospects and challenges. Drug Deliv. 2022, 29(1):1142-1149.
