Background
Common anti-tumor drugs have the disadvantages of fast release and poor water solubility, which makes it difficult to release drugs in a concentrated manner at the tumor site, resulting in poor therapeutic effects and serious toxic side effects on the patient's normal tissues or organs. Using stimulus-responsive carriers for drug delivery can achieve on-demand release of drugs at specific sites, time and dosage, and reduce the toxic side effects of drugs. In order to enhance the therapeutic effect of drugs, targeting materials or groups such as folic acid, hyaluronic acid (HA), mannose, galactose, etc. are usually added or used in carrier materials. The delivery carrier formed by HA has the characteristics of tumor targeting and sustained release of drugs, which can enhance the anti-tumor effect. CD44 is an HA receptor discovered earlier. It plays an important role in promoting tumor cell transformation and metastasis, and is conducive to identifying anti-tumor drug carrier materials modified with HA. HA can be cross-linked with other components to prepare nano drug delivery carriers with different characteristics of composite HA. After being injected into the body, the nano drug delivery carrier will bind to tumor cells containing CD44 receptors and deposit them on the surface of tumor cells. Under endogenous and exogenous stimulation, the drug carrier undergoes physical or chemical changes to achieve drug release. This can not only maintain its original biocompatibility but also increase its mechanical strength, viscoelasticity, and resistance to nuclease degradation, so that the drug can be quickly and accurately targeted to the tumor microenvironment and concentratedly released, thereby enhancing the drug's efficacy while minimizing the drug's toxic side effects. Nano drug delivery carriers use multiple stimuli instead of a single stimulus, which can better control the delivery and release of drugs, allowing drugs to be actively targeted and delivered, improving the therapeutic effect. The technical means of stimulus-responsive nano drug delivery systems have gradually become a research hotspot in the field of precision targeted tumor treatment.
Figure 1. Schematic diagram of stimuli-responsive nanomaterials used for triggered drug release. (Pham SH, et al.; 2020)
Exogenous Stimulus Responsive Drug Delivery System
Exogenous stimulus-responsive drug delivery systems can use specific responses generated by external stimulation methods such as temperature, magnetic field, and light to induce apoptosis and necrosis of tumor cells. Under exogenous stimulation conditions, HA-conjugated nanocarriers can be targeted to the patient, increasing selectivity and biological safety, thereby improving drug utilization and significantly reducing systemic toxicity caused by conventional therapies.
- Temperature-responsive Drug Delivery System
Commonly used polymers in temperature-responsive drug delivery systems mainly include poly(N-isopropylacrylamide) (PNIPAM), vinyl caprolactam (VCL), polyether F127, chitosan, cellulose, etc. These polymer materials are relatively sensitive to changes in temperature. Temperature-responsive drug delivery systems composed of them usually produce a nonlinear and sharply changing temperature response due to changes in ambient temperature, causing the internal polymer materials to undergo property mutations, thus Triggers the release of the drug. Under normal body temperature (37°C) conditions, the temperature-responsive drug delivery system can remain stable; under heating conditions, such as when the temperature rises to 40-42°C, the properties of the polymer material change, allowing the drug to be quickly released. - Magnetic Responsive Drug Delivery System
Magnetic response is one of the best choices for physical stimulation-triggered or magnetically targeted enhanced cancer treatment. The magnetic responsive drug delivery system forms a stable system of drugs, magnetic substances and carrier materials. Under the guidance of the magnetic field, the drugs can be selectively released from the carrier, improve the targeting efficiency of the drugs, and effectively exert the therapeutic effect of the drugs at the patient's site, and avoid the toxic side effects caused by the systemic distribution of the drugs. - Light Responsive Drug Delivery System
Under the stimulation of light, nanocarriers will also undergo physical or chemical changes, enhance the stability of drug carriers, and thus slowly release and prolong the duration of drug action, maximizing the efficacy of the drugs while reducing damage to other tissues in the body. At present, widely used photothermal therapeutic agents are mainly divided into two categories: inorganic nanomaterials and organic nanomaterials. Inorganic nanomaterials include gold nanomaterials, carbon nanomaterials and copper sulfide nanomaterials. The advantage is high photothermal efficiency, and the disadvantage is that they have certain toxicity and are not easy to degrade, which limits their application. Organic nanomaterials have good performance in biodegradation and tissue compatibility, including organic near-infrared dyes, near-infrared II zone materials, polymers (such as polyaniline, polypyrrole, polydopamine), etc.
Endogenous Stimulus Response Drug Delivery System
The main mechanism of action of the Endogenous Stimulus Response Drug Delivery System is to deliver anti-tumor drug carriers into cells by CD44 receptor-mediated endocytosis or EPR effect, to respond rapidly and accurately at the patient site to endogenous stimuli such as pH and enzymes, and to release drugs in a precise and targeted manner while reducing drug damage to other normal tissue cells.
- pH-sensitive Drug Delivery System
The functions of pH changes are diverse, but their main function is to help distinguish normal tissue from diseased tissue. Under normal conditions, the microenvironment of tumor tissue is slightly acidic because the metabolic process of tumor cells is dominated by anaerobic glycolysis. In this state, the pH of lysosomes and endosomes in tumors will also gradually decrease. The pH will also fluctuate depending on the type of tumor, and the pH will be different in different parts of the whole tumor tissue. In a low pH environment, the growth of tumor blood vessels cannot provide the nutrients needed for rapidly dividing cells, resulting in a lack of nutrients and oxygen for tumor cells, leading to the accumulation of lactic acid and further lowering the pH of tumor tissue. In experimental studies, pH-responsive nanocarriers can use differences in pH gradients to change their structure and surface properties, and can also sense small changes in the pH of the internal environment, thereby meeting the different requirements for the loading of materials in tumor targeting and other aspects. The drug can be specifically targeted and released at the site of disease. By linking the drug to the carrier via a pH-sensitive hydrazone or ester linkage, release can be triggered under appropriate pH conditions in lysosomes or endosomes. A large number of experiments have confirmed that pH-sensitive drug delivery technology has the characteristics of effective smart and targeted drug delivery, and its integrated diagnosis and treatment system has shown good application prospects for the diagnosis and treatment of tumors and other diseases. - Redox-responsive Drug Delivery System
Redox-responsive drug delivery system is one of the most effective drug delivery systems for stimulus-responsive cancer and gene therapy. Because the metabolic activity of tumor tissue is more vigorous than that of normal cells, the levels of reactive oxygen species (ROS) and glutathione (GSH) in most tumor cells are higher than those in normal cells, which leads to redox heterogeneity in the microenvironment of tumor cells. This redox heterogeneity exists in large quantities in tumor cells of different regions, types and growth stages, which provides favorable conditions for the precise release of drugs. Compared with other stimuli such as pH, redox drug delivery systems can respond well to high levels of GSH in tumor cells, release drugs directly into the nucleus and cytoplasm, and remain stable in the extracellular environment with low GSH levels. On this basis, researchers have developed a redox-responsive drug delivery system based on the redox responsiveness of special chemical bonds. - Enzyme-responsive Drug Delivery System
The reason why enzymes can be used to prepare stimulus-responsive drug delivery systems is that the expression of some enzymes will be upregulated or downregulated in specific diseases. At the same time, enzyme responsiveness has the advantages of rapidity and efficiency compared with other types of stimuli. Under pathological conditions, changes in the expression levels of some specific enzymes can serve as control switches for the accumulation and release of drugs at specific sites.
Reference
- Pham SH, et al.; Stimuli-Responsive Nanomaterials for Application in Antitumor Therapy and Drug Delivery. Pharmaceutics. 2020, 12(7):630.
