Simultaneous delivery of two drugs, light-controlled release drugs, tumor-targeting
new drug carriers to reduce the side effects of chemotherapy
The team used gold nanoparticles to hybridize the organometallic framework in situ to obtain a nanocarrier capable of simultaneously delivering chemotherapeutic drugs and immunosensitizing drugs.
At the same time, a variety of chemical modifications are used to make the nanocarrier have the functions of light-controlled release and tumor targeting, which greatly improves the accuracy and effectiveness of the treatment of hepatobiliary and pancreatic tumors, and reduces the side effects of drugs.
◎Hong Hengfei, Du Yang, our reporter Jiang Yun
The combined application of chemotherapeutic drugs and indoleamine 2,3-dioxygenase (IDO) inhibitors can significantly activate the human body's anti-tumor immune response and improve the efficacy.
However, this combination therapy, which is expected to become a glimmer of the clinical treatment of malignant tumors, will inevitably cause certain side effects, which limits the application and popularization of this therapy.
The team of Professor Wang Weilin, Dean of the Second Affiliated Hospital of Zhejiang University School of Medicine and leader of the Department of Hepatobiliary and Pancreatic Surgery, and Professor Mao Zhengwei from the Department of Polymer Science of Zhejiang University, used gold nanoparticles to hybridize the organometallic framework in situ, thereby achieving simultaneous delivery of chemotherapy Nano-carriers for drugs and immunosensitizing drugs.
Related research was published in the recently published international top journal "Advanced Materials".
"At the same time, we have also used a variety of chemical modifications to make the nanocarrier have the functions of light-controlled drug release and tumor targeting, which greatly improves the accuracy and effectiveness of the treatment of hepatobiliary and pancreatic tumors, and reduces the side effects of drugs." Introduction by one author, Dr. Yuan Ding from the Second Affiliated Hospital of Zhejiang University School of Medicine.
Combination therapy to treat tumors has certain side effects on the human body
Tumor immunotherapy is an emerging tumor treatment method in recent years.
Human immune cells fight tumors and need to recognize and present tumor antigens.
Once the tumor hides its own specific antigen, the immune system cannot recognize it and cannot produce an anti-tumor immune response.
The principle of immunotherapy is to relieve the invisibility of tumors, and to encourage immune cells to recognize and kill tumor cells.
Due to the heterogeneity of tumors, after receiving immunotherapy, only a small proportion of patients will produce effective T cells to kill tumor cells in an immune response.
"Tumor cell antigens can stimulate specific immune cells to activate, proliferate, and differentiate, and ultimately produce antibodies and effector T cells. This feature is called tumor immunogenicity." Wang Weilin said, because tumor immunogenicity is weak , So it is difficult to cause a strong immune killing response.
"This is an important mechanism for tumors to evade the body's immune surveillance, leading to poor immunotherapy effects."
Chemotherapeutic drugs can increase the sensitivity of tumors to immunotherapy, induce strong and continuous immunogenic death of tumor cells, and enhance the effectiveness of immunotherapy.
At this time, using IDO inhibitors can further activate T cells to produce an immune response and ultimately eliminate tumor tissues and improve the efficacy of chemotherapy.
"Currently, IDO inhibitors have not been approved for marketing, but since 2015, clinical trials of their combined use with chemotherapeutic drugs have been initially carried out on an international scale. At present, many clinical studies have entered Phase III, and formal clinical applications are just around the corner. "Wang Weilin said that chemotherapy drugs and IDO inhibitors complement each other, but after entering the human body, due to non-specific enrichment, they will still cause certain side effects to the human body.
Near-infrared light controlled targeted release of nano-medicine
"The team used gold nanoparticles to hybridize the organometallic framework in situ." Mao Zhengwei explained that by adding a chloroauric acid solution to the organometallic framework, gold nanoparticles grow on the surface of the organometallic framework through a series of chemical reactions. The overall shape is like a spherical cake with many raisins embedded on the surface.
In recent years, gold nanoparticles have been widely used in biosensing and medical detection due to the characteristics of surface plasmon resonance absorption.
For example, the colloidal gold detection method of the new coronavirus, the colloidal gold modified with the antibody generates a detection signal after binding to an antigen such as a virus.
4-Aminobenzenethiol can be combined with gold nanoparticles, and is catalyzed by plasmons on the gold surface to form dimers under light, increasing the signal intensity.
The research team got inspiration from this and tried to use the dimerization characteristics of the combination of drugs and gold nanoparticles to carry out research on the light-controlled release of drugs.
"Light has very good controllability, but the use of light to control the release of drugs is rare in the past, and a technical problem needs to be solved first." Mao Zhengwei said that in the past it was usually only possible to use ultraviolet light, visible light, etc. Low-wavelength light has short wavelength and poor penetration.
"But the penetrability of near-infrared light is greatly improved compared to them, from a few microns to a thickness of a few centimeters, making it easier to achieve controlled-release drugs in the body."
After the research team irradiated the tumor site with near-infrared light, the nanomedicine enriched in the tumor site can be released responsively and specifically, which can significantly reduce the damage to normal cells.
Prevent interference or remove "armed transformation" of transport carriers
In the research, gold nanoparticles acted as prodrug carriers and near-infrared responders.
The organometallic framework is mainly used as the matrix of the entire nano-medicine, and the IDO inhibitor is adsorbed in its pores through hydrophobic effect, and plays a role of drug-carrying.
"Another problem is that the drug is easily bound by proteins in the blood in the body and cleared by macrophages." Mao Zhengwei said that the team modified the structure of the carrier to make it have a high degree of blood circulation stability and tumor targeting specificity. The nano-drug can be delivered to the tumor site continuously, stably and accurately, and enriched. It strives to accurately target the tumor with the smallest dose and activate the chemotherapeutic drugs and IDO inhibitors through the near-infrared light-responsive release technology, thereby triggering Human body's anti-tumor immune response to achieve precise tumor treatment.
Fluorescence imaging shows that the anti-cancer drugs delivered in this way can be specifically swallowed by tumor cells. Under the control of near-infrared light irradiation, only tumor cells can be specifically activated, and cells in normal tissues outside the illuminated area will not be Activate, so the side effects of the drug are greatly avoided.
"During the treatment period, the weight of the mice injected with the nanomedicine was not significantly reduced, and no obvious symptoms of toxicity were monitored." Ding Yuan said that the follow-up team will also carry out long-term in-depth safety research.
"At present, the new anti-tumor drugs developed using gold nanocarriers have completed small animal experiments to verify their effectiveness and safety. The team is ready to further systematically evaluate its biological safety in large animals, laying the foundation for clinical research." Wang Weilin said , The team is also working on methods for large-scale and stable production of nano-medicine, with a view to realizing the industrialization of the drug as soon as possible.