Author | Pool Han
In martial arts novels, the gangs are often jealous and hateful, and encounter evil people rushing up to compete with them. Scientists have found that if the calcium ions in the human body are partially enriched in the tumor lesion area, the "calcium gang" formed can cause tumor cells to die due to "calcium overload", a process called "calcium death".
Recently, a joint research team composed of Bu Wenbo, professor of the School of Chemistry and Molecular Engineering of East China Normal University, Shanghai Key Laboratory of Green Chemistry and Chemical Process Greening, Liu Xiaogang, professor of the Department of Chemistry of the National University of Singapore, and Yao Zhenwei, director of the Department of Radiology of Huashan Hospital affiliated to Fudan University, published an article in Chemistry that investing calcium peroxide nanoparticles into tumor foci can make tumors lose calcium regulation ability, produce "calcium overload" effect, achieve tumor inhibition, and for the first time propose a new tumor treatment strategy - Ion interference therapy.
Indispensable cell "calcium gang"
Bu Wenbo told China Science News that calcium ions, as the second messenger of intracellular signal transmission, play a vital role in regulating various physiological functions of the body, such as cell migration and proliferation, muscle contraction, and neuronal excitement.
Many functions of cells depend on extremely high differences in calcium ion concentrations inside and outside the cell, and once this concentration difference is altered, cell function is disrupted and even causes cell death.
Studies have shown that under normal circumstances, cells have a careful regulatory mechanism for the concentration of calcium in their environment, making it more difficult for cell calcium overload to occur; however, in the state of oxidative stress, the ability of cells to regulate calcium ions will gradually decrease, resulting in calcium ions gathering and causing calcium overload; after reducing oxidative stress, cells can return to normal state.
Oxidative stress and calcium overload in cells also have mutually reinforcing synergies, which provide theoretical support for efficient treatment of tumors based on calcium overload.
Clinicians have found that after radiation or chemotherapy in tumor patients, CT images show that many patients with significant therapeutic effects have calcified spots in the tumor lesion area.
This kind of phenomenon has caused scientists to think, is there an inevitable connection between the development of calcification in the tumor lesion area and the therapeutic effect?
In addition, from the perspective of materials science, the main component of calcification points produced in the tumor lesion area is hydroxyapatite.
Bu Wenbo envisions that if this clinical medical phenomenon can be combined with the science of inorganic materials, it may inspire a new class of high-efficiency treatment strategies for tumors.
Precise and efficient nano "missile"
Based on the above considerations, the research team used wet chemistry to design and synthesize a class of calcium peroxide nanoparticles with a particle size of less than 5 nanometers, and coated its surface with a layer of sodium hyaluronate, and obtained ultra-small hyaluronic acid modified calcium peroxide nanoparticles.
Zhang Meng, the first author of the article and a doctoral student at Bu Wenbo, told China Science Daily that there are multiple considerations for using ultra-small nanoparticles.
First of all, particles larger than 100 nanometers in size are easily captured and removed by the reticuloendothelial system in blood circulation, resulting in greatly reduced enrichment in the tumor area and greatly reduced treatment effect.
The ultra-small size of the nanoparticles can effectively escape the capture of the reticuloendothelial system, significantly increasing the enrichment of the material in the tumor area.
Secondly, as the size of the nanoparticles decreases, their crystallinity decreases, increasing the reactivity of the material and making it easier to decompose under acidic conditions.
Therefore, ultra-small calcium peroxide nanoparticles are more likely to degrade to produce calcium ions in the acidic microenvironment of the tumor area, so as to induce calcium death.
In addition, ultra-small nanoparticles are mainly through renal metabolism to achieve rapid clearance from the body, that is, excreted from the body through urine, such circulating metabolism is fast.
If larger sized nanoparticles are used, they pass through the hepatic metabolic pathway and are eventually excreted through feces, which have a long cycle and may cause accumulation in the body.
Zhang Meng introduced that the research team used mice as model animals to establish a mouse in situ breast cancer model, and evaluated the inhibitory effect of calcium peroxide nanoparticles on tumors.
The results show that nanoparticles have a significant tumor treatment effect. Massive necrosis of tumor cells in the treatment group can be seen by HE staining of tumor tissue. This shows that calcium peroxide nanoparticles have a good effect.
The inorganic stone attacks the anti-cancer jade
According to Bu Wenbo, the new ultra-small calcium peroxide nanodrugs have the following advantages: First, because the special biological effects of calcium ions exist in almost all tumor cells, therefore, the nanodrug is theoretically universal for tumor treatment.
Secondly, in normal cells, ultra-small calcium peroxide decomposes extremely slowly, and the hydrogen peroxide produced by slow decomposition can be quickly decomposed into oxygen and water by catalase, so it is impossible to induce normal cells to produce oxidative stress, thus avoiding calcium overload.
At the same time, calcium is an essential element of the human body and has good biosafety.
Finally, the room temperature synthesis process of the nanodrug is simple and convenient, and it is suitable for batch preparation.
Based on the above points, with the gradual improvement of basic research such as the molecular mechanism and pharmacokinetics of "calcium death" inhibition of tumors, it is expected that such new hyaluronic acid-calcium peroxide nanomedicines will have great clinical transformation potential.
Bu Wenbo told reporters that at present, the research of various inorganic nanomaterials for tumor treatment has made great progress, but unfortunately, the biocompatibility of inorganic nanomaterials is still a bottleneck hindering their clinical application.
Based on the special biological effects of calcium ions in this work, scientists believe that the special biological effects of functional ions or ion clusters produced by the degradation of nanomaterials themselves can be used to interfere with or hinder the metabolic and proliferative processes of tumor cells, or in a broad sense, by regulating the interaction between biologically active ions and physiological processes of tumor cells, inducing tumor cell metabolic disorders, thereby playing a role in inhibiting tumor growth and metastasis.
The research team defines this new tumor treatment strategy as ion interference therapy.
Bu Wenbo believes that the proposal of ion interference therapy will open up a new way for the application of inorganic nanomaterials in clinical tumor treatment.
Related paper information:
https://doi.org/10.1016/j.chempr.2019.06.003
China Science Daily (2019-07-09 3rd Edition General)
