New probes for mitochondrial autophagy process developed by Institute of Chemistry and strategies for interfering with autophagy process

[ Instrument R&D of Instrument Network ] As a protection mechanism of cellular stress response, autophagy plays an important role in tumor development. Degradation of intracellular substances by autophagy can provide nutrition for the rapid proliferation of tumor cells, and the activation of autophagy will also promote tumor metastasis. Designing chemical intervention molecules with autophagy as the target to inhibit tumor cell growth and metastasis can not only overcome the drug resistance and anti-apoptosis produced by tumor cells during conventional cancer treatment, but also recruit immune factors to further enhance the tumor treatment effect. Therefore, it has received much attention in recent years.

With the support of the National Natural Science Foundation of China, the Ministry of Science and Technology and the Chinese Academy of Sciences, the research team of Zhang Deqing, a researcher of the Key Laboratory of Organic Solids, Institute of Chemistry, Chinese Academy of Sciences, and the research group of Zhao Rui, a researcher of the Key Laboratory of In Vitro Analytical Chemistry Tumor targeting fluorescent molecular design with styrene as the key skeleton has made a series of progress. Designed and synthesized probe molecules with tumor cell specificity, established a new method of tumor treatment under the guidance of imaging, and found that changes in anions can regulate the size, fluorescence emission and surface properties of molecular aggregates, which can achieve tumor cell selectivity, The regulation of penetration ability and subcellular localization achieves efficient killing of tumor cells.

Fluorescence, also known as "fluorescence", refers to a cold glow phenomenon of photoluminescence. When a certain temperature substance is irradiated by a certain wavelength of incident light (usually ultraviolet or X-ray), it absorbs light energy and enters an excited state, and immediately de-excites and emits outgoing light longer than the wavelength of the incident light (usually the wavelength is visible Band); Once many fluorescent substances stop incident light, the luminescence phenomenon will disappear immediately. The outgoing light with this property is called fluorescence. In addition, some substances can still emit light for a long time after the incident light is removed. This phenomenon is called afterglow. In daily life, people generally refer to all kinds of faint light as fluorescence, without carefully investigating and distinguishing its light-emitting principle.

Recently, they designed and synthesized tetrastyrene pyridine salt molecules with alkyl side chains of different lengths. They found that these molecules can spontaneously assemble with albumin in the blood to form a complex, and target the tumor tissue through blood circulation. Further research found that as the length of the alkyl chain increases, the binding force between the molecule and the hydrophobic cavity of albumin (albumin) is enhanced, and the ability to localize mitochondria of tumor cells is also enhanced. More importantly, locating the molecule to the mitochondria causes oxidative damage to the mitochondria, which causes the mitochondria to swell and deform.

As a specific marker of oxidative damage in vivo, protein oxidation products mediated by free radicals are one of the hotspots of free radical biology research in recent years. In the internal and external environment of cells, proteins are the main targets of free radicals and other oxidants. It is estimated that among the large molecules in cells, free radicals scavenged by proteins account for 50% to 75% of the total active free radicals. Because some proteins have a long half-life, it is easy to cause the accumulation of oxidative damage, so the formation of protein oxidative damage may be a highly sensitive indicator of mammalian oxidative damage.

Oxidative protein damage caused by reactive oxygen species is associated with aging, tumors, diabetes and many neurodegenerative diseases. Protein carbonyl is the most commonly used marker for oxidative damage to proteins. Changes in carbonyl levels in the body can reflect the degree of oxidative damage to proteins.

Biological transmission electron microscopy and fluorescent autophagy indication analysis proved that the molecule not only caused the accumulation of autophagosomes (autophagosomes) in tumor cells, but also inhibited the fusion of autophagosomes and lysosomes, which blocked the autophagy pathway and eventually caused tumor Cell death. They used a tumor-bearing mouse model to trace the characteristics of molecular penetration into the tumor for enrichment; through a new way of autophagy intervention, it effectively suppressed highly malignant brain tumors.

Source: Encyclopedia, Institute of Chemistry