Activate the initiative to make nanodrugs "latent" in tumors and kill tumors from inside to outside

Antitumor nanodrugs, such as adriamycin liposome "ribadox", act as a direct "package" of tumor and transport the drug to the focus site more specifically However, currently widely used nanodrugs in clinical only reduce the side effects caused by drugs, and can not significantly improve the efficacy of the original drug One of the reasons for this is that nanodrugs deliver drugs to tumors, but not to every tumor cell It's like a package sent by express delivery to the delivery room of the community, but not to the user How to express drugs directly to home (tumor cells)? Recently, Professor Shen Youqing from the school of chemical engineering and bioengineering of Zhejiang University and Professor Gu Zhen from UCLA worked together to propose a new mechanism of active infiltration of nanodrugs into tumor tissue In order to solve this problem, nanodrugs can penetrate into every corner of solid tumors and deliver anti-tumor drugs to every tumor cell, and many animal models verify that this method can significantly improve the anti-tumor effect This research was published in the international well-known journal Nature Nanotechnology (DOI: 10.1038 / s41565-019-0485-z) The first author of this paper is Zhou Quan and Shao Shiqun The nanodrugs that bypass "miyin" to "change the way" for nanodrugs to treat cancer are obtained by loading small molecular anti-tumor drugs into nano sized carriers The diameter of nanodrugs is 10-100 nanometers, dozens of times that of small molecular drugs It can be said that nanodrugs are worthy of the name of "elephant drugs" Compared with small molecular drugs, nanodrugs have the advantage of avoiding renal filtration after injection into the blood, so they can stay in the blood for a long time and accumulate more in the tumor But its too large volume makes its own motion (diffusion) ability very weak At the same time, there is a lack of capillary network, a very dense extracellular matrix and a very high cell density in the tumor, so such a large volume of nanodrugs can pass through the cells Therefore, the diffusion of nanodrugs in tumor tissue is as difficult as that of an elephant in the primitive dense forest with branches " Shen Youqing said This leads to the fact that even if nanodrugs can be stored in tumors, they cannot deliver the drugs directly to every cell Scholars at home and abroad have made many efforts to solve this problem, including reducing the density of tumor tissue, reducing the size of nanodrugs and other methods to reduce the penetration resistance of nanodrugs in tumor However, these efforts have not solved the problems of large size of nanodrugs, weak self motion and diffusion ability, resulting in poor passive penetration ability in tumor relying on self diffusion Is it possible to give full play to the "initiative" of tumor cells and allow them to "actively" deliver nanodrugs? In this way, the high-end cell density in the tumor is utilized, and the nano medicine can directly pass through the tumor cells and bypass the "dense vine" obstacles such as tumor extracellular matrix To this end, Shen Youqing and others designed a method for tumor cells to actively deliver drugs: let tumor cells swallow nano drugs at the same time, and then spit out some of them at the other side, so that the nano drugs can be transmitted from the tumor capillaries to each tumor cell in a cyclic manner The key to this process is that the cells can quickly phagocytize enough nanodrugs, and "the cells will only discharge some if they eat enough" For this reason, Shen Youqing and others use the principle of positive and negative charge absorption "The surface of tumor cells is negatively charged, so the positively charged nanodrugs can be easily adsorbed on the cell surface and swallowed," Shen Youqing said One of the key designs of this work is that nanodrugs are electrically neutral in the blood Only when tumor blood vessels or tumor cells are attached, they will be positively charged, which will trigger rapid endocytosis and active tumor infiltration The switch that triggers the electropositive transformation is the overexpression of GGT on the endothelial cells of tumor blood vessels and tumor cells near the vessels Researchers use GGT responsive groups to mask the positive charge; GGT enzyme removes the modifier in the tumor to make it positive How to make the nanomedicine "generously" spit out some after swallowing it inside the cell? Shen Youqing said that the so-called efflux link is the function of the cell itself Golgi is an important cell sorter in cells It is like a express transport station The materials delivered to Golgi are packed and sent out Therefore, the second key design of this paper is to control the nanodrug structure so that the nanodrug will go to Golgi body instead of other organelles Active "active infiltration" brings high curative effect In this study, researchers also used a variety of animal models to investigate the nano drug with the new structure The results showed that the nano drug injected by tail vein can cure the small tumor with a volume of 100 cubic mm, and rapidly shrink the large tumor with a volume of 500 cubic mm After half a month of discontinuation, there was no rebound And for the "pancreatic cancer", which is the king of cancer, it also has the ability to significantly inhibit tumor growth and prolong the survival period Professor hae Lin Jang and Professor shiladitya sengupta of Harvard Medical School highly praised the work They believed that the nanodrug made use of the mechanism of cell transport to obtain the deep penetration of tumor and achieved high curative effect Shen Youqing said that this strategy of passive infiltration as an active one makes nanodrugs avoid the natural biological barrier formed by the dense microenvironment of tumor tissue, overcomes the natural defect of the low diffusion ability caused by the large size of nanodrugs, is expected to solve the problem of nanodrugs' penetration in tumor tissue, and opens up a new idea for the design of nanodrugs in the next stage.