Wang ruibing research group, University of Macau: a glutathione responsive drug delivery system based on calixarenes was developed by emulsification

The main research directions of Wang ruibing research group, Chinese Academy of medicine, Macau University, Cheng Qian are supramolecular pharmaceutics, supramolecular pharmaceutics and supramolecular biomaterials The research focuses on regulating the biological activity / toxicity of load molecules and realizing the efficient delivery of drugs through the unique response mechanism of supramolecular system Recently, the research group cleverly developed a glutathione responsive drug delivery system based on calixarenes by emulsification method, which realized the selective release of paclitaxel loaded with natural anticancer drug in cancer cells The related achievements are as follows: 1 Published in chemical communications (chem Commun 2018, 54, 8128-8131) The first author of this paper is Cheng Qian, a postgraduate of the University of Macau The corresponding authors are Professor Wang ruibing of the University of Macau and Professor WIM dehaen of the University of Leuven, Belgium Calixarenes are macrocyclic compounds composed of methylene bridged phenol units They are called calixarenes because their structure is like a wine cup Unlike cyclodextrin and cucurbitamide, the unmodified calixarenes are almost insoluble in water and have strict selectivity to the guest molecules, which makes them rarely used in the study of drug carriers Therefore, a lot of research work is devoted to the development and preparation of hydrophilic calixarene derivatives with drug delivery potential Unlike the calixarene of the conventional methylene bridged phenol unit, the main molecule in this study, homodithiacalix [4] arene (hdt-c4a, figure 1), uses a disulfide bond that can respond to glutathione instead of methylene to bridge Because cancer cells usually have higher glutathione concentration than normal cells, the authors use hdt-c4a to construct a new delivery system in response to glutathione release drugs Emulsification is a common method of preparing nanoparticles in pharmaceutics For example, Professor Wang ruibing's research group and Professor Zhang Jianxiang's research group used supramolecular force to prepare high-performance drug loaded nanoparticles (ACS center SCI., 2018, 4, 600-605) by emulsion method in their previous cooperative research In this work, hdt-c4a was directly prepared into nanoparticles by emulsification, and paclitaxel (PTX), a first-line anticancer drug, which is difficult to dissolve in water and has obvious side effects, was loaded into the nanoparticles, and the tumor tissue was passively or actively targeted by EPR effect The tumor cells were identified and the disulfide bond was broken to release the drug selectively by using the high concentration glutathione environment in the tumor cells On the contrary, because the glutathione concentration of normal cells is only one tenth of that of cancer cells, the release of PTX is blocked, which greatly reduces the toxicity of PTX in normal cells The nanoparticles directly formed by emulsification have a uniform spherical appearance with a diameter of 214 nm The author first verified the response of nanoparticles to different concentrations of glutathione The results showed that only at the concentration of 10 mm of glutathione, the nanoparticles in cancer cells would decompose and swell as a whole due to a large number of disulfide bond breaks, thus releasing drugs (Fig 1), and be stable in low concentration glutathione environment The laser confocal microscopy images further showed that the fluorescent labeled nanoparticles could effectively enter the cancer cells after 8 to 12 hours In the subsequent cytotoxic test, paclitaxel loaded nanoparticles showed significant antitumor activity on cancer cells, and had lower toxic and side effects on normal cells The results of apoptosis test and cytotoxicity test were consistent, which further confirmed that nanoparticles can selectively improve the apoptosis rate of cancer cells Figure 1 Preparation of hdt-c4a nanoparticles and schematic diagram of selective release of paclitaxel (source: chem Commin.) in conclusion, hdt-c4a nanoparticles can effectively enter into cancer cells, selectively exert efficacy, thereby reducing the toxicity and side effects of drug delivery and enhancing the therapeutic effect This study provides the first responsive nanoparticle based on calixarene derivatives, which does not involve any guest molecules, so as to increase the drug loading efficiency and load to enhance the therapeutic effect, and provides a new design idea for responsive nanomedicine based on macrocyclic molecules as carrier matrix in drug delivery system A review of previous reports of Wang ruibing's group: Wang ruibing's group of University of Macau