Sialic acid-targeted drug delivery and imaging system for pH- and glutathione-triggered multiple anticancer drug release and enhanced oxidative stress

摘要

The emergence of multiple drug delivery systems can solve the disadvantages of single-drug therapy, such as high dose and easy generation of drug resistance. Here, we designed a sialic acid-targeted dextran-mercaptopurine prodrug linked by carbonyl vinyl sulfide for coordinate ZnO quantum dots to achieve multiple drug delivery (doxorubicin, 5-fluorouracil, 6-mercaptopurine), which can be released under the trigger of pH and glutathione. To enhance the antitumor effect, we used inorganic photosensitizer CdSe quantum dots to achieve photodynamic therapy, which can produce cytotoxic reactive oxygen species (hydroxyl radicals) under light conditions. Notably, we found that glutathione is consumed by the delivery of 6-mercaptopurine. It is able to efficiently amplify intracellular oxidative stress via increasing center dot OH generation. After chelating Tc-99m(4+) radioisotopes by diethylenetriamine pentaacetic acid, the drug delivery system could be tracked under in vivo single-photon emission computed tomography imaging. The results showed that the phenylboronic acid targeting substance can specifically recognize sialic acid, so that the drug system has a good accumulation in the tumor site, which can better increase the therapeutic effect. Compared to free doxorubicin, the drug system can reduce the IC50 value of cells 4.4-fold under light conditions and significantly inhibit tumor growth in vivo. These data indicate that the sialic acid-targeted nanomedicine system has achieved ideal antitumor effects and apparent photodynamic therapy effects and has broad application prospects.