Doxorubicin-loaded natural daptomycin micelles with enhanced targeting and anti-tumor effect in vivo

• Published in: European journal of medicinal chemistry Vol. 222; p. 113582
• Main Authors: Guo, Quanling, Zhang, Lu, He, Mengmeng, Jiang, Xiaohua, Tian, Jingrui, Li, Qiurong, Liu, Zhiwei, Wang, Longgang, Sun, Haotian
• Format: Journal Article
• Language: English
• Published: Elsevier Masson SAS 15.10.2021
• Subjects: Biocompatibility; Daptomycin; Doxorubicin; Drug delivery; Micelles; Zwitterionic; Biocompatibility; Drug delivery; Doxorubicin; Micelles; Daptomycin; Zwitterionic
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2021.113582

Development of a simple method to enhance targeting and anti-tumor effect of the chemotherapeutic agents in vivo is a major problem. Amphipathic and natural daptomycin is biocompatible antibacterial polypeptide used in clinical practice. Herein, doxorubicin (DOX) was stabilized by zwitterionic daptomycin (Dap) micelles in aqueous solution to form a zwitterionic nanodrug (Dap-DOX micelles). The hydrodynamic size and zeta potential of Dap-DOX micelles were 85 nm and −10 mV, respectively. The study on the controlled release showed that more DOX molecules were released from Dap-DOX micelles at acidic condition of tumor tissue than that at neutral condition of normal tissue which was due to pH responsiveness of Dap-DOX micelles. Dap-DOX micelles exhibited good stability in fibrinogen solution. Moreover, MTT studies showed that Dap-DOX micelles had higher cytotoxicity than free DOX. Notably, the results of flow cytometry indicated that the average fluorescence intensity of Dap-DOX micelle-treated cells was higher than that of free DOX-treated cells, and acidic conditions were more favorable for Dap-DOX micelles than normal pH in cell uptake assay. More importantly, Dap-DOX micelles were biocompatible in vivo based on the changes of weight and blood indexes of mice. Dap-DOX micelles were selectively accumulated at tumor sites in vivo through EPR effect, which reduced the toxicity of free DOX and achieved excellent tumor inhibition effect. The tumor inhibition rate of Dap-DOX micelles reached 96%. Dap-DOX micelles also effectively inhibited the growth of bacterial. Taken together, Dap-based drug delivery systems are promising and effective in cancer therapy. [Display omitted] •The drug-loaded micelles Dap-DOX were first prepared by self-assembly method.•Dap-DOX micelles had good protein stability and pH response.•Dap-DOX micelles enriched in tumor site and had good antitumor effect.•Dap-DOX micelles had a certain inhibitory effect on bacteria.