期刊
ADVANCED FUNCTIONAL MATERIALS
卷 29, 期 32, 页码 -出版社
WILEY-V C H VERLAG GMBH
DOI: 10.1002/adfm.201901896
关键词
GSH-sensitive drug dimers; immune-chemotherapy; PD-L1 antibody; PEGylated bilirubin nanoparticles; tumor microenvironment response
类别
资金
- National Natural Science Foundation of China [81872806, 31571016]
- Young Elite Scientists Sponsorship Program by CAST [2017QNRC001]
- Fundamental of Research Funds for the Central University [SCU2017A001]
The application of combinational therapy makes up for the limitation of monotherapy and achieves superior treatment against cancer. However, the combinational therapy remains restricted by the poor tumor-specific delivery and the abscopal effect. Herein, reactive oxygen species (ROS)-responsive PEGylated bilirubin nanoparticles (BRNPs) are developed to encapsulate two glutathione-activatable drugs, including dimer-7-ethyl-10-hydroxycamptothecin (d-SN38) and dimer-lonidamine (d-LND). Dimerization of the drugs significantly increases the drug loading capacity and the encapsulation efficiency of nanoparticles. With the assistance of iRGD peptide (cRGDKGPDC), the cellular uptake of BRNPs is more than double when compared with the control. In response to high levels of intracellular ROS, d-SN38 and d-LND are rapidly released from nanoparticles (SL@BRNPs). Furthermore, the pharmacodynamic experiments verify combining SL@BRNPs with anti-PD-L1 antibody greatly inhibits the primary tumor of breast cancer, improves CD8+ T cells levels, and CD8+ T cells/Tregs ratios in the tumor. Additionally, it shows high immune memory effect and can prevent the growth of lung metastasis. Taken together, the strategy pioneers a new way for the rational design of nanoassemblies through the combination of activatable drug dimers and stimuli-responsive drug release, and a successful application of novel drug delivery systems in combination with the immune checkpoint blockade antibody.
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