Journal
JOURNAL OF CONTROLLED RELEASE
Volume 287, Issue -, Pages 12-23Publisher
ELSEVIER SCIENCE BV
DOI: 10.1016/j.jconrel.2018.08.012
Keywords
Lactoferrin nanoparticle; Reactive oxygen species; Tumor-associated macrophages; Brain-targeted delivery; Biomimetic delivery; Cell penetrating peptide; Fenretinide; Simvastatin
Funding
- 973 Program, China [2014CB931900]
- NFSC [814022883, 81422048, 81673382, 81521005]
- Strategic Priority Research Program of CAS [XDA12050307]
- National Special Project for Significant New Drugs Development [2018ZX09711002-010-002]
- CAS Scientific Research and Equipment Development Project [YZ201437]
- Fudan-SIMM Joint Research Fund [FU-SIMM20174009]
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Effective treatment of malignant glioma still remains a formidable challenge due to lack of the effective BBB-permeable drugs and efficient brain delivery methods, and the pharmacotherapy options are very limited. Therefore, to develop an effective therapeutic strategy is a pressing need. In this work, a noncytotoxic drug combination (i.e., simvastatin and fenretinide) was revealed to be potent for treating glioma, which was co-encapsulated into a TPGS-TAT-embedded lactoferrin nanoparticle system for achieving brain-targeted biomimetic delivery via the LRP-1 receptor. It was shown that the lactoferrin nanoparticle repolarized the tumor-associated macrophages from the M2 phenotype to M1 via regulating the STAT6 pathway, as well as induced the ROS-mediated mitochondrial apoptosis by inhibiting the Ras/Raf/p-Erk pathway in the glioma cells. The antiglioma efficacy was further demonstrated in both the subcutaneous and orthotopic glioma models. The repolarization of tumor-associated macrophages not only prompted the ROS generation but also induced the innate immunity (e.g., anti-tumor cytokine release). This delivery and therapeutic strategy provides a novel modality for the glioma treatment.
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