期刊
NANO LETTERS
卷 17, 期 6, 页码 3822-3829出版社
AMER CHEMICAL SOC
DOI: 10.1021/acs.nanolett.7b01193
关键词
Tumor microenvironment; Lancer chemoimmunotherapy; tumor-associated macrophages (TAMs); pH-responsive; spatial targeting
类别
资金
- National Basic Research Program of China [2015CB932100, 2013CB933900]
- National Natural Science Foundation of China [51390482, 51633008, 91542123]
- Fundamental Research Funds for the Central Universities
Chemoimmunotherapy, which combines chemotherapeutics with immune-modulating agents, represents an appealing approach for improving cancer therapy. To optimize its therapeutic efficacy, differentially delivering multiple therapeutic drugs to target cells is desirable. Here we developed an immunostimulatory nanocarrier (denoted as BLz-945SCNS/Pt) that could spatially target tumor-associated macrophages (TAMs) and tumor cells for cancer chemoimmunotherapy. (BLz-945)SCNs/Pt undergo supersensitive structure collapse in the prevascular regions of tumor tissues and enable the simultaneous release of platinum (Pt)-prodrug conjugated small particles and (BLz-945), a small molecule inhibitor of colony stimulating-, factor 1 receptor (CSF-1R) of TAMs. The released BLZ-945 can be preferentially taken up by TAMs to cause TAMs depletion from tumor tissues, while the small particles carrying Pt-prodrug enable deep tumor penetration as well as intracellularly specific drug release to kill more cancer cells. Our studies demonstrate that (BLz-945)SCNs/Pt outperform their monotherapy counterparts in multiple tumor models. The underlying mechanism studies suggest that the designer pH-sensitive codelivery nanocarrier not only induces apoptosis of tumor cells but also modulates the tumor immune environment to eventually augment the antitumor effect of CD8+ cytotoxic T cells through TAMs depletion.
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