期刊
NANO LETTERS
卷 20, 期 4, 页码 2219-2229出版社
AMER CHEMICAL SOC
DOI: 10.1021/acs.nanolett.9b03883
关键词
Self-delivery nanoparticles; LMWH; TOS; premetastatic niche; circulating tumor cells; postoperative metastasis and recurrence of tumors
类别
资金
- National Natural Science Foundation of China [81974499]
- Major Program of the National Natural Science Foundation of China [81690261]
- Sichuan Science and Technology Program [2018RZ0136]
Distal metastases of tumors result from the interaction between seeds (circulating tumor cells, CTCs) and soil (premetastatic niche, PMN). Various strategies focus on CTC inhibition, but only a few strategies inhibit PMN formation. The main predisposition of PMN formation in melanoma lies in the pulmonary recruitment of granulocytic myeloid-derived suppressor cells (G-MDSCs, CD11b(+)Ly6G(+) cells) induced by tumors, which increase vascular permeability by secreting matrix metalloproteinase-9 (MMP-9) and result in immunosuppression by secreting interleukin-10 (IL-10) in premetastatic lungs. Here, a micellar hypotoxic low molecular weight heparin-tocopherol succinate nanoparticle (LMWH-TOS nanoparticle, LT NP) was established and investigated for its influence on PMN formation in this study. We first demonstrated that the hydrophilic segment LMWH in LT NPs can inhibit early pulmonary recruitment of G-MDSCs through interrupting their extravasation by inhibiting P-selectin/PSGL-1-mediated adhesion between vascular endothelial cells and G-MDSCs. In addition, the hydrophobic segment (TOS) in LT NPs significantly inhibited the expression of MMP-9 in G-MDSCs. As a result, the drug-free nanoparticles could maintain the normal microenvironment of lungs, thus effectively inhibiting implantation and colonization of CTCs. Further, phenylboronic acid (PBA)-modified and doxorubicin/immunopotentiator alpha-galactosylceramide (alpha GC)-coloaded nanoparticles (PLT/DOX/alpha GC NPs) were exploited. PBA modification achieved targeted chemotherapy by binding to overexpressed sialic acid residues on the tumor cell surface. This nanosystem effectively inhibited the postoperative metastasis and tumor recurrence simultaneously. Our work provides a proof of concept that the prevention of PMN formation through interfering G-MDSCs with self-delivery nanosystems is a safe and effective antimetastasis strategy.
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