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Minerva Medica 2020 Apr 08

DOI: 10.23736/S0026-4806.20.06564-7


language: English

M1 macrophage-derived exosome-encapsulated cisplatin can enhance its anti-lung cancer effect

Jun LI 1, Ning LI 2, Jing WANG 2

1 Department of Hematology and Oncology, China-Japan Union Hospital of Jinlin University, Changchun, China; 2 Department of Respiratory Medicine, China-Japan Union Hospital of Jinlin University, Changchun, China


BACKGROUND: To study the efficacy of cisplatin-loaded M1 macrophage secreted-exosomes (DDP-M1-Exos) in enhancing DDP anti-tumor effect.
METHODS: M1-Exos were first extracted using density gradient centrifugation, and the DDP-M1-Exos system was established via electroporation. Then, the morphology, particle size and maker proteins of the DDP-M1-Exos system were assessed using transmission electron microscope (TEM), DLS and Western blotting, respectively. The uptake of Exos by mouse Lewis lung cancer (LLC) cells was observed under a confocal laser scanning microscope, and the influence of the DDP-M1-Exos system on the viability of Lewis cells was determined using methyl thiazolyl tetrazolium (MTT) assay and 4',6-diamidino-2-phenylindole (DAPI) staining. Besides, its impacts on the messenger ribonucleic acid (mRNA) levels and protein expression levels of B-cell lymphoma 2 (Bcl-2), Bcl-2 associated X protein (Bax) and Caspase-3 in LLC cells were examined using quantitative real-time PCR (qRT-PCR) and Western blotting(WB), respectively. Finally, with the LLC-bearing mouse model as the object of study, the efficacy was evaluated using terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) and hematoxylin-eosin staining (HE) staining in vivo.
RESULTS: Saucer-shaped Exos with a bilayer membrane, uniform particle size and highly expressed CD81, Alix and HSP70 were successfully isolated from M1 macrophages via density gradient centrifugation, and they were absorbed by LLC cells. Meanwhile, the DDP-M1-Exos drug delivery system was successfully prepared using electroporation technique. Compared with Control group, DDP and DDP-M1-Exos groups exhibited a decrease in the proliferation rate of mouse LLC cells and an increase in their apoptosis rate (*P<0.05), and the apoptosis rate in DDP-M1-Exos group was substantially higher than that in DDP group (#P<0.01). According to the qRT-PCR and WB results, DDP-M1-Exos up-regulated Bax and Caspase-3 in the apoptosis signaling pathway to induce tumor cell apoptosis, thereby resisting tumors. Moreover, through in vivo experiments, it was found that M1-Exos alone had a potential to suppress tumor growth, and that the carrier of M1-Exos could not only kill tumor cells, but also encapsulate DDP to enhance its anti-lung cancer effect.
CONCLUSIONS: The DDP-M1-Exos drug delivery system is prepared using Exos extracted via density gradient centrifugation by electroporation, and the drug-loaded Exos are able to effectively inhibit the proliferation of tumor cells and induce their apoptosis, exerting an anti-tumor effect.

KEY WORDS: M1-macrophanges; Exosomes; Lewis cells; Cell apoptosis

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