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Exosomes from M1-Polarized Macrophages Enhance Paclitaxel Antitumor Activity by Activating Macrophages-Mediated Inflammation.

ABSTRACT: Objective: Exosomes (Exos) are membrane-encased vesicles derived by nearly all cell types for intercellular communication and regulation. They also received attention for their use as natural therapeutic platforms and drug delivery system. Classically activated M1 macrophages suppress tumor growth by releasing pro-inflammatory factors. This study investigated the suitability of M1-exosomes (M1-Exos) as drug carrier and their effect on the NF-?B signal pathway and further detected whether macrophages repolarization can potentiate the antitumor activities of chemotherapeutics. Methods: M1-Exos were isolated from M1-macrophages by ultracentrifugation and characterized by transmission electron, nanoparticle tracking analysis, dynamic light scattering and western blot. Then M1-Exos were used as Paclitaxel (PTX) carriers to prepare a nano-formulation (PTX- M1-Exos). A relatively simple slight sonication method was used to prepare the drug delivery system (PTX-M1-Exos). The cytotoxicity of PTX-M1-Exos on cancer cells was detected by MTT and flow cytometry in vitro. 4T1 tumor bearing mice were used to perform the therapeutic effect of PTX-M1-Exos in vivo. Results: The expression of caspase-3 in breast cancer cells was increased when co-incubated with macrophages in the presence of M1-Exos in vitro. The production of pro-inflammatory cytokines was increased after exposure of macrophages in M1-Exos. M1-Exos provided a pro-inflammatory environment which enhanced the anti-tumor activity via caspase-3 mediated pathway. The treatment of M1-Exos to the tumor bearing mice exhibit anti-tumor effects in vivo. Meanwhile, the treatment of PTX-M1-Exos demonstrated higher anti-tumor effects than the M1-Exos or PTX group. Conclusion: The results in our study indicate that the M1-Exos act as the carrier to deliver PTX into the tumor tissues, and also enhance the anti-tumor effects of chemotherapeutics in tumor bearing mice.

SUBMITTER: Wang P

PROVIDER: S-EPMC6485189 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Exosomes from M1-Polarized Macrophages Enhance Paclitaxel Antitumor Activity by Activating Macrophages-Mediated Inflammation.

Wang Piaopiao P Wang Huihui H Huang Qianqian Q Peng Can C Yao Liang L Chen Hong H Qiu Zhen Z Wu Yifan Y Wang Lei L Chen Weidong W

Theranostics 20190228 6

<b>Objective:</b> Exosomes (Exos) are membrane-encased vesicles derived by nearly all cell types for intercellular communication and regulation. They also received attention for their use as natural therapeutic platforms and drug delivery system. Classically activated M1 macrophages suppress tumor growth by releasing pro-inflammatory factors. This study investigated the suitability of M1-exosomes (M1-Exos) as drug carrier and their effect on the NF-κB signal pathway and further detected whether ...[more]

PMID: 31037133

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Project description:BackgroundThe anti-inflammatory properties of the cannabinoid 2 receptor (CB2R) in injury and inflammatory diseases have been widely substantiated. Specifically, the anti-inflammatory effect of CB2R may be achieved by regulating macrophage polarisation. Several research findings suggested that the activation of CB2R could attenuate inflammation by reducing pro-inflammatory M1 macrophage polarisation and promoting anti-inflammatory M2 polarisation. However, considering CB2R inhibits fibrosis and M2 promotes fibrosis, that the activation of CB2R may lead to an increase in M2 macrophages seems contradictory. Therefore, we hypothesised that the activation of CB2R to attenuate inflammation is not achieved by up-regulating M2 macrophages.MethodsWe established an incised wound model using mouse skin and used this to evaluate the effect of CB2R agonists (JWH133 or GP1a) and an antagonist (AM630) on wound healing. At various post-injury intervals, we used western blot analysis, immunofluorescence staining, enzyme-linked immunosorbent assay and quantitative reverse transcription polymerase chain reaction assays to determine CB2R protein expression, M1/M2 macrophage infiltration, and the protein and gene expression of M1/M2-associated markers and cytokines in skin lesions.ResultsActivation of CB2R significantly reduced M1 macrophage infiltration and slightly increased M2 macrophage infiltration. Similarly, gene expression and protein levels of M1-associated markers and cytokines (interleukin [IL]-6, IL-12, CD86 and inducible nitric oxide synthase) were significantly down-regulated after CB2R agonist administration; in contrast, markers and cytokines were increased in the CB2R antagonist-treated group. Conversely, the administration of agonists slightly increased gene expression and protein levels of M2-associated markers and cytokines (IL-4, IL-10, CD206 and arginase-1 [Arg-1]); however, a statistical significance at most time points post-injury was not noted.ConclusionIn summary, our findings suggested that during incised skin wound healing in mice, increased levels of CB2R may affect inflammation by regulating M1 rather than M2 macrophage subtype polarisation. These results offer a novel understanding of the molecular mechanisms involved in the inhibition of inflammation by CBR2 that may lead to new treatments for cutaneous inflammation.

Dataset Information

Exosomes from M1-Polarized Macrophages Enhance Paclitaxel Antitumor Activity by Activating Macrophages-Mediated Inflammation.

Publications

Exosomes from M1-Polarized Macrophages Enhance Paclitaxel Antitumor Activity by Activating Macrophages-Mediated Inflammation.

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