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-κB 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 vitr o. 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.

<p>Exosome: A Review of Its Classification, Isolation Techniques, Storage, Diagnostic and Targeted Therapy Applications</p>

“…106,107 Recently, studies using exosomal delivery of PTX to address this deficiency have been widely reported. For example, Wang et al 108 selected classical activated M1-type macrophage-derived exosomes as a carrier to reduce the toxicity of PTX and improve its bioavailability. Not only has PTX been successfully delivered to tumor tissue of mice, but also by activating NF-κB pathway it establishes a pro-inflammatory environment to enhance the therapeutic effect of PTX.…”

Exosomes from bone marrow mesenchymal stem cells enhance fracture healing through the promotion of osteogenesis and angiogenesis in a rat model of nonunion

“…Western blotting was performed according to previous studies [20]. The obtained PVDF membrane was incubated overnight with primary antibodies against BMP-2 (1:1000), RUNX2 (1:1000), Smad1 (1:1000), HIF-1α (1: 1000), OPN (1:1000), OGN (1:1000) (Cell Signaling Technology, MA, USA) and VEGFA (1:1000) (Abcam, Cambridge, UK) at 4°C.…”

Exploiting the Natural Properties of Extracellular Vesicles in Targeted Delivery towards Specific Cells and Tissues

“…While tumor-associated macrophages have been shown to promote tumor progression, angiogenesis, immunosuppression and metastasis, a study by Cheng et al describes that their EVs actually promote inflammation-related responses, which can enhance immunotherapy effects against cancer cells [88]. Moreover, other studies suggest that by using EVs from macrophages polarized towards an M1-like phenotype (which has antitumoral features), it is possible to decrease the proliferation of malignant cells, enhance immune responses and increase the effectiveness of drugs [89].…”