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RGD-expressed bacterial membrane-derived nanovesicles enhance cancer therapy via multiple tumorous targeting.

ABSTRACT: Background: A tumor microenvironment is a complicated multicellular system comprised of tumor cells, immune cells and blood vessels. Blood vessels are the barriers for drug tissue penetration. Effectively treating a cancer requires drug delivery systems to overcome biological barriers present in tumor microenvironments (TMEs). Methods: We designed a drug delivery system made of bacterial (Escherichia coli) double layer membrane-derived nanovesicles (DMVs) with the expression of RGD peptides and endogenous targeting ligands of bacteria. The physical and biological characteristics of DMVs were assessed by cryogenic transmission electron microscopy, western blotting, flow cytometry and confocal microscopy. Doxorubicin (DOX) was loaded in DMVs via a pH gradient driven drug loading method. Therapeutical effects of DOX-loaded DMVs were studied in a melanoma xenograft mouse model. Results: In vitro and in vivo experiments showed that DMVs can target neutrophils and monocytes that mediated the transport of DMVs across blood vessel barriers and they can also directly target tumor vasculature and tumor cells, resulting in enhanced delivery of therapeutics to TMEs. Furthermore, we developed a remote drug loading approach to efficiently encapsulate DOX inside DMVs, and the drug loading was 12% (w/w). In the B16-F10 melanoma mouse model, we showed that DOX-RGD-DMVs significantly inhibited the tumor growth compared to several controls. Conclusion: Our studies reveal that DMVs are a powerful tool to simultaneously target multiple cells in TMEs, thus increasing drug delivery for improved cancer therapies.

SUBMITTER: Gao J

PROVIDER: S-EPMC7847689 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

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RGD-expressed bacterial membrane-derived nanovesicles enhance cancer therapy via multiple tumorous targeting.

Gao Jin J Wang Sihan S Dong Xinyue X Wang Zhenjia Z

Theranostics 20210115 7

Background: A tumor microenvironment is a complicated multicellular system comprised of tumor cells, immune cells and blood vessels. Blood vessels are the barriers for drug tissue penetration. Effectively treating a cancer requires drug delivery systems to overcome biological barriers present in tumor microenvironments (TMEs). Methods: We designed a drug delivery system made of bacterial (Escherichia coli) double layer membrane-derived nanovesicles (DMVs) with the expression ...[more]

PMID: 33537088

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Project description:BACKGROUND:Sepsis remains a source of high mortality in hospitalized patients despite proper antibiotic approaches. Encouragingly, mesenchymal stromal cells (MSCs) and their produced extracellular vesicles (EVs) have been shown to elicit anti-inflammatory effects in multiple inflammatory conditions including sepsis. However, EVs are generally released from mammalian cells in relatively low amounts, and high-yield isolation of EVs is still challenging due to a complicated procedure. To get over these limitations, vesicles very similar to EVs can be produced by serial extrusions of cells, after which they are called nanovesicles (NVs). We hypothesized that MSC-derived NVs can attenuate the cytokine storm induced by bacterial outer membrane vesicles (OMVs) in mice, and we aimed to elucidate the mechanism involved. METHODS:NVs were produced from MSCs by the breakdown of cells through serial extrusions and were subsequently floated in a density gradient. Morphology and the number of NVs were analyzed by transmission electron microscopy and nanoparticle tracking analysis. Mice were intraperitoneally injected with Escherichia coli-derived OMVs to establish sepsis, and then injected with 2?×?109 NVs. Innate inflammation was assessed in peritoneal fluid and blood through investigation of infiltration of cells and cytokine production. The biodistribution of NVs labeled with Cy7 dye was analyzed using near-infrared imaging. RESULTS:Electron microscopy showed that NVs have a nanometer-size spherical shape and harbor classical EV marker proteins. In mice, NVs inhibited eye exudates and hypothermia, signs of a systemic cytokine storm, induced by intraperitoneal injection of OMVs. Moreover, NVs significantly suppressed cytokine release into the systemic circulation, as well as neutrophil and monocyte infiltration in the peritoneum. The protective effect of NVs was significantly reduced by prior treatment with anti-interleukin (IL)-10 monoclonal antibody. In biodistribution study, NVs spread to the whole mouse body and localized in the lung, liver, and kidney at 6?h. CONCLUSIONS:Taken together, these data indicate that MSC-derived NVs have beneficial effects in a mouse model of sepsis by upregulating the IL-10 production, suggesting that artificial NVs may be novel EV-mimetics clinically applicable to septic patients.

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RGD-expressed bacterial membrane-derived nanovesicles enhance cancer therapy via multiple tumorous targeting.

Publications

RGD-expressed bacterial membrane-derived nanovesicles enhance cancer therapy <i>via</i> multiple tumorous targeting.

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