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.

Innovative Approaches of Engineering Tumor-Targeting Bacteria with Different Therapeutic Payloads to Fight Cancer: A Smart Strategy of Disease Management

“…Alleviation of systemic toxicity of the chemotherapeutic agent [ 126 ] DMV from E. coli Doxorubicin B16F10 tumor Bioengineered with high expression of RGD motifs to target the tumor. Targeting of the monocytes or neutrophils that mediate transportation towards the tumor [ 127 ] OMV from Salmonella Tegafur@F127 nanomicelles B16FIO and 4T1 tumors Surface is modified with RGD to preferentially accumulate in cancerous tissues. Combination of immunotherapy and chemotherapy [ 128 ] Paclitaxel Ehrlich ascites carcinoma (EAC) Passive accumulation in tumor tissues through the EPR effect.…”

Targeting Integrins for Cancer Therapy - Disappointments and Opportunities

“…The cationic liposomes decorated with the cRGD peptide were then able to deliver negatively charged siRNA into melanoma cells and effectively induce cell death (Khabazian et al, 2021). Alternatively, Gao et al developed a double membrane vesicle (DMV), presenting not only the RGD peptide, but also lipopolysaccharides (LPS) (Gao et al, 2021). The association of LPS (normally exposed in the outer membrane of growth for lung and hepatocellular carcinoma in in vivo models (Fu et al, 2021;Gong et al, 2021).…”

“…Low treatment efficacy with this approach is caused by ineffective reach of the tumor. The introduction of RGD peptides on the surface of liposomal like vesicles has generally enhanced both drug accumulation in the tumor and anti-tumor efficacy of the drug in mouse models ( Fu et al, 2021 ; Gao et al, 2021 ; Gong et al, 2021 ; Khabazian et al, 2021 ). Additional adjustments were made to the vesicles to further improve their drug transporting characteristics ( Figure 2 ).…”

Nanotechnology-Employed Bacteria-Based Delivery Strategy for Enhanced Anticancer Therapy

“… 94 For example, Vipul Gujrati 86 utilized the addressing ability of ClyA to display a high-affinity anti-human epidermal growth factor receptor 2 (HER2) affibody in the MV surface for the purpose of targeted delivery of therapeutic siRNA targeting kinesin spindle protein ( Figure 6 ). Gao et al 95 exploited and expressed RGD4C-EGFP at the C-terminus of ClyA on the surface of MVs, to monitor and enhance the tumor targeting by specifically identifying and interacting with Integrin α v β 3 on tumor cell. After packing DOX into the above MVs, they showed promising potential in tumor growth inhibition.…”

“…94 For example, Vipul Gujrati 86 utilized the addressing ability of ClyA to display a high-affinity anti-human epidermal growth factor receptor 2 (HER2) affibody in the MV surface for the purpose of targeted delivery of therapeutic siRNA targeting kinesin spindle protein (Figure 6). Gao et al 95 exploited and expressed RGD4C-EGFP at the…”