Modification of erythrocytes by internalizing Arg-Gly-Asp (iRGD) in boosting the curative effect of radiotherapy for gastric carcinoma

Abstract

Background: Radiation resistance remains the leading cause of radiotherapy (RT) failure. The development of tumor-specific targeted sensitizers is key to overcoming radiation resistance. Our early data showed that cancer cell penetration was simulated by internalizing arginine-glycine-aspartic acid (iRGD), and the irradiation efficacy was improved. The present study aims to design and fabricate iRGD-modified red blood cell (RBCs) for tumor targeting and RT enhancement, and to evaluate its safety and efficacy in vivo.Methods: 1,2-Distearoyl-sn-glycero-3-phosphoethanolamine-poly ethylene glycol-iRGD (DSPE-PEG-iRGD) was used to modify RBCs by a lipid-insertion method without direct chemical bioconjugation.Fluorescent dyes were used to trace the functional RBCs through confocal microscopy examination. In vitro stability evaluation was performed using cell culture medium incubation for 48 h followed by fluorescence decay assay. Furthermore, a subcutaneous cancer cell mouse model was constructed with MKN-45 cells for target efficacy and RT enhancement evaluation with DSPE-PEG-iRGD-modified RBCs (RBC-iRGD).Results: Successful construction of RBC-iRGD was verified by the presence of the yellow fluorescence, and an approximately 10 8 iRGD molecules were labeled on a single RBC. The final RBC-iRGD showed good stability without any hemolytic effects in the cell culture medium. Moreover, higher fluorescence intensity and decreased liver and spleen accumulation could be observed in RBC-iRGD compared to RBC + iRGD in vivo. The RBC-iRGD exerted enhanced radiosensitivity in subcutaneous gastric tumor mice. Conclusions:The RBC-iRGD exerted good tumor-targeting efficacy and favorable effects for RT enhancement in vivo.

Recent advances in the tumor‐penetrating peptide internalizing RGD for cancer treatment and diagnosis

“…(3) iRGD is linked to the membrane of biological cells, such as T cells (Ding et al, 2019) or red blood cells (RBCs) (C. Zhou et al, 2022), for treatment.…”

“…Nanoparticles are often loaded with a variety of chemicals, including chemotherapeutic drugs (Dai et al, 2015; Jin et al, 2016; Song et al, 2012), nucleic acid molecules (Guan et al, 2021; Lo et al, 2018), small‐molecule inhibitors (J. Wang et al, 2016), photosensitizers (Yan et al, 2016; H. Zhang et al, 2022), nanoimaging probes (Yu et al, 2022), and so on. The nucleotide sequence of iRGD is linked to the nucleotide sequence of a protein or peptide via a peptide bond and expressed by an expression system to produce a recombinant antibody (Sha, Li, et al, 2015; Sha, Zou, et al, 2015) or recombinant protein (Lao et al, 2013, 2015; Yang, Yang, et al, 2019), or it can be coupled to a short peptide through a total chemical synthesis (Qifan et al, 2016). iRGD is linked to the membrane of biological cells, such as T cells (Ding et al, 2019) or red blood cells (RBCs) (C. Zhou et al, 2022), for treatment. The sequence of iRGD was inserted into the adenoviral vector and expressed on the surface of the adenovirus, conferring vector targeting (Al‐Zaher et al, 2018; Puig‐Saus et al, 2014). iRGD can be due in part to nanosystems that effectively target the TME (M. Liu et al, 2021; Ray et al, 2019; X. Xu et al, 2016).…”