EGF Receptor-Targeting Cancer Therapy Using CD47-Engineered Cell-Derived Nanoplatforms

Moon Jung Choi,1 Kang Chan Choi,1 Do Hyun Lee,1 Hwa Yeon Jeong,1 Seong Jae Kang,1 Min Woo Kim,1 In Ho Jeong,1 Young Myoung You,1 Jin Suk Lee,2 Yeon Kyung Lee,1 Chan Su Im,1 Yong Serk Park1 1Department of Biomedical Laboratory Science, Yonsei University, Wonju, Republic of Korea; 2Department of Anatomy, Yonsei University Wonju College of Medicine, Wonju, Republic of KoreaCorrespondence: Chan Su Im; Yong Serk Park, Department of Biomedical Laboratory Science, Yonsei University, Wonju, Gangwon, 220-710, Republic of Korea, Email chanzzhu@nate.com; parkys@yonsei.ac.krIntroduction: Avoiding phagocytic cells and reducing off-target toxicity are the primary hurdles in the clinical application of nanoparticles containing therapeutics. For overcoming these errors, in this study, nanoparticles expressing CD47 proteins inhibiting the phagocytic attack of immune cells were prepared and then evaluated as an anti-cancer drug delivery vehicle.Methods: The CD47+ cell-derived nanoparticles (CDNs) were prepared from the plasma membranes of human embryonic kidney cells transfected with a plasmid encoding CD47. And the doxorubicin (DOX) was loaded into the CDNs, and anti-EGF receptor (EGFR) antibodies were conjugated to the surface of the CDNs to target tumors overexpressing EGFR.Results: The CD47+iCDNs-DOX was successfully synthesized having a stable structure. The CD47+CDNs were taken up less by RAW264.7 macrophages compared to control CDNs. Anti-EGFR CD47+CDNs (iCDNs) selectively recognized EGFR-positive MDA-MB-231 cells in vitro and accumulated more effectively in the target tumor xenografts in mice. Moreover, iCDNs encapsulating doxorubicin (iCDNs-DOX) exhibited the highest suppression of tumor growth in mice, presumably due to the enhanced DOX delivery to tumor tissues, compared to non-targeting CDNs or CD47- iCDNs.Discussion: These results suggest that the clinical application of biocompatible cell membrane-derived nanocarriers could be facilitated by functionalization with macrophage-avoiding CD47 and tumor-targeting antibodies.Graphical Abstract: Keywords: cell-derived nanoparticles, immune surveillance, CD47, doxorubicin, tumor targeting, cancer therapy