Gp350-anchored extracellular vesicles: promising vehicles for delivering therapeutic drugs of B cell malignancies

Huiqing Xiu; Xi Nan; Danfeng Guo; Jiaoli Wang; Jiahui Li; Yanmei Peng; Guirun Xiong; Shibo Wang; Changjun Wang; Gensheng Zhang; Yunshan Yang; Zhijian Cai

doi:10.1016/j.ajps.2022.03.004

Gp350-anchored extracellular vesicles: promising vehicles for delivering therapeutic drugs of B cell malignancies

Asian J Pharm Sci. 2022 May;17(3):462-474. doi: 10.1016/j.ajps.2022.03.004. Epub 2022 Apr 30.

Authors

Huiqing Xiu¹, Xi Nan¹, Danfeng Guo², Jiaoli Wang^{3

4}, Jiahui Li⁵, Yanmei Peng¹, Guirun Xiong⁶, Shibo Wang¹, Changjun Wang⁷, Gensheng Zhang⁵, Yunshan Yang⁸, Zhijian Cai¹

Affiliations

¹ Institute of Immunology, and Department of Orthopedics of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
² Henan Key Laboratory for Digestive Organ Transplantation, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
³ Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, China.
⁴ Zhejiang University Cancer Centre, Hangzhou, China.
⁵ Department of Critical Care Medicine of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
⁶ Department of Emergency Medicine, Tongde Hospital of Zhejiang Province, Hangzhou, China.
⁷ Second Affiliated Hospital of Zhejiang University School of Medicine, Zhejiang Provincial Key Lab of Ophthalmology, Hangzhou, China.
⁸ Department of Medical Oncology, The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, China.

Abstract

Although chimeric antigen receptor-modified (CAR) T cell therapy has been successfully applied in the treatment of acute B lymphocytic leukemia, its effect on Burkitt lymphoma (BL) and chronic B lymphocytic leukemia (B-CLL) is unsatisfactory. Moreover, fatal side effects greatly impede CAR T cell application. Extracellular vesicles (EVs) are excellent carriers of therapeutic agents. Nevertheless, EVs mainly accumulate in the liver when administered without modification. As an envelope glycoprotein of Epstein-Barr viruses, gp350 can efficiently bind CD21 on B cells. Here, gp350 was directly anchored onto red blood cell EVs (RBC-EVs) via its transmembrane region combined with low-voltage electroporation. The results showed that gp350 could anchor to RBC-EVs with high efficiency and that the resulting gp350-anchored RBC-EVs (RBC-EVs/gp350^Etp) exhibited increased targeting to CD21⁺ BL and B-CLL relative to RBC-EVs. After the loading of doxorubicin or fludarabine, RBC-EVs/gp350^Etp had powerful cytotoxicity and therapeutic efficacy on CD21⁺ BL or B-CLL, respectively. Moreover, RBC-EVs/gp350^Etp loaded with a drug did not exhibit any apparent systemic toxicity and specifically induced the apoptosis of tumor B cells but not normal B cells. Therefore, our findings indicate that drug-loaded RBC-EVs/gp350^Etp may be adopted in the treatment of CD21⁺ B cell malignancies.

Keywords: B cell malignancies; CD21; Extracellular vesicles; Gp350; Red blood cells.