Targeted Therapy of Central Nervous System Acute Lymphoblastic Leukemia with an Integrin α6-Targeted Self-Assembling Proapoptotic Nanopeptide

Engineering ›› 2024, Vol. 35 ›› Issue (4) : 236 -251. DOI: 10.1016/j.eng.2023.11.012

Research

Article

Author information +

^aGuangdong Provincial Key Laboratory of New Drug Screening & NMPA Key Laboratory of Drug Metabolism Research and Evaluation, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China

^bState Key Laboratory of Oncology in South China & Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou 510060, China

^cSchool of Pharmaceutical Sciences (Shenzhen), Shenzhen Campus of Sun Yat-sen University, Shenzhen 518107, China

^dGuangdong Provincial Key Laboratory of Construction and Detection in Tissue Engineering, Biomaterials Research Center, School of Biomedical Engineering, Southern Medical University, Guangzhou 510515, China

^eState Key Laboratory of Organ Failure Research, Guangdong Provincial Institute of Nephrology, Southern Medical University, Guangzhou 510515, China

E⁃mail: gaoyf29@mail.sysu.edu.cn (Y.-F. Gao)

liusw@smu.edu.cn (S.-W. Liu)

zengmsh@sysucc.org.cn (M.-S. Zeng)

fengguok@sysucc.org.cn (G.-K. Feng)

Show less

History +

Received	Accepted	Published
2023-06-20	2023-11-08	2024-04-01
Issue Date	Revised Date
2024-06-12	2023-11-07

PDF (5893KB)

Abstract

There is currently no effective targeted therapeutic strategy for the treatment of central nervous system acute lymphoblastic leukemia (CNS-ALL). Integrin α6 is considered a potential target for CNS-ALL diagnosis and therapy because of its role in promoting CNS-ALL disease progression. The targeted peptide _D(RWYD) (abbreviated RD), with nanomolar affinity to integrin α6 was identified by peptide scanning techniques such as alanine scanning, truncation, and D-substitution. Herein, we developed a therapeutic nanoparticle based on the integrin α6-targeted peptide for treating CNS-ALL. The self-assembled proapoptotic nanopeptide _D(RWYD)-_D(KLAKLAK)₂-G_D(FFY) (abbreviated RD-KLA-Gffy) contains the integrin α6-targeted peptide RD, the well-known proapoptotic peptide _D(KLAKLAK)₂ (abbreviated KLA), and the self-assembling tetrapeptide G_D(FFY) (abbreviated Gffy). The functional mechanism of RD-KLA-Gffy is clarified using different experiments. Our results demonstrate that RD-KLA-Gffy is highly enriched in CNS-ALL lesions and induces tumor cell apoptosis, thus reducing CNS-ALL disease burden and prolonging the survival of CNS-ALL mice without obvious toxicity. Moreover, the combined use of RD-KLA-Gffy and methotrexate (MTX) shows a potent antitumor effect in treating CNS-ALL, indicating that RD-KLA-Gffy plays an important role in suppressing CNS-ALL progression either as a single agent or in combination with MTX, which shows promise for application in CNS-ALL therapy.

Graphical abstract

Keywords

Central nervous system acute lymphoblastic leukemia / Integrin α6 / Targeted peptide / Proapoptotic / Nanopeptide

Cite this article

Download citation ▾

Jia-Cong Ye, Wan-Qiong Li, Mei-Ling Chen, Qian-Kun Shi, Hua Wang, Xin-Ling Li, Ying-He Li, Jie Yang, Qiao-Li Wang, Fang Hu, Yan-Feng Gao, Shu-Wen Liu, Mu-Sheng Zeng, Guo-Kai Feng, , , , , , , , , , , , , , . Targeted Therapy of Central Nervous System Acute Lymphoblastic Leukemia with an Integrin α6-Targeted Self-Assembling Proapoptotic Nanopeptide. Engineering, 2024, 35(4): 236-251 DOI:10.1016/j.eng.2023.11.012