Targeted Therapy of Central Nervous System Acute Lymphoblastic Leukemia with an Integrin α6-Targeted Self-Assembling Proapoptotic Nanopeptide
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
Affiliations
Jia-Cong Ye
Guangdong 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; State 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
Wan-Qiong Li
School of Pharmaceutical Sciences (Shenzhen), Shenzhen Campus of Sun Yat-sen University, Shenzhen 518107, China
Mei-Ling Chen
State 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
Qian-Kun Shi
Guangdong Provincial Key Laboratory of Construction and Detection in Tissue Engineering, Biomaterials Research Center, School of Biomedical Engineering, Southern Medical University, Guangzhou 510515, China
Hua Wang
State 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
Xin-Ling Li
State 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
Ying-He Li
State 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
Jie Yang
State 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
Qiao-Li Wang
State 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
Fang Hu
Guangdong Provincial Key Laboratory of Construction and Detection in Tissue Engineering, Biomaterials Research Center, School of Biomedical Engineering, Southern Medical University, Guangzhou 510515, China
Yan-Feng Gao
School of Pharmaceutical Sciences (Shenzhen), Shenzhen Campus of Sun Yat-sen University, Shenzhen 518107, China; Corresponding authors.
Shu-Wen Liu
Guangdong 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; State Key Laboratory of Organ Failure Research, Guangdong Provincial Institute of Nephrology, Southern Medical University, Guangzhou 510515, China; Corresponding authors.
Mu-Sheng Zeng
State 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; Corresponding authors.
Guo-Kai Feng
State 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; Corresponding authors.
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-GD(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 GD(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.
