Targeted Therapy of Central Nervous System Acute Lymphoblastic Leukemia with an Integrin a 6-Targeted Self-Assembling Proapoptotic Nanopeptide
Targeted Therapy of Central Nervous System Acute Lymphoblastic Leukemia with an Integrin a 6-Targeted Self-Assembling Proapoptotic Nanopeptide
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DOI：
10.1016/j.eng.2023.11.012
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发表时间：
2024-06-08
期刊：
影响因子：
12.8
通讯作者：
Feng，Guo -Kai
中科院分区：
文献类型：
--
作者：
Ye，Jia-Cong;Li，Wan-Qiong;Feng，Guo -Kai
中枢神经系统急性淋巴细胞白血病（CNS-ALL）的治疗目前尚无有效的靶向治疗策略。整合素α6因其在促进CNS-ALL疾病进展中的作用而被认为是CNS-ALL诊断和治疗的潜在靶点。通过肽扫描技术如丙氨酸扫描、截短和D-取代鉴定对整合素α6具有纳摩尔亲和力的靶向肽D（RWYD）（缩写为RD）。在此，我们开发了一种基于整合素α6靶向肽的治疗性纳米粒，用于治疗CNS-ALL。自组装的促凋亡纳米肽D（RWYD）-D（KLAKLAK）2-GD（FFY）（缩写为RD-KLA-Gffy）包含整合素α6靶向肽RD、众所周知的促凋亡肽D（KLAKLAK）2（缩写为KLA）和自组装四肽GD（FFY）（缩写为Gffy）。通过不同的实验阐明了RD-KLA-Gffy的作用机理。我们的研究结果表明，RD-KLA-Gffy在CNS-ALL病变中高度富集并诱导肿瘤细胞凋亡，从而降低CNS-ALL疾病负担并延长CNS-ALL小鼠的生存期，而没有明显的毒性。此外，联合使用RD-KLA-Gffy和甲氨蝶呤（MTX）在治疗CNS-ALL中显示出有效的抗肿瘤作用，表明RD-KLA-Gffy作为单药或与MTX组合在抑制CNS-ALL进展中起重要作用，这显示出在CNS-ALL治疗中应用的前景。
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 peptideD(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 nanopeptideD(RWYD)-D(KLAKLAK)2-GD(FFY) (abbreviated RD-KLA-Gffy) contains the integrin α6-targeted peptide RD, the well-known proapoptotic peptideD(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.