Enhancing the anticancer efficacy of a LL-37 peptide fragment analog using peptide-linked PLGA conjugate micelles in tumor cells
Enhancing the anticancer efficacy of a LL-37 peptide fragment analog using peptide-linked PLGA conjugate micelles in tumor cells
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DOI：
10.1016/j.ijpharm.2021.120891
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发表时间：
2021-08-10
影响因子：
5.8
通讯作者：
Ishibashi, Daisuke
中科院分区：
文献类型：
--
作者：
Mori, Takeshi;Hazekawa, Mai;Ishibashi, Daisuke
LL-37 是一种著名的抗菌人类肽，是一种阳离子肽，可为受损皮肤提供重要的抗菌防御机制。越来越多的证据表明，LL-37 对结肠癌、胃癌、血液恶性肿瘤和口腔鳞状细胞癌也显示出抗癌作用。然而，LL-37肽片段类似物的抗癌活性尚未见报道。细胞间易位不良可能是缺乏观察到的抗癌活性的原因之一。在本研究中，利用半胱氨酸的硫醇基团，将 N 末端带有半胱氨酸的 LL-37 肽片段类似物与可生物降解聚合物乳酸/乙醇酸共聚物 (PLGA) 缀合。本研究的目的是利用胶束系统提高肽的细胞通透性，然后评估其抗癌活性。进行细胞增殖、迁移和侵袭测定，以评估四种高转移癌细胞系 HM-1、B16/BL6、HeLa 和 HepG2 的抗癌活性。与单独的肽相比，LL-37 片段肽类似物连接的 PLGA 缀合物可有效抑制细胞增殖、迁移和侵袭，并且在所有癌细胞系中具有增加的细胞通透性。这些结果表明，LL-37 片段肽类似物 (CKR12) 连接的 PLGA 缀合物胶束可用于癌症治疗的开发。
LL-37, a well-known antimicrobial human peptide, is a cationic peptide that provides an important antimicrobial defense mechanism in damaged skin. Accumulating evidence indicates that LL-37 also displays an anticancer effect in colon cancer, gastric cancer, hematologic malignancy and oral squamous cell carcinoma. However, anticancer activity of LL-37 peptide fragment analogs has not been reported. Poor intercellular translocation may be one of the causes for this lack of observed anticancer activity. In this study, a LL-37 peptide fragment analog with cysteine at the N-terminus was conjugated with the biodegradable polymer, lactic acid/glycolic acid copolymer (PLGA), using the thiol group of cysteine. The purpose of this study was to improve the cell permeability of the peptide using a micellar system and then evaluate the anticancer activity. Cell proliferation, migration, and invasion assays were performed to evaluate the anticancer activity in four cancer cell lines with high metastasis, HM-1, B16/BL6, HeLa, and HepG2. The LL-37 fragment peptide analog-linked PLGA conjugate was shown to effectively inhibit cell proliferation, migration, and invasion and had increased cell permeability in all the cancer cell lines, compared with the peptide alone. These results suggested that LL-37 fragment peptide analog (CKR12)-linked PLGA conjugate micelles could be useful in the development of cancer therapeutics.