Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun 130022, PR China; School of Applied Chemistry and Engineering, University of Science and Technology of China, Hefei 230026, PR China.
Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun 130022, PR China.
Acta Biomater. 2024 Jun;181:415-424. doi: 10.1016/j.actbio.2024.04.044. Epub 2024 May 3.
Host defense peptide-mimicking cationic oncolytic polymers have attracted increasing attention for cancer treatment in recent years. However, polymers with large amounts of positive charge may cause rapid clearance and severe off-target toxicity. To facilitate in vivo application, an alkaline phosphatase (ALP)-responsive oncolytic polypeptide precursor (C-PLL/PA) has been reported in this work. C-PLL/PA could be hydrolyzed into the active form of the oncolytic polypeptide (C-PLL) by the extracellular alkaline phosphatase within solid tumors, thereby resulting in the conversion of the negative charge to positive charge and restoring its membrane-lytic activity. Detailed mechanistic studies showed that C-PLL/PA could effectively destroy cancer cell membranes and subsequently result in rapid necrosis of cancer cells. More importantly, C-PLL/PA significantly inhibited the tumor growth in the 4T1 orthotopic breast tumor model with negligible side effects. In summary, these findings demonstrated that the shielding of the amino groups with phosphate groups represents a secure and effective strategy to develop cationic oncolytic polypeptide, which represents a valuable reference for the design of enzyme-activated oncolytic polymers. STATEMENT OF SIGNIFICANCE: Recently, there has been a growing interest in fabricating host defense peptide-mimicking cationic oncolytic polymers for cancer therapy. However, there remain concerns about the tumor selectivity and off-target toxicity of these cationic polymers. In this study, an alkaline phosphatase-responsive oncolytic polypeptide precursor (C-PLL/PA) has been developed to selectively target cancer cells while sparing normal cells. Mechanistic investigations demonstrated that C-PLL/PA effectively disrupted cancer cell membranes, leading to rapid necrosis. Both in vitro and in vivo experiments showed promising anticancer activity and reliable safety of C-PLL/PA. The findings suggest that this synthetic enzyme-responsive polypeptide holds potential as a tumor-specific oncolytic polymer, paving the way for future applications in cancer therapy.
近年来，模拟宿主防御肽的阳离子溶瘤聚合物在癌症治疗方面受到了越来越多的关注。然而，带大量正电荷的聚合物可能会导致快速清除和严重的脱靶毒性。为了便于体内应用，本工作报道了一种碱性磷酸酶（ALP）响应性溶瘤多肽前体（C-PLL/PA）。C-PLL/PA 可以在实体瘤的细胞外碱性磷酸酶的作用下水解成活性形式的溶瘤多肽（C-PLL），从而使负电荷转化为正电荷并恢复其膜裂解活性。详细的机制研究表明，C-PLL/PA 可以有效地破坏癌细胞膜，随后导致癌细胞迅速坏死。更重要的是，C-PLL/PA 可显著抑制 4T1 原位乳腺癌模型中的肿瘤生长，且副作用可忽略不计。总之，这些发现表明，用磷酸基团屏蔽氨基是开发阳离子溶瘤多肽的一种安全有效的策略，为酶激活的溶瘤聚合物的设计提供了有价值的参考。
最近，人们越来越感兴趣地用模拟宿主防御肽的阳离子溶瘤聚合物来治疗癌症。然而，这些阳离子聚合物的肿瘤选择性和脱靶毒性仍然存在问题。在这项研究中，开发了一种碱性磷酸酶响应性溶瘤多肽前体（C-PLL/PA），以选择性地靶向癌细胞而不伤害正常细胞。机制研究表明，C-PLL/PA 有效地破坏了癌细胞膜，导致迅速坏死。体内外实验均显示出 C-PLL/PA 具有良好的抗癌活性和可靠的安全性。这些发现表明，这种合成的酶响应多肽有作为肿瘤特异性溶瘤聚合物的潜力，为癌症治疗的未来应用铺平了道路。
