Institute of Bioengineering and Bioimaging, 31 Biopolis Way, Singapore 138669, Singapore.
Institute of Bioengineering and Bioimaging, 31 Biopolis Way, Singapore 138669, Singapore; School of Materials Science and Engineering, Nanyang Technological University, 50 Nanyang Avenue, Singapore 639798, Singapore.
J Control Release. 2022 May;345:464-474. doi: 10.1016/j.jconrel.2022.03.034. Epub 2022 Mar 22.
Cationic synthetic anticancer polymers and peptides have attracted increasing attention for advancing cancer treatment without causing drug resistance development. To circumvent in vivo instability and toxicity caused by cationic charges of the anticancer polymers/peptides, we report, for the first time, a nanoparticulate delivery system self-assembled from a negatively charged pH-sensitive polypeptide poly(ethylene glycol)-b-poly(ʟ-lysine)-graft-cyclohexene-1,2-dicarboxylic anhydride and a cationic anticancer polypeptide guanidinium-functionalized poly(ʟ-lysine) (PLL-Gua) via electrostatic interaction. The formation of nanoparticles (Gua-NPs) neutralized the positive charges of PLL-Gua. Both PLL-Gua and Gua-NPs killed cancer cells in a dose- and time-dependent manner, and induced cell death via apoptosis. Confocal microscopic studies demonstrated that PLL-Gua and Gua-NPs readily entered cancer cells, and Gua-NPs were taken up by the cells via endocytosis. Notably, Gua-NPs and PLL-Gua exhibited similar in vitro anticancer efficacy against MCF-7 and resistant MCF-7/ADR. PLL-Gua and Gua-NPs also induced similar morphological changes in MCF-7/ADR cells compared to MCF-7 cells, further indicating their ability to bypass drug resistance mechanisms in the MCF-7/ADR cells. More importantly, Gua-NPs with higher LD and enhanced tumor accumulation significantly inhibited tumor growth with negligible side effects in vivo. Our findings shed light on the in vivo delivery of anticancer peptides and opened a new avenue for cancer treatment.
阳离子合成抗癌聚合物和肽已引起越来越多的关注，因为它们可以在不引起耐药性发展的情况下推进癌症治疗。为了规避抗癌聚合物/肽的阳离子电荷引起的体内不稳定性和毒性，我们首次报道了一种由带负电荷的 pH 敏感多肽聚乙二醇-b-聚赖氨酸-g-接枝环己烯-1,2-二羧酸酐和阳离子抗癌多肽胍基功能化聚赖氨酸（PLL-Gua）通过静电相互作用自组装而成的纳米颗粒递药系统。纳米颗粒（Gua-NPs）的形成中和了 PLL-Gua 的正电荷。PLL-Gua 和 Gua-NPs 均以剂量和时间依赖的方式杀死癌细胞，并通过细胞凋亡诱导细胞死亡。共聚焦显微镜研究表明，PLL-Gua 和 Gua-NPs 容易进入癌细胞，并且 Gua-NPs 通过内吞作用被细胞摄取。值得注意的是，Gua-NPs 和 PLL-Gua 对 MCF-7 和耐药 MCF-7/ADR 表现出相似的体外抗癌功效。与 MCF-7 细胞相比，PLL-Gua 和 Gua-NPs 也在 MCF-7/ADR 细胞中引起相似的形态变化，进一步表明它们能够绕过 MCF-7/ADR 细胞中的耐药机制。更重要的是，具有更高 LD 和增强肿瘤积累的 Gua-NPs 显著抑制肿瘤生长，体内副作用可忽略不计。我们的研究结果为抗癌肽的体内递药提供了新的思路，并为癌症治疗开辟了新的途径。
