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Enzyme-sensitive cytotoxic peptide–dendrimer conjugates enhance cell apoptosis and deep tumor penetration†
Biomaterials Science ( IF 5.8 ) Pub Date : 2018-01-25 00:00:00 , DOI: 10.1039/c7bm01182b Fu-Hua Liu 1, 2, 3, 4, 5 , Chun-Yuan Hou 5, 6, 7, 8, 9 , Di Zhang 5, 6, 7, 8, 9 , Wen-Jing Zhao 1, 2, 3, 4, 5 , Yong Cong 5, 6, 7, 8, 9 , Zhong-Yu Duan 1, 2, 3, 4 , Zeng-Ying Qiao 1, 2, 3, 4, 5 , Hao Wang 1, 2, 3, 4, 5
Biomaterials Science ( IF 5.8 ) Pub Date : 2018-01-25 00:00:00 , DOI: 10.1039/c7bm01182b Fu-Hua Liu 1, 2, 3, 4, 5 , Chun-Yuan Hou 5, 6, 7, 8, 9 , Di Zhang 5, 6, 7, 8, 9 , Wen-Jing Zhao 1, 2, 3, 4, 5 , Yong Cong 5, 6, 7, 8, 9 , Zhong-Yu Duan 1, 2, 3, 4 , Zeng-Ying Qiao 1, 2, 3, 4, 5 , Hao Wang 1, 2, 3, 4, 5
Affiliation
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Peptide nanodrugs have been developed as promising antitumor chemotherapeutics because they partially overcome the drawbacks of free peptide drugs, but insufficient tumor penetration and interference of peptide function limit their further application. In this work, we have developed multifunctional peptide conjugated dendrimers for improving tumor penetration, cancer cell-specific peptide delivery and anticancer ability. The cytotoxic peptide KLAK, cell-penetrating peptide TAT and matrix metalloproteinase 2 (MMP2)-sensitive peptide-poly(ethylene glycol) (PEG) were conjugated onto dendrimers by one-pot synthesis to gain PKT-S-PEG. The enzyme-sensitive properties and incubation stability of the dendrimers were investigated by dynamic light scattering (DLS) and transmission electron microscopy (TEM). Moreover, the cell viability, internalization pathway, mitochondria-regulated apoptosis and tumor penetration ability were measured by CCK-8 assay, lysosome colocalization, JC-1 assay and multicellular spheroid (MCS) experiments, respectively, in human primary glioblastoma (U87) cells. PKT-S-PEG showed significantly enhanced intracellular delivery performance, antitumor efficacy and deep tumor penetration capacity compared to a control non-MMP2 sensitive dendrimer PKT-C-PEG. The MMP2-overexpressing tumor microenvironment caused deprotection by removal of PEG, resulting in the decrease of particle size and exposure of KLAK and TAT, which enhanced tumor penetration, the entry of bioactive peptides into cells and subsequently the effective disruption of mitochondria. We believe that the peptide–dendrimer conjugate has potential for specific and effective delivery of peptide-based therapeutics into tumors.
中文翻译：
酶敏感的细胞毒性肽-树状大分子缀合物可增强细胞凋亡和深层肿瘤浸透†
肽纳米药物已被开发为有前途的抗肿瘤化疗药物，因为它们部分地克服了游离肽药物的缺点，但是肿瘤穿透力不足和对肽功能的干扰限制了它们的进一步应用。在这项工作中，我们开发了多功能肽缀合的树状聚合物，以改善肿瘤的渗透性，癌细胞特异性肽的传递和抗癌能力。通过一锅法合成将细胞毒性肽KLAK，细胞穿透肽TAT和基质金属蛋白酶2（MMP2）敏感肽-聚乙二醇（PEG）偶联到树枝状聚合物上，从而获得PKT-S-PEG。通过动态光散射（DLS）和透射电子显微镜（TEM）研究了树枝状大分子的酶敏感性和孵育稳定性。而且，细胞活力 在人原发性胶质母细胞瘤（U87）细胞中，分别通过CCK-8分析，溶酶体共定位，JC-1分析和多细胞球体（MCS）实验测量了内化途径，线粒体调节的细胞凋亡和肿瘤穿透能力。与对照非MMP2敏感的树状大分子PKT-C-PEG相比，PKT-S-PEG显示出显着增强的细胞内递送性能，抗肿瘤功效和深层的肿瘤穿透能力。过度表达MMP2的肿瘤微环境通过去除PEG引起脱保护作用，导致粒径减小以及KLAK和TAT暴露，从而增强了肿瘤的渗透，生物活性肽进入细胞并随后有效地破坏了线粒体。
更新日期：2018-01-25
中文翻译：
酶敏感的细胞毒性肽-树状大分子缀合物可增强细胞凋亡和深层肿瘤浸透†
肽纳米药物已被开发为有前途的抗肿瘤化疗药物，因为它们部分地克服了游离肽药物的缺点，但是肿瘤穿透力不足和对肽功能的干扰限制了它们的进一步应用。在这项工作中，我们开发了多功能肽缀合的树状聚合物，以改善肿瘤的渗透性，癌细胞特异性肽的传递和抗癌能力。通过一锅法合成将细胞毒性肽KLAK，细胞穿透肽TAT和基质金属蛋白酶2（MMP2）敏感肽-聚乙二醇（PEG）偶联到树枝状聚合物上，从而获得PKT-S-PEG。通过动态光散射（DLS）和透射电子显微镜（TEM）研究了树枝状大分子的酶敏感性和孵育稳定性。而且，细胞活力 在人原发性胶质母细胞瘤（U87）细胞中，分别通过CCK-8分析，溶酶体共定位，JC-1分析和多细胞球体（MCS）实验测量了内化途径，线粒体调节的细胞凋亡和肿瘤穿透能力。与对照非MMP2敏感的树状大分子PKT-C-PEG相比，PKT-S-PEG显示出显着增强的细胞内递送性能，抗肿瘤功效和深层的肿瘤穿透能力。过度表达MMP2的肿瘤微环境通过去除PEG引起脱保护作用，导致粒径减小以及KLAK和TAT暴露，从而增强了肿瘤的渗透，生物活性肽进入细胞并随后有效地破坏了线粒体。
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