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首页> 外文期刊>Biomaterials Science >Enzyme-sensitive cytotoxic peptide-dendrimer conjugates enhance cell apoptosis and deep tumor penetration
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Enzyme-sensitive cytotoxic peptide-dendrimer conjugates enhance cell apoptosis and deep tumor penetration

机译：酶敏感的细胞毒性肽 - 树枝状蛋白缀合物增强细胞凋亡和深肿瘤渗透

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摘要

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-over expressing 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.
机译：肽纳米醛植物被开发为具有前景的抗肿瘤化学治疗剂，因为它们部分地克服了游离肽药物的缺点，但肿瘤渗透性不足和肽函数的干扰限制了它们的进一步应用。在这项工作中，我们已经开发了多官能肽共轭树枝状过敏仪，用于改善肿瘤渗透，癌细胞特异性肽递送和抗癌能力。细胞毒性肽Klak，细胞渗透肽TAT和基质金属蛋白酶2（MMP2） - 密封肽 - 聚（乙二醇）（MMP2）通过单罐合成缀合到树枝状体上，以获得PKT-S-PEG。通过动态光散射（DLS）和透射电子显微镜（TEM）研究了树枝状过敏仪的酶敏感性和孵育稳定性。此外，通过CCK-8测定，溶酶体聚胞嘧啶化，JC-1测定和多细胞球体（MCS）实验，在人的原发性胶质母细胞瘤（U87）细胞中，测量细胞活力，内化途径，线粒体调节的细胞凋亡和肿瘤渗透能力。与对照非MMP2敏感的树枝PKT-C-PEG相比，PKT-S-PEG显示出显着增强的细胞内输送性能，抗肿瘤效力和深肿瘤渗透能力。 MMP2-obs表达表达肿瘤微环境通过去除PEG引起脱保护，导致Klak和TAT暴露的降低，增强肿瘤渗透，生物活性肽进入细胞中并随后产生线粒体的有效破坏。我们认为肽 - 树枝状聚合物缀合物具有特异性和有效地将基于肽的治疗剂递送到肿瘤中的潜力。

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  • 来源
    《Biomaterials Science》 |2018年第3期|共10页
  • 作者

    Liu Fu-Hua; Hou Chun-Yuan; Zhang Di; Zhao Wen-Jing; Cong Yong; Duan Zhong-Yu; Qiao Zeng-Ying; Wang Hao;

  • 作者单位

    Hebei Univ Technol Sch Chem Engn &

    Technol Tianjin 300130 Peoples R China;

    Natl Ctr Nanosci &

    Technol NCNST CAS Key Lab Biomed Effects Nanomat &

    Nanosafety CAS Ctr Excellence Nanosci Beijing 100190 Peoples R China;

    Natl Ctr Nanosci &

    Technol NCNST CAS Key Lab Biomed Effects Nanomat &

    Nanosafety CAS Ctr Excellence Nanosci Beijing 100190 Peoples R China;

    Hebei Univ Technol Sch Chem Engn &

    Technol Tianjin 300130 Peoples R China;

    Natl Ctr Nanosci &

    Technol NCNST CAS Key Lab Biomed Effects Nanomat &

    Nanosafety CAS Ctr Excellence Nanosci Beijing 100190 Peoples R China;

    Hebei Univ Technol Sch Chem Engn &

    Technol Tianjin 300130 Peoples R China;

    Hebei Univ Technol Sch Chem Engn &

    Technol Tianjin 300130 Peoples R China;

    Hebei Univ Technol Sch Chem Engn &

    Technol Tianjin 300130 Peoples R China;

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  • 正文语种 eng
  • 中图分类 分子生物学;
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