MMP9 敏感的 PEG 脱落纳米脂质体用于将厄洛替尼和阿霉素靶向共递送到 MDA-MB-231 细胞,ACS Applied Polymer Materials

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MMP9 敏感的 PEG 脱落纳米脂质体用于将厄洛替尼和阿霉素靶向共递送到 MDA-MB-231 细胞
ACS Applied Polymer Materials ( IF 4.4 ) Pub Date : 2021-11-02 , DOI: 10.1021/acsapm.1c01228
So-Yeon Kim _{1,

2} , Ji Young Yoon ₃ , Haesoo Lee ₄ , Cheong-Weon Cho ₄ , Hasoo Seong ₁

Affiliation

肿瘤微环境敏感纳米脂质体 (TMS-NLs) 被制备为三阴性乳腺癌 (TNBC) 特异性载体，用于协同治疗。NLs 通过癌细胞分泌的基质金属蛋白酶 9 (MMP9) 释放聚乙二醇 (PEG)，暴露细胞穿透肽 X 肽，并因此被内化为癌细胞过度表达的 Syndecan-4。制备了含有前所未有的共轭物棕榈酰-X-MMP9 可裂解肽 (M)-甲氧基 PEG2000 的 TMS-NL，并与厄洛替尼 (ERL) 和阿霉素 (DOX) 共封装。ERL 后 DOX 的处理代表了对 MDA-MB-231 细胞的协同细胞毒性。MMP9 由 XMX 肽产生的 X 肽被内化到癌细胞中。用 Cy5 标记的 ERL 和 DOX 共封装的 TMS-NL。图 5 证明了 NL 内化到癌细胞中。ED-TMS-NLs 对 MDA-MB-231 细胞具有细胞毒性，而不是 MCF-7 细胞。与其他 ED-NL 制剂相比，PEG 脱落的 ED-TMS-NL 对 MDA-MB-231 细胞显示出更高的细胞摄取和细胞毒性，以及 DOX 向细胞核的转运。在 MDA-MB-231 肿瘤异种移植小鼠模型中，ED-TMS-NL 的肿瘤生长抑制优于 ED-PEGylated-NL。MMP9 敏感 PEG 脱落和 syndecan-4 靶向 TMS-NL 可以成为 TNBC 细胞微环境敏感转运系统的协同治疗平台。以及 DOX 转运到细胞核。在 MDA-MB-231 肿瘤异种移植小鼠模型中，ED-TMS-NL 的肿瘤生长抑制优于 ED-PEGylated-NL。MMP9 敏感 PEG 脱落和 syndecan-4 靶向 TMS-NL 可以成为 TNBC 细胞微环境敏感转运系统的协同治疗平台。以及 DOX 转运到细胞核。在 MDA-MB-231 肿瘤异种移植小鼠模型中，ED-TMS-NL 的肿瘤生长抑制优于 ED-PEGylated-NL。MMP9 敏感 PEG 脱落和 syndecan-4 靶向 TMS-NL 可以成为 TNBC 细胞微环境敏感转运系统的协同治疗平台。

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MMP9-Sensitive PEG-Shedding Nanoliposomes for Targeted Codelivery of Erlotinib and Doxorubicin to MDA-MB-231 Cells

Tumor microenvironment-sensitive nanoliposomes (TMS-NLs) were prepared as triple negative breast cancer (TNBC)-specific carriers for synergistic therapeutics. The NLs shed polyethylene glycol (PEG) by matrix metalloproteinase 9 (MMP9) secreted from the cancer cells, expose a cell-penetrating peptide, the X peptide, and are consequently internalized into syndecan-4 overexpressed by the cancer cells. TMS-NLs containing an unprecedented conjugate, palmitoyl-X-MMP9-cleavable peptide (M)-methoxy PEG2000, were prepared and coencapsulated with erlotinib (ERL) and doxorubicin (DOX). Treatment of DOX after ERL represented synergistic cytotoxicity against MDA-MB-231 cells. The X peptide generated from the XMX peptide by MMP9 was internalized into the cancer cells. The ERL and DOX-coencapsulated TMS-NL labeled with Cy5.5 demonstrated internalization of the NL into the cancer cells. ED-TMS-NLs were cytotoxic against MDA-MB-231 cells, not MCF-7 cells. Compared with other ED-NL formulations, the PEG-shedding ED-TMS-NL showed higher cellular uptake and cytotoxicity against MDA-MB-231 cells, as well as DOX transport to the nucleus. In the MDA-MB-231 tumor-xenografted mouse model, the tumor growth inhibition of the ED-TMS-NL was superior to that of the ED-PEGylated-NL. The MMP9-sensitive PEG-shedding and syndecan-4-targeting TMS-NL can be a platform for a TNBC cell microenvironment-sensitive transport system of synergistic therapeutics.

更新日期：2021-11-12

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