Tumor-Microenvironment-Adaptive Nanoparticles Codeliver Paclitaxel and siRNA to Inhibit Growth and Lung Metastasis of Breast Cancer
Tumor-Microenvironment-Adaptive Nanoparticles Codeliver Paclitaxel and siRNA to Inhibit Growth and Lung Metastasis of Breast Cancer
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DOI：
10.1002/adfm.201601703
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发表时间：
2016-09-06
影响因子：
19
通讯作者：
Li, Yaping
中科院分区：
文献类型：
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作者：
Tang, Shan;Meng, Qingshuo;Li, Yaping
延长循环时间、肿瘤细胞特异性有效摄取以及细胞内药物快速释放是药物递送系统战胜转移性乳腺癌的三个主要因素。在这项工作中，制备了一种共负载紫杉醇（PTX）和靶向Twist的抗转移siRNA的肿瘤微环境适应性纳米颗粒。该纳米颗粒由 pH 敏感核、阳离子壳和通过肽接头缀合的基质金属蛋白酶 (MMP) 可裂解的聚乙二醇 (PEG) 冠组成。 PEG会在肿瘤部位被MMP切除，从而赋予纳米颗粒更小的粒径和更高的正电荷，与具有不可去除的PEG的纳米颗粒相比，在4T1荷瘤小鼠模型中，肿瘤细胞更有效地摄取PTX和siRNA，并且PTX和siRNA在肿瘤内的积累更高。此外，内质/溶酶体中酸触发的药物释放是通过 pH 敏感核心实现的。结果，MMP/pH双敏感纳米粒子显着抑制肿瘤生长和肺转移。因此，这种肿瘤微环境适应性纳米颗粒由于同时满足长循环时间、高效肿瘤细胞靶向和快速细胞内药物释放的要求，可以成为有效治疗转移性乳腺癌的有前途的共递送载体。
Prolonged circulation, specific and effective uptake by tumor cells, and rapid intracellular drug release are three main factors for the drug delivery systems to win the battle against metastatic breast cancer. In this work, a tumor microenvironment-adaptive nanoparticle co-loading paclitaxel (PTX) and the anti-metastasis siRNA targeting Twist is prepared. The nanoparticle consists of a pH-sensitive core, a cationic shell, and a matrix metalloproteinase (MMP)-cleavable polyethylene glycol (PEG) corona conjugated via a peptide linker. PEG will be cut away by MMPs at the tumor site, which endows the nanoparticle with smaller particle size and higher positive charge, leading to more efficient cellular uptake in tumor cells and higher intra-tumor accumulation of both PTX and siRNA in the 4T1 tumor-bearing mice models compared to the nanoparticles with irremovable PEG. In addition, acid-triggered drug release in endo/lysosomes is achieved through the pH-sensitive core. As a result, the MMP/pH dual-sensitive nanoparticles significantly inhibit tumor growth and pulmonary metastasis. Therefore, this tumor-microenvironment-adaptive nanoparticle can be a promising codelivery vector for effective therapy of metastatic breast cancer due to simultaneously satisfying the requirements of long circulating time, efficient tumor cell targeting, and fast intracellular drug release.