PDF(Pubmed)
Abstract：
Breast cancer is the most common malignant tumor in women and is a big challenge to clinical treatment due to the high morbidity and mortality. The pH/ROS dual-responsive nanoplatforms may be an effective way to significantly improve the therapeutic efficacy of breast cancer. Herein, we report a docetaxel (DTX)-loaded pH/ROS-responsive NP that could achieve active targeting of cancer cells and selective and complete drug release for effective drug delivery. The pH/ROS-responsive NPs were fabricated using nanocarriers that consist of an ROS-responsive moiety (4-hydroxymethylphenylboronic acid pinacol ester, HPAP), cinnamaldehyde (CA, an aldehyde organic compound with anticancer activities) and cyclodextrin (α-CD). The NPs were loaded with DTX, modified with a tumor-penetration peptide (circular RGD, cRGD) and named DTX/RGD NPs. The cRGD could promote DTX/RGD NPs penetration into deep tumor tissue and specifically target cancer cells. After internalization by cancer cells through receptor-mediated endocytosis, the pH-responsive acetal was cleaved to release CA in the lysosomal acidic environment. Meanwhile, the high ROS in tumor cells induced the disassembly of NPs with complete release of DTX. In vitro cellular assays verified that DTX/RGD NPs could be effectively internalized by 4T1 cells, obviously inducing apoptosis, blocking the cell cycle of 4T1 cells and consequently, killing tumor cells. In vivo animal experiments demonstrated that the NPs could target to the tumor sites and significantly inhibit the tumor growth in 4T1 breast cancer mice. Both in vitro and in vivo investigations demonstrated that DTX/RGD NPs could significantly improve the antitumor effect compared to free DTX. Thus, the DTX/RGD NPs provide a promising strategy for enhancing drug delivery and cancer therapy.
摘要：
乳腺癌是女性最常见的恶性肿瘤，由于其发病率和死亡率高，对临床治疗提出了巨大挑战。pH/ROS双响应纳米平台可能是显著提高乳腺癌治疗效果的有效途径。在这里，我们报道了一种负载多西他赛(DTX)的pH/ROS反应性NP,它可以实现癌细胞的主动靶向和选择性的完全药物释放以实现有效的药物递送.使用由ROS响应部分（4-羟甲基苯基硼酸频哪醇酯，HPAP),肉桂醛（CA，具有抗癌活性的醛有机化合物）和环糊精（α-CD）。NP装载了DTX，用肿瘤穿透肽修饰(环状RGD，cRGD)并命名为DTX/RGDNPs。cRGD可以促进DTX/RGDNPs渗透到深部肿瘤组织中并特异性靶向癌细胞。在通过受体介导的内吞作用被癌细胞内化后，pH响应性缩醛在溶酶体酸性环境中被裂解以释放CA。同时,肿瘤细胞中的高ROS诱导了NPs的拆解，并完全释放了DTX。体外细胞试验证实DTX/RGDNPs可被4T1细胞有效内化,明显诱导细胞凋亡，阻断4T1细胞的细胞周期，因此，杀死肿瘤细胞。体内动物实验表明，NPs可以靶向肿瘤部位并显着抑制4T1乳腺癌小鼠的肿瘤生长。体外和体内研究均表明，与游离DTX相比，DTX/RGDNP可以显着提高抗肿瘤作用。因此，DTX/RGDNP为增强药物递送和癌症治疗提供了有希望的策略.
