Paclitaxel-Loaded Folate-Coated pH-Sensitive Liposomes Enhance Cellular Uptake and Antitumor Activity
Paclitaxel-Loaded Folate-Coated pH-Sensitive Liposomes Enhance Cellular Uptake and Antitumor Activity
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DOI：
10.1021/acs.molpharmaceut.9b00329
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发表时间：
2019-08-01
影响因子：
4.9
通讯作者：
Leite, Elaine A.
中科院分区：
文献类型：
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作者：
Monteiro, Liziane O. F.;Fernandes, Renata S.;Leite, Elaine A.
紫杉醇(PTX)是一种广泛用于治疗乳腺癌的微管稳定剂。然而，该药物的低溶解度和现有商业制剂的副作用限制了其临床应用。通过这种方式，本课题组最近描述了PTX叶酸包衣长循环pH敏感脂质体(SPHL-叶酸-PTX)的制备。因此，我们设计了一项概念验证研究，以证明SPHL-叶酸-PTX对乳腺肿瘤细胞株MDA-MB-231的可行性。对脂质体和PTX的细胞摄取进行评价。流式细胞仪检测细胞凋亡率和细胞周期。在荷瘤的BALB/c裸鼠体内进行了抗肿瘤活性实验。细胞摄取实验表明，SPHL-叶酸-PTX具有较高的细胞转运能力，具有较强的细胞毒性和细胞凋亡通路的激活作用。与游离PTX和SPHL-PTX(不含叶酸)相比，SPHL-叶酸-PTX处理诱导G0/G1期细胞表达增加。体内研究表明，SPHL-叶酸-PTX组的肿瘤生长显著减少，放射性药物摄取较低，表明其疗效高于游离PTX和SPHL-PTX。组织形态计量学分析显示，SPHL-叶酸-PTX治疗的动物坏死区和炎症区增加。免疫组织化学分析显示，SPHL-叶酸-PTX治疗后，增殖细胞减少，细胞凋亡率增加。因此，这些数据证实了SPHL-叶酸-PTX作为一种替代抗肿瘤治疗的潜力，特别是对乳腺癌。
Paclitaxel (PTX) is a microtubule-stabilizing agent widely used to treat breast cancer. Nevertheless, the low solubility of the drug and the side effects of commercial formulations available limit its clinical use. In this way, our group recently described the preparation of PTX-loaded folate-coated long-circulating and pH-sensitive liposomes (SpHL-folate-PTX). Therefore, a proof-of-concept study was designed in order to demonstrate the feasibility of SpHL-folate-PTX against breast tumor cell line MDA-MB-231. Cellular uptake of the liposomes and PTX was evaluated. Apoptosis and cell cycle were analyzed by flow cytometry. In vivo antitumor activity was carried out in MDA-MB-231 tumor-bearing BALB/c nude mice. Cellular uptake assay showed a high cell delivery of PTX by SpHL-folate-PTX, which leads to superior cytotoxicity and activation of apoptosis pathways. The SpHL-folate-PTX treatment induces an expressive increase of cells in the G0/G1 phase compared to free PTX and SpHL-PTX (without folate). In vivo studies showed a significant reduction in the tumor growth and a lower uptake of a radiopharmaceutical in the scintigraphic images for the SpHL-folate-PTX group, suggesting its higher efficacy compared with free PTX and SpHL-PTX. Histomorphometric analyses demonstrated an increase in necrosis and inflammation areas in animals treated with SpHL-folate-PTX. A decrease in the proliferative cells and a higher percentage of apoptotic cells were observed by immunohistochemical analyses after the treatment with SpHL-folate-PTX. Therefore, the data confirmed the potential of SpHL-folate-PTX as an alternative antitumor therapy, especially for breast cancer.