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负载新型AKT/PDK1抑制剂PHT-427的纳米颗粒对头颈部鳞状细胞癌的抗肿瘤活性

Antitumor Activity of Nanoparticles Loaded with PHT-427, a Novel AKT/PDK1 Inhibitor, for the Treatment of Head and Neck Squamous Cell Carcinoma.

作者信息

Yanes-Díaz Joaquín, Palao-Suay Raquel, Aguilar María Rosa, Riestra-Ayora Juan Ignacio, Ferruelo-Alonso Antonio, Rojo Del Olmo Luis, Vázquez-Lasa Blanca, Sanz-Fernández Ricardo, Sánchez-Rodríguez Carolina

机构信息

Department Otolaryngology, Hospital Universitario de Getafe, Getafe (Madrid), Carretera de Toledo, km 12.500, 28905 Madrid, Spain.

Department of Polymeric Nanomaterials and Biomaterials Institute of Polymer Science and Technology CSIC, C/Juan de la Cierva, 3, 28006 Madrid, Spain.

出版信息

Pharmaceutics. 2021 Aug 12;13(8):1242. doi: 10.3390/pharmaceutics13081242.

DOI:10.3390/pharmaceutics13081242
PMID:34452203
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8401941/
Abstract

Currently, new treatments are required to supplement the current standard of care for head and neck squamous cell carcinoma (HNSCC). The phosphatidylinositol3-kinase (PI3K) signaling pathway is commonly altered and activated in HNSCC. PHT-427 is a dual PI3K-mammalian target of the AKT/PDK1 inhibitor; however, to the best of our knowledge, the effect of the PHT-427 inhibitor on HNSCC has not been investigated. This study aims to evaluate the antitumoral effect of PHT-427-loaded polymeric nanoparticles based on α-tocopheryl succinate (α-TOS). The in vitro activity of PHT-427 was tested in hypopharynx carcinoma squamous cells (FaDu) to measure the cell viability, PI3KCA/AKT/PDK1 gene expression, and PI3KCA/AKT/PDK1 levels. Apoptosis, epidermal growth factor receptor (EGFR), and reactive oxygen species (ROS) were also measured. The presence of PHT-427 significantly enhances its antiproliferative and proapoptotic activity by inactivating the PI3K/AKT/PDK1 pathway. Nanoparticles (NPs) effectively suppress AKT/PDK1 expression. Additionally, NPs loaded with PHT-427 produce high oxidative stress levels that induce apoptosis. In conclusion, these results are promising in the use of this nanoformulation as a PHT-427 delivery system for effective HNSCC treatment.

摘要

目前，需要新的治疗方法来补充头颈部鳞状细胞癌（HNSCC）的现行标准治疗方案。磷脂酰肌醇3激酶（PI3K）信号通路在HNSCC中通常发生改变并被激活。PHT-427是一种双PI3K-AKT/PDK1哺乳动物靶点抑制剂；然而，据我们所知，尚未研究PHT-427抑制剂对HNSCC的作用。本研究旨在评估基于琥珀酸生育酚（α-TOS）的负载PHT-427的聚合物纳米颗粒的抗肿瘤作用。在下咽癌鳞状细胞（FaDu）中测试了PHT-427的体外活性，以测量细胞活力、PI3KCA/AKT/PDK1基因表达以及PI3KCA/AKT/PDK1水平。还检测了细胞凋亡、表皮生长因子受体（EGFR）和活性氧（ROS）。PHT-427的存在通过使PI3K/AKT/PDK1通路失活，显著增强了其抗增殖和促凋亡活性。纳米颗粒（NPs）有效抑制AKT/PDK1表达。此外，负载PHT-427的NPs产生高氧化应激水平，诱导细胞凋亡。总之，这些结果对于将这种纳米制剂用作有效的HNSCC治疗的PHT-427递送系统很有前景。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ff50/8401941/beccd45950c2/pharmaceutics-13-01242-g010.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ff50/8401941/3832a739dd14/pharmaceutics-13-01242-g001.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ff50/8401941/d05755659609/pharmaceutics-13-01242-g003.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ff50/8401941/c67f5f50397d/pharmaceutics-13-01242-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ff50/8401941/5ff45ae009f4/pharmaceutics-13-01242-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ff50/8401941/6f7d106f40fc/pharmaceutics-13-01242-g009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ff50/8401941/beccd45950c2/pharmaceutics-13-01242-g010.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ff50/8401941/3832a739dd14/pharmaceutics-13-01242-g001.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ff50/8401941/d05755659609/pharmaceutics-13-01242-g003.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ff50/8401941/fd95ebc9fd7c/pharmaceutics-13-01242-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ff50/8401941/4d5ee971de20/pharmaceutics-13-01242-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ff50/8401941/c67f5f50397d/pharmaceutics-13-01242-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ff50/8401941/5ff45ae009f4/pharmaceutics-13-01242-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ff50/8401941/6f7d106f40fc/pharmaceutics-13-01242-g009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ff50/8401941/beccd45950c2/pharmaceutics-13-01242-g010.jpg

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