Discipline of Chemistry, Indian Institute of Technology (IIT) Gandhinagar, Palaj, Gandhinagar, Gujarat 382355, India.
Discipline of Biological Engineering, Indian Institute of Technology (IIT) Gandhinagar, Palaj, Gandhinagar, Gujarat 382355, India.
ACS Appl Bio Mater. 2021 Sep 20;4(9):6799-6806. doi: 10.1021/acsabm.1c00527. Epub 2021 Aug 11.
In recent years, antibiotics have emerged as alternative medicines in cancer therapy due to their capability of mitochondrial dysfunction in cancer cells. However, antibiotics render collateral damage in noncancerous cells by targeting mitochondrial transcription and translational machinery. To address this, herein, we have engineered three different mitochondria-targeted cationic antibiotic (tigecycline)-loaded nanoparticles from cholesterol conjugates. Dynamic light scattering and electron microscopy confirmed the spherical morphology and a less than 200 nm hydrodynamic diameter for these nanoparticles. The triphenylphosphine-coated tigecycline-loaded nanoparticle (Mito-TPP-Tig-NP) was shown to be homed into the mitochondria of A549 lung cancer cells compared to the other cationic nanoparticles. These Mito-TPP-Tig-NPs indeed triggered mitochondrial morphology damage and generation of reactive oxygen species (ROS). All the mitochondria-targeted tigecycline-loaded nanoparticles showed improved cancer cell killing ability in A549 and HeLa cervical cancer cells compared to free tigecycline. Moreover, Mito-TPP-Tig-NPs showed much less toxicity toward noncancerous human embryonic kidney cells (HEK293) compared to free tigecycline. These antibiotic-loaded mitochondria-targeted nanoparticles can open up an avenue toward anticancer therapy.
近年来，由于抗生素能够使癌细胞线粒体功能失调，因此它们被作为癌症治疗的替代药物出现。然而，抗生素通过靶向线粒体转录和翻译机制，对非癌细胞造成附带损伤。为了解决这个问题，我们设计了三种不同的由胆固醇缀合物制成的线粒体靶向阳离子抗生素（替加环素）负载的纳米粒子。动态光散射和电子显微镜证实了这些纳米粒子具有球形形态和小于 200nm 的水动力直径。与其他阳离子纳米粒子相比，三苯基膦包覆的替加环素负载的纳米粒子（Mito-TPP-Tig-NP）被证明能够进入 A549 肺癌细胞的线粒体。这些 Mito-TPP-Tig-NPs 确实引发了线粒体形态损伤和活性氧（ROS）的产生。与游离替加环素相比，所有的线粒体靶向替加环素负载的纳米粒子在 A549 和 HeLa 宫颈癌细胞中都表现出了更好的癌细胞杀伤能力。此外，与游离替加环素相比，Mito-TPP-Tig-NPs 对非癌细胞（人胚肾细胞 293 细胞）的毒性要小得多。这些负载抗生素的靶向线粒体的纳米粒子为癌症治疗开辟了新途径。
