Multifunctional tumor-targeted PLGA nanoparticles delivering Pt(IV)/siBIRC5 for US/MRI imaging and overcoming ovarian cancer resistance
Multifunctional tumor-targeted PLGA nanoparticles delivering Pt(IV)/siBIRC5 for US/MRI imaging and overcoming ovarian cancer resistance
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多功能肿瘤靶向 PLGA 纳米颗粒可传递 Pt(IV)/siBIRC5，用于 US/MRI 成像并克服卵巢癌耐药性。
DOI：
10.1016/j.biomaterials.2020.120478
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发表时间：
2021-02-03
期刊：
影响因子：
14
通讯作者：
Sun, Ying
中科院分区：
文献类型：
--
作者：
Zhang, Yanhua;Dong, Yang;Sun, Ying
顺铂（Pt（II））耐药是卵巢癌高死亡率的重要因素。在此，我们合成了多功能肿瘤靶向聚乳酸-羟基乙酸共聚物（PLGA）纳米颗粒（NPs-cRGD），用于通过双模式成像监测治疗效果和克服顺铂耐药性。粒径均一的NPs-cRGD在体外表现出药物和基因的控释和缓释、优异的基因负载和基因保护能力、良好的储存稳定性和无血清诱导的聚集。NPs-cRGD在体内表现出清晰、靶向和延长的超声成像和磁共振成像（MRI）。NPs-cRGD的靶向结合超声促进纳米颗粒渗透到细胞中;进入是时间依赖性的。NPs-cRGD从溶酶体逃逸，从而阻止siBIRC 5降解，这使得siBIRC 5能够有效抑制SKO 3-DDP中BIRC 5的抗凋亡作用，以克服耐药细胞的抗凋亡特性。此外，NPs-cRGD中的Pt（IV）耗尽谷胱甘肽（GSH），从而增加药物积累以有效地增加Pt（II）水平。铂（II）与DNA的结合抑制了基因的表达，上调了p53的表达，从而诱导了线粒体凋亡途径。GSH活性的降低和Pt（II）的产生进一步促进了高水平的活性氧（ROS）以诱导细胞凋亡。因此，NPs-cRGD与超声通过多种机制促进耐药卵巢癌细胞的凋亡，包括增加细胞药物积累，逆转siBIRC 5的抗凋亡作用，以及提高ROS水平。在荷瘤裸鼠模型中，NPs-cRGD与US显示出优异的肿瘤靶向性、高效的肿瘤抑制和低的全身毒性。因此，NPs-cRGD提供了一种监测治疗过程的手段，并且可以与超声治疗相结合，以克服体外和体内卵巢癌耐药性。
Cisplatin (Pt(II)) resistance is an important factor in the high mortality rates of ovarian cancer. Herein, we synthesized multifunctional tumor-targeted poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs-cRGD) for monitoring therapeutic effects by dual-mode imaging and overcoming cisplatin resistance. Uniformly sized NPs-cRGD demonstrated controlled and sustained release of drugs and genes, excellent gene loading and gene protection capacity, good storage stability and no serum-induced aggregation in vitro. NPs-cRGD demonstrated clear, targeting and prolonged ultrasound imaging and magnetic resonance imaging (MRI) in vivo. The targeting of NPs-cRGD combined with ultrasound facilitated nanoparticle penetrattion into cells; entry was time-dependent. NPs-cRGD escaped from lysosomes, thereby preventing siBIRC5 degradation, which enabled siBIRC5 to efficiently inhibit the antiapoptosis effects of BIRC5 in SKO3-DDP to overcome the antiapoptosis properties of resistant cells. Furthermore, Pt(IV) in NPs-cRGD exhausted glutathione (GSH), thereby increasing drug accumulation to effectively increase Pt(II) levels. The subsequent combination of Pt(II) with DNA prevented the expressions of genes and upregulated the expression of p53 to induce the mitochondria apoptosis pathway. The reduced GSH activity and the generation of Pt(II) further promoted high levels of reactive oxygen species (ROS) to induce cell apoptosis. Therefore, NPs-cRGD with ultrasound promoted the apoptosis of resistant ovarian cancer cells by multiple mechanisms, including increased cellular drug accumulation, reversed antiapoptotic effects by siBIRC5, and enhanced ROS levels. In a tumor-bearing nude mice model, NPs-cRGD with US demonstrated excellent tumor-targeting, high efficiency tumor inhibition and low systemic toxicity. Therefore, NPs-cRGD provides a means to monitor treatment processes and can be combined with ultrasound treatment to overcome ovarian cancer resistance in vitro and in vivo.