State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200032, China.
State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200032, China.
Biomaterials. 2021 Feb;269:120478. doi: 10.1016/j.biomaterials.2020.120478. Epub 2020 Nov 12.
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.
顺铂（Pt（II））耐药是卵巢癌高死亡率的一个重要因素。在此，我们合成了多功能肿瘤靶向聚（乳酸-共-乙醇酸）（PLGA）纳米粒（NPs-cRGD），通过双模成像来监测治疗效果，并克服顺铂耐药。均匀大小的 NPs-cRGD 表现出药物和基因的控制和持续释放、优异的基因负载和基因保护能力、良好的储存稳定性以及在体外无血清诱导聚集。NPs-cRGD 表现出清晰、靶向和延长的超声成像和磁共振成像（MRI）在体内。NPs-cRGD 的靶向与超声相结合，促进了纳米颗粒穿透细胞；这是一个时间依赖性的过程。NPs-cRGD 从溶酶体中逃脱，从而防止 siBIRC5 降解，使 siBIRC5 能够有效地抑制 SKO3-DDP 中 BIRC5 的抗凋亡作用，从而克服耐药细胞的抗凋亡特性。此外，NPs-cRGD 中的 Pt(IV)耗尽了谷胱甘肽（GSH），从而增加了药物积累，有效地增加了 Pt(II)水平。随后，Pt(II)与 DNA 结合，阻止基因表达并上调 p53 的表达，从而诱导线粒体凋亡途径。减少的 GSH 活性和 Pt(II)的产生进一步促进了高水平的活性氧（ROS）的产生，诱导细胞凋亡。因此，超声促进的 NPs-cRGD 通过多种机制促进耐药卵巢癌细胞的凋亡，包括增加细胞内药物积累、通过 siBIRC5 逆转抗凋亡作用以及增强 ROS 水平。在荷瘤裸鼠模型中，超声增强的 NPs-cRGD 表现出优异的肿瘤靶向性、高效的肿瘤抑制作用和低系统毒性。因此，NPs-cRGD 为监测治疗过程提供了一种手段，并可与超声治疗相结合，在体外和体内克服卵巢癌耐药性。
