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））耐药性是卵巢癌高死亡率的重要因素。在这里，我们合成了多功能靶向肿瘤的聚乳酸-乙醇酸共聚物（PLGA）纳米粒子（NPs-cRGD），用于通过双模式成像和克服顺铂耐药性来监测治疗效果。大小均一的NPs-cRGD表现出药物和基因的控制和持续释放，优异的基因加载和基因保护能力，良好的储存稳定性以及体外无血清诱导的聚集。NPs-cRGD在体内表现出清晰，有针对性的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了纳米颗粒渗透进入细胞；进入是时间相关的。NPs-cRGD从溶酶体中逃逸，从而防止siBIRC5降解，这使siBIRC5能够有效抑制SIRC3-DDP中BIRC5的抗凋亡作用，从而克服了耐药细胞的抗凋亡特性。此外，NPs-cRGD中的Pt（IV）消耗了谷胱甘肽（GSH），从而增加了药物蓄积，从而有效地提高了Pt（II）的水平。随后Pt（II）与DNA的结合阻止了基因的表达并上调了p53的表达，从而诱导线粒体凋亡途径。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）诱导细胞凋亡。因此，具有超声作用的NPs-cRGD通过多种机制促进耐药卵巢癌细胞的凋亡，包括增加细胞药物蓄积，通过siBIRC5逆转抗凋亡作用以及提高ROS水平。在具有荷瘤的裸鼠模型中，具有US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的全身毒性。因此，NPs-cRGD提供了一种监测治疗过程的方法，可以与超声治疗相结合来克服卵巢癌的耐药性体外和体内。