Wan Xiaofeng, Chen Chuanrong, Zhan Jianmin, Ye Shuke, Li Runsheng, Shen Ming
National Health Commission (NHC) Key Lab of Reproduction Regulation (Shanghai Institute for Biomedical and Pharmaceutical Technologies), Shanghai, China.
Department of Oncology, Yijishan Hospital of Wannan Medical College, Wuhu, China.
Front Bioeng Biotechnol. 2024 Aug 1;12:1415191. doi: 10.3389/fbioe.2024.1415191. eCollection 2024.
Drug resistance is common in triple-negative breast cancer (TNBC) therapy. To identify a method to overcome chemotherapy resistance in TNBC cells, an siRNA targeting the AXL gene (siAXL), which can overcome drug resistance, was used in this study. A nanodelivery system was constructed to co-deliver siAXL and paclitaxel (PTX). A biodegradable and tumor microenvironment (TME)-sensitive mPEG-coated dendritic polylysine material (PDPLL) was synthesized. This material was used to construct single-molecule nanoparticles to co-deliver PTX and siAXL. The drug encapsulation and morphological properties of the nanoparticles (NPs) were characterized. The sensitivity of the NPs to the TME was evaluated with a dialysis method. The tumor-targeting effect of the PDPLL NPs was evaluated by fluorescence imaging and drug distribution evaluation . The ability to overcome drug resistance was evaluated using PTX-resistant 4T1 cells (4T1/PTX cells) in both and models. PDPLL NPs had a particle size of 49.6 ± 5.9 nm and a zeta potential of 7.87 ± 0.68 mV. The PTX drug loading (DL)% was 2.59%. The siAXL DL was 2.5 mg PDPLL: 10 nmol siAXL. The release of PTX showed sustained release performance. The release of siAXL showed sensitivity for the TME. The NPs were stable in the plasma. The NPs promoted cell uptake by PTX-resistant 4T1 cells (4T1/PTX) and promoted tumor targeting and permeability . siAXL enhanced the toxicity and apoptosis efficiency of PTX in 4T1/PTX cells, as well as the cycle arrest efficiency caused by PTX. The NPs improved the above effects. In mouse 4T1/PTX orthotopic tumors, the NPs enhanced the sensitization of PTX to siAXL. The PDPLL NP co-delivery system possesses good encapsulating potential not only for PTX but also for siRNA. It can enhance the tumor-targeting effect and overcome the drug resistance of 4T1/PTX both and . This system is a potential delivery system for RNAs.
耐药性在三阴性乳腺癌（TNBC）治疗中很常见。为了确定一种克服TNBC细胞化疗耐药性的方法，本研究使用了一种靶向AXL基因的小干扰RNA（siAXL），其能够克服耐药性。构建了一种纳米递送系统，用于共递送siAXL和紫杉醇（PTX）。合成了一种可生物降解且对肿瘤微环境（TME）敏感的甲氧基聚乙二醇包被的树枝状聚赖氨酸材料（PDPLL）。该材料用于构建单分子纳米颗粒以共递送PTX和siAXL。对纳米颗粒（NPs）的药物包封率和形态特性进行了表征。采用透析法评估了NPs对TME的敏感性。通过荧光成像和药物分布评估来评价PDPLL NPs的肿瘤靶向作用。在体内和体外模型中，使用对PTX耐药的4T1细胞（4T1/PTX细胞）评估克服耐药性的能力。PDPLL NPs的粒径为49.6±5.9 nm，zeta电位为7.87±0.68 mV。PTX的药物负载量（DL）%为2.59%。siAXL的DL为2.5 mg PDPLL: 10 nmol siAXL。PTX的释放表现出缓释性能。siAXL的释放在TME中表现出敏感性。NPs在血浆中稳定。NPs促进了对PTX耐药的4T1细胞（4T1/PTX）对药物的摄取，并促进了肿瘤靶向性和通透性。siAXL增强了PTX在4T1/PTX细胞中的毒性和凋亡效率，以及PTX引起的细胞周期阻滞效率。NPs改善了上述效果。在小鼠4T1/PTX原位肿瘤中，NPs增强了PTX对siAXL的敏感性。PDPLL NP共递送系统不仅对PTX而且对siRNA都具有良好的包封潜力。它可以增强肿瘤靶向作用，并在体内和体外克服4T1/PTX的耐药性。该系统是一种潜在的RNA递送系统。
