Wang Honglan, Liu Huiwen, Sun Chunyan, Liu Chunying, Jiang Ting, Yin Yanxue, Xu Aoshuang, Pang Zhiqing, Zhang Bo, Hu Yu
Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science & Technology, Wuhan 430022, China.
Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai 201203, China.
Pharmaceutics. 2021 Feb 18;13(2):274. doi: 10.3390/pharmaceutics13020274.
Cancer-associated fibroblasts (CAFs) and myeloma cells could mutually drive myeloma progression, indicating that drug delivery to kill both CAFs and myeloma cells simultaneously could achieve better therapeutic benefits than to kill each cell type alone. Here, we designed a dual-targeting drug delivery system by conjugating paclitaxel (PTX)-loaded poly(ethylene glycol)-poly(lactic acid) nanoparticles (NPs) with a cyclic peptide (CNPs-PTX) with a special affinity with platelet-derived growth factor/platelet-derived growth factor receptor (PDGFR-β) overexpressed on both CAFs and myeloma cells. Cellular uptake experiments revealed that the cyclic peptide modification on CNPs could significantly enhance CNPs uptake by both CAFs and myeloma cells compared with unmodified NPs. Cytotoxicity tests showed that CNPs-PTX was more toxic to both CAFs and myeloma cells compared with its counterpart PTX-loaded conventional NPs (NPs-PTX). In vivo imaging and biodistribution experiments showed that CNPs could abundantly accumulate in tumors and were highly co-localized with CAFs and myeloma cells. The in vivo anti-tumor experiments confirmed that the anti-myeloma efficacy of CNPs-PTX was significantly stronger than that of NPs-PTX and free drugs. In summary, it is the first time that a dual-targeting strategy was utilized in the field of myeloma treatment through targeting both CAFs and myeloma cells simultaneously, which harbors a high potential of clinical translation for myeloma treatment.
癌症相关成纤维细胞（CAFs）与骨髓瘤细胞可相互推动骨髓瘤进展，这表明相较于单独杀死每种细胞类型，同时杀死CAFs和骨髓瘤细胞的药物递送能带来更好的治疗效果。在此，我们通过将负载紫杉醇（PTX）的聚（乙二醇）-聚（乳酸）纳米颗粒（NPs）与一种对CAFs和骨髓瘤细胞上均过度表达的血小板衍生生长因子/血小板衍生生长因子受体（PDGFR-β）具有特殊亲和力的环肽（CNPs-PTX）偶联，设计了一种双靶向药物递送系统。细胞摄取实验表明，与未修饰的NPs相比，CNPs上的环肽修饰可显著增强CAFs和骨髓瘤细胞对CNPs的摄取。细胞毒性测试显示，与负载PTX的传统NPs（NPs-PTX）相比，CNPs-PTX对CAFs和骨髓瘤细胞均更具毒性。体内成像和生物分布实验表明，CNPs可大量积聚在肿瘤中，并与CAFs和骨髓瘤细胞高度共定位。体内抗肿瘤实验证实，CNPs-PTX的抗骨髓瘤疗效显著强于NPs-PTX和游离药物。总之，首次在骨髓瘤治疗领域通过同时靶向CAFs和骨髓瘤细胞运用双靶向策略，这对骨髓瘤治疗具有很高的临床转化潜力。
