Department of Clinical Laboratory & Center for Gene Diagnosis, Zhongnan Hospital of Wuhan University, Wuhan, Hubei 430071, China; Department of Clinical Laboratory, Xiamen Children's Hospital (Children's Hospital of Fudan University Xiamen Branch), Xiamen, Fujian 361006, China.
Department of Pathology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei 430071, China.
Int J Pharm. 2022 Aug 25;624:121969. doi: 10.1016/j.ijpharm.2022.121969. Epub 2022 Jul 5.
Transmembrane TNF-α (tmTNF), a transmembrane form of TNF-α, was reported overexpressed in approximately 84% of triple-negative breast cancer (TNBC) patients and has emerged as a valid candidate biomarker for targeting TNBC. Paclitaxel is a first-line chemotherapeutic agent for the treatment of triple-negative breast cancer, but suffers from low water solubility, resulting in its low bioavailability. To achieve site-specific delivery of the anticancer chemotherapeutic drug (paclitaxel) on TNBC, we developed tmTNF-α monoclonal antibody (mAb)-conjugated paclitaxel (PTX) nanoparticles (NPs) (tmTNF-α mAb-PTX NPs) as potential nanocarriers. This targeted delivery-therapy nanocarriers was conducted by using an emulsification-evaporation method. tmTNF-α mAb-PTX NPs displayed favorable physicochemical properties. Compared with the control groups, tumor growth in human MDA-MB-231 xenograft mice was suppressed significantly by tmTNF-α mAb-PTX NPs. TmTNF-α mAb-PTX NPs exerts anti-tumor effects via promoting apoptosis and regulating mitogen-activated protein kinase (MAPK), phosphatidylinositol 3-kinase (PI3K) / protein kinase B (AKT)/ mammalian target of rapamycin (mTOR) cascade, as well as AMP-activated protein kinase (AMPK) and nuclear factor Kappa-B (NF-κB) pathways. Moreover, tmTNF-α mAb-PTX NPs can inhibit the process of epithelial-mesenchymal transition (EMT) in TNBC to suppress tumor progression and metastasis. Together, the novel tmTNF-α mAb-PTX NPs based targeted drug delivery system is a potentially highly effective approach for treating TNBC.
跨膜 TNF-α（tmTNF）是 TNF-α 的一种跨膜形式，据报道约 84%的三阴性乳腺癌（TNBC）患者中过度表达，已成为针对 TNBC 的有效候选生物标志物。紫杉醇是治疗三阴性乳腺癌的一线化疗药物，但水溶性低，导致生物利用度低。为了实现对 TNBC 的抗癌化疗药物（紫杉醇）的靶向递药，我们开发了 tmTNF-α 单克隆抗体（mAb）-缀合的紫杉醇（PTX）纳米颗粒（NPs）（tmTNF-α mAb-PTX NPs）作为潜在的纳米载体。这种靶向递药-治疗纳米载体是通过乳化-蒸发法进行的。tmTNF-α mAb-PTX NPs 表现出良好的物理化学性质。与对照组相比，tmTNF-α mAb-PTX NPs 显著抑制了人 MDA-MB-231 异种移植小鼠的肿瘤生长。tmTNF-α mAb-PTX NPs 通过促进细胞凋亡和调节丝裂原活化蛋白激酶（MAPK）、磷脂酰肌醇 3-激酶（PI3K）/蛋白激酶 B（AKT）/哺乳动物雷帕霉素靶蛋白（mTOR）级联，以及 AMP 激活的蛋白激酶（AMPK）和核因子 Kappa-B（NF-κB）途径发挥抗肿瘤作用。此外，tmTNF-α mAb-PTX NPs 可以抑制 TNBC 中的上皮-间充质转化（EMT）过程，从而抑制肿瘤的进展和转移。总之，新型 tmTNF-α mAb-PTX NPs 靶向药物递送系统为治疗 TNBC 提供了一种很有前途的高效方法。
