Belfiore Lisa, Saunders Darren N, Ranson Marie, Vine Kara L
Illawarra Health and Medical Research Institute, Wollongong, NSW 2522, Australia.
School of Chemistry and Molecular Bioscience, Faculty of Science Medicine and Health, University of Wollongong, Wollongong, NSW 2522, Australia.
Pharmaceutics. 2020 Jul 7;12(7):641. doi: 10.3390/pharmaceutics12070641.
The urokinase plasminogen activator and its receptor (uPA/uPAR) are biomarkers for metastasis, especially in triple-negative breast cancer. We prepared anti-mitotic -alkylisatin (-AI)-loaded liposomes functionalized with the uPA/uPAR targeting ligand, plasminogen activator inhibitor type 2 (PAI-2/SerpinB2), and assessed liposome uptake in vitro and in vivo. Receptor-dependent uptake of PAI-2-functionalized liposomes was significantly higher in the uPA/uPAR overexpressing MDA-MB-231 breast cancer cell line relative to the low uPAR/uPAR expressing MCF-7 breast cancer cell line. Furthermore, -AI cytotoxicity was enhanced in a receptor-dependent manner. In vivo, PAI-2 -AI liposomes had a plasma half-life of 5.82 h and showed an increased accumulation at the primary tumor site in an orthotopic MDA-MB-231 BALB/c-Fox1nu/Ausb xenograft mouse model, relative to the non-functionalized liposomes, up to 6 h post-injection. These findings support the further development of -AI-loaded PAI-2-functionalized liposomes for uPA/uPAR-positive breast cancer, especially against triple-negative breast cancer, for which the prognosis is poor and treatment is limited.
尿激酶型纤溶酶原激活剂及其受体（uPA/uPAR）是转移的生物标志物，尤其是在三阴性乳腺癌中。我们制备了用uPA/uPAR靶向配体纤溶酶原激活剂抑制剂2型（PAI-2/SerpinB2）功能化的负载抗有丝分裂 - 烷基异吲哚酮（-AI）的脂质体，并评估了脂质体在体外和体内的摄取情况。相对于低uPAR/uPAR表达的MCF-7乳腺癌细胞系，在uPA/uPAR过表达的MDA-MB-231乳腺癌细胞系中，PAI-2功能化脂质体的受体依赖性摄取显著更高。此外，-AI的细胞毒性以受体依赖性方式增强。在体内，PAI-2 -AI脂质体的血浆半衰期为5.82小时，相对于未功能化的脂质体，在原位MDA-MB-231 BALB/c-Fox1nu/Ausb异种移植小鼠模型中，在注射后长达6小时，其在原发肿瘤部位的积累增加。这些发现支持进一步开发用于uPA/uPAR阳性乳腺癌，尤其是针对三阴性乳腺癌的负载 -AI的PAI-2功能化脂质体，三阴性乳腺癌预后较差且治疗有限。
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