Salzano G, Zappavigna S, Luce A, D'Onofrio N, Balestrieri M L, Grimaldi A, Lusa S, Ingrosso D, Artuso S, Porru M, Leonetti C, Caraglia M, De Rosa G
J Biomed Nanotechnol. 2016 Apr;12(4):811-30. doi: 10.1166/jbn.2016.2214.
The treatment of glioblastoma (GBM) is a challenge for the biomedical research since cures remain elusive. Its current therapy, consisted on surgery, radiotherapy, and concomitant chemotherapy with temozolomide (TMZ), is often uneffective. Here, we proposed the use of zoledronic acid (ZOL) as a potential agent for the treatment of GBM. Our group previously developed self-assembling nanoparticles, also named PLCaPZ NPs, to use ZOL in the treatment of prostate cancer. Here, we updated the previously developed nanoparticles (NPs) by designing transferrin (Tf)-targeted self-assembling NPs, also named Tf-PLCaPZ NPs, to use ZOL in the treatment of brain tumors, e.g., GBM. The efficacy of Tf-PLCaPZ NPs was evaluated in different GBM cell lines and in an animal model of GBM, in comparison with PLCaPZ NPs and free ZOL. Tf-PLCaPZ NPs were characterized by a narrow size distribution and a high incorporation efficiency of ZOL. Moreover, the presence of Tf significantly reduced the hemolytic activity of the formulation. In vitro, in LN229 cells, a significant uptake and cell growth inhibition after treatment with Tf-PLCaPZ NPs was achieved. Moreover, the sequential therapy of TMZ and Tf-PLCaPZ NPs lead to a superior therapeutic activity compared to their single administration. The results obtained in mice xenografted with U373MG, revealed a significant anticancer activity of Tf-PLCaPZ NPs, while the tumors remained unaffected with free TMZ. These promising results introduce a novel type of easy-to-obtain NPs for the delivery of ZOL in the treatment of GBM tumors.
胶质母细胞瘤（GBM）的治疗是生物医学研究面临的一项挑战，因为治愈方法仍然难以捉摸。其目前的治疗方法包括手术、放疗以及与替莫唑胺（TMZ）联合化疗，但往往效果不佳。在此，我们提出使用唑来膦酸（ZOL）作为治疗GBM的潜在药物。我们团队之前开发了自组装纳米颗粒，也称为PLCaPZ NPs，用于将ZOL用于前列腺癌的治疗。在此，我们通过设计转铁蛋白（Tf）靶向的自组装纳米颗粒（也称为Tf-PLCaPZ NPs）对之前开发的纳米颗粒进行了更新，以将ZOL用于脑肿瘤（如GBM）的治疗。与PLCaPZ NPs和游离ZOL相比，在不同的GBM细胞系和GBM动物模型中评估了Tf-PLCaPZ NPs的疗效。Tf-PLCaPZ NPs的特点是粒径分布窄且ZOL的包封效率高。此外，Tf的存在显著降低了制剂的溶血活性。在体外，在LN229细胞中，用Tf-PLCaPZ NPs处理后实现了显著的摄取和细胞生长抑制。此外，与单独给药相比，TMZ和Tf-PLCaPZ NPs的序贯治疗导致了更高的治疗活性。在用U373MG异种移植的小鼠中获得的结果显示，Tf-PLCaPZ NPs具有显著的抗癌活性，而游离TMZ对肿瘤没有影响。这些有前景的结果引入了一种新型的易于获得的纳米颗粒，用于在GBM肿瘤治疗中递送ZOL。
