a Université Catholique de Louvain, Advanced Drug Delivery and Biomaterials, Louvain Drug Research Institute , Brussels , Belgium.
b Université Catholique de Louvain, Nuclear and Electron Spin Technologies Platform (NEST), Louvain Drug Research Institute , Brussels , Belgium.
J Drug Target. 2019 Jun-Jul;27(5-6):614-623. doi: 10.1080/1061186X.2019.1567738. Epub 2019 Jan 24.
We hypothesised that the active targeting of αvβ3 integrin overexpressed in neoangiogenic blood vessels and glioblastoma (GBM) cells combined with magnetic targeting of paclitaxel- and SPIO-loaded PLGA-based nanoparticles could improve accumulation of nanoparticles in the tumour and therefore improve the treatment of GBM.
PTX/SPIO PLGA nanoparticles with or without RGD-grafting were characterised. Their in vitro cellular uptake and cytotoxicity was evaluated by fluorospectroscopy and MTT assay. In vivo safety and anti-tumour efficacy of different targeting strategies were evaluated in orthotopic U87MG tumour model over multiple intravenous injections.
The nanoparticles of 250 nm were negatively charged. RGD targeted nanoparticles showed a specific and higher cellular uptake than untargeted nanoparticles by activated U87MG and HUVEC cells. In vitro IC50 of PTX after 48 h was ∼1 ng/mL for all the PTX-loaded nanoparticles. The median survival time of the mice treated with magnetic targeted nanoparticles was higher than the control (saline) mice or mice treated with other evaluated strategies. The 6 doses of PTX did not induce any detectable toxic effects on liver, kidney and heart when compared to Taxol.
The magnetic targeting strategy resulted in a better therapeutic effect than the other targeting strategies (passive, active).
我们假设，通过靶向整合素 αvβ3（在新生血管和胶质母细胞瘤（GBM）细胞中过表达）并联合载紫杉醇和 SPIO 的 PLGA 纳米粒的磁靶向作用，能够增加纳米粒在肿瘤中的聚集，从而改善 GBM 的治疗效果。
对载紫杉醇和 SPIO 的 PLGA 纳米粒进行 RGD 接枝或未接枝处理，并对其进行表征。通过荧光分光光度法和 MTT 测定评估其体外细胞摄取和细胞毒性。通过多次静脉注射，在 U87MG 肿瘤模型的原位模型中评估不同靶向策略的体内安全性和抗肿瘤疗效。
粒径为 250nm 的纳米粒带负电荷。RGD 靶向纳米粒与激活的 U87MG 和 HUVEC 细胞的特异性和摄取率均高于未靶向纳米粒。所有载紫杉醇纳米粒在 48h 时的 PTX IC50 约为 1ng/ml。与生理盐水组或其他评估策略组相比，接受磁靶向纳米粒治疗的小鼠的中位生存时间更长。与 Taxol 相比，6 个剂量的 PTX 未对肝脏、肾脏和心脏产生任何可检测的毒性作用。
与其他靶向策略（被动、主动）相比，磁靶向策略的治疗效果更好。
