Department of Pharmaceutical Technology, Faculty of Pharmacy, Hacettepe University, Ankara, Turkey.
Institute of Neurological Sciences and Psychiatry, Hacettepe University, Ankara, Turkey.
Int J Pharm. 2020 Mar 30;578:119076. doi: 10.1016/j.ijpharm.2020.119076. Epub 2020 Jan 24.
Malignant gliomas are highly lethal. Delivering chemotherapeutic drugs to the brain in sufficient concentration is the major limitation in their treatment due to the blood-brain barrier (BBB). Drug delivery systems may overcome this limitation and can improve the transportation through the BBB. Paclitaxel is an antimicrotubule agent with effective anticancer activity but limited BBB permeability. R-Flurbiprofen is a nonsteroidal antienflammatory drug and has potential anticancer activity. Accordingly, we designed an approach combining R-flurbiprofen and paclitaxel and positively-charged chitosan-modified poly-lactide-co-glycolic acid (PLGA) nanoparticles (NPs) and to transport them to glioma tissue. NPs were characterized and, cytotoxicity and cellular uptake studies were carried out in vitro. The in vivo efficacy of the combination and formulations were evaluated using a rat RG2 glioma tumor model. Polyethylene glycol (PEG) modified and chitosan-coated PLGA NPs demonstrated efficient cytotoxic activity and were internalized by the tumor cells in RG2 cell culture. In vivo studies showed that the chitosan-coated and PEGylated NPs loaded with paclitaxel and R-flurbiprofen exhibited significantly higher therapeutic activity against glioma. In conclusion, PLGA NPs can efficiently carry their payloads to glioma tissue and the combined use of anticancer and anti-inflammatory drugs may exert additional anti-tumor activity.
恶性脑胶质瘤的致死率极高。由于血脑屏障（BBB）的存在，将化疗药物以足够的浓度递送到大脑是治疗中的主要限制因素。药物递送系统可以克服这一限制，并可以改善通过 BBB 的运输。紫杉醇是一种具有有效抗癌活性的微管抑制剂，但 BBB 通透性有限。R-氟比洛芬是非甾体类抗炎药，具有潜在的抗癌活性。因此，我们设计了一种将 R-氟比洛芬和紫杉醇与带正电荷的壳聚糖修饰的聚乳酸-羟基乙酸共聚物（PLGA）纳米颗粒（NPs）结合并将其递送至脑胶质瘤组织的方法。对 NPs 进行了表征，并在体外进行了细胞毒性和细胞摄取研究。使用大鼠 RG2 脑胶质瘤肿瘤模型评估了该组合和制剂的体内疗效。聚乙二醇（PEG）修饰和壳聚糖包被的 PLGA NPs 在 RG2 细胞培养中表现出有效的细胞毒性活性，并被肿瘤细胞内化。体内研究表明，载有紫杉醇和 R-氟比洛芬的壳聚糖包被和 PEG 化 NPs 对脑胶质瘤表现出显著更高的治疗活性。总之，PLGA NPs 可以有效地将其有效载荷递送到脑胶质瘤组织，并且抗癌和抗炎药物的联合使用可能会发挥额外的抗肿瘤活性。
