a Division of Pharmaceutics , College of Pharmacy, The Ohio State University , Columbus , OH , USA.
b Rexahn Pharmaceuticals, Inc. , Rockville , MD , USA.
J Drug Target. 2018 Jun-Jul;26(5-6):466-473. doi: 10.1080/1061186X.2018.1433678. Epub 2018 Feb 8.
RX-0201 is an antisense oligonucleotide (ASO) against Akt1 currently in clinical trial for metastatic renal cancer.
To improve the delivery of RX-0201 using folate receptor-targeted lipid-albumin nanoparticles (F-LAN).
F-LAN were synthesized with the composition of DOTAP/soyPC/TPGS/folate-PEG-DSPE (25:70:4:1 m/m), a cationic human serum albumin-pentaethylenehexamine (HSA-PEHA) conjugate and RX-0201. The nanoparticles were evaluated in KB human carcinoma cells in vitro and in a KB murine xenograft tumour model in vivo for pharmacokinetics and antitumor activities.
The F-LAN-RX-0201 had a mean particle size of 108.6 ± 5.8 nm, zeta potential of 10.5 ± 3.2 mV and ASO loading efficiency of 71.5 ± 4.5%. In KB cells, uptake and Akt1 inhibition by F-LAN-RX-0201 were greater than those of non-targeted LAN-RX-0201 and could be partially blocked by excess free folate. F-LAN-RX-0201 inhibited cell growth with an IC of 11.9 μM. In contrast, LAN-RX-0201 showed lower cytotoxicity with an IC of 32.0 μM. No significant cytotoxicity was observed with up to 250 µM of free RX-0201. Pharmacokinetic studies showed that F-LAN-RX-0201 had a longer terminal half-life than free RX-0201 (442 vs. 219 min). In a KB xenograft tumour model, F-LAN-RX-0201 exhibited greater tumour inhibition than LAN-RX-0201 at 16 mg/kg. Moreover, F-LAN-RX-0201 at 16 mg/kg showed comparable tumour inhibition compared to free RX-0201 at a much higher dose of 90 mg/kg.
F-LAN-RX-0201 showed promise as a therapeutic agent for tumours with elevated folate-receptor expression.
RX-0201 是一种针对 Akt1 的反义寡核苷酸（ASO），目前正在进行转移性肾细胞癌的临床试验。
使用叶酸受体靶向脂质-白蛋白纳米粒（F-LAN）来提高 RX-0201 的递送效率。
使用 DOTAP/大豆卵磷脂/TPGS/叶酸-PEG-DSPE（25:70:4:1 m/m）、阳离子人血清白蛋白-五乙烯六胺（HSA-PEHA）缀合物和 RX-0201 合成 F-LAN。在体外的 KB 人癌细胞和体内的 KB 鼠异种移植肿瘤模型中评估了纳米粒的药代动力学和抗肿瘤活性。
F-LAN-RX-0201 的平均粒径为 108.6±5.8nm，zeta 电位为 10.5±3.2mV，ASO 载药量为 71.5±4.5%。在 KB 细胞中，F-LAN-RX-0201 的摄取和 Akt1 抑制作用大于非靶向 LAN-RX-0201，并且可以被过量的游离叶酸部分阻断。F-LAN-RX-0201 的细胞生长抑制 IC 为 11.9μM。相比之下，LAN-RX-0201 的细胞毒性较低，IC 为 32.0μM。高达 250μM 的游离 RX-0201 没有观察到明显的细胞毒性。药代动力学研究表明，F-LAN-RX-0201 的终末半衰期长于游离 RX-0201（442 比 219min）。在 KB 异种移植肿瘤模型中，F-LAN-RX-0201 在 16mg/kg 时的肿瘤抑制作用大于 LAN-RX-0201。此外，F-LAN-RX-0201 在 16mg/kg 时的肿瘤抑制作用与游离 RX-0201 在高得多的 90mg/kg 剂量时相当。
F-LAN-RX-0201 有望成为叶酸受体表达升高的肿瘤的治疗药物。
