Bol Guus Martinus, Khan Raheela, Heerma van Voss Marise Rosa, Tantravedi Saritha, Korz Dorian, Kato Yoshinori, Raman Venu
Division of Cancer Imaging Research, The Russell H. Morgan Department of Radiology and Radiological Sciences, The Johns Hopkins University School of Medicine, 720 Rutland Ave, Traylor 340, Baltimore, MD, 21205, USA.
Department of Pathology, University Medical Center Utrecht Cancer Center, 3508 GA, Utrecht, The Netherlands.
Cancer Chemother Pharmacol. 2015 Oct;76(4):821-7. doi: 10.1007/s00280-015-2851-3. Epub 2015 Sep 2.
The DDX3 helicase inhibitor RK-33 is a newly developed anticancer agent that showed promising results in preclinical research (Bol et al. EMBO Mol Med, 7(5):648-649, 2015). However, due to the physicochemical and pharmacological characteristics of RK-33, we initiated development of alternative formulations of RK-33 by preparing sustained release nanoparticles that can be administered intravenously.
In this study, RK-33 was encapsulated in poly(lactic-co-glycolic acid) (PLGA), one of the most well-developed biodegradable polymers, using the emulsion solvent evaporation method.
Hydrodynamic diameter of RK-33-PLGA nanoparticles was about 245 nm with a negative charge, and RK-33-PLGA nanoparticles had a payload of 1.4 % RK-33. RK-33 was released from the PLGA nanoparticles over 7 days (90 ± 5.7 % released by day 7) and exhibited cytotoxicity to human breast carcinoma MCF-7 cells in a time-dependent manner. Moreover, RK-33-PLGA nanoparticles were well tolerated, and systemic retention of RK-33 was markedly improved in normal mice.
PLGA nanoparticles have a potential as a parenteral formulation of RK-33.
DDX3解旋酶抑制剂RK-33是一种新开发的抗癌药物，在临床前研究中显示出有前景的结果（Bol等人，《EMBO分子医学》，7(5):648 - 649，2015年）。然而，由于RK-33的物理化学和药理学特性，我们通过制备可静脉给药的缓释纳米颗粒，启动了RK-33替代制剂的研发。
在本研究中，采用乳液溶剂蒸发法将RK-33包裹于聚乳酸-乙醇酸共聚物（PLGA）中，PLGA是最成熟的可生物降解聚合物之一。
RK-33-PLGA纳米颗粒的流体动力学直径约为245 nm，带负电荷，RK-33-PLGA纳米颗粒的载药量为1.4%的RK-33。RK-33从PLGA纳米颗粒中释放超过7天（到第7天释放90±5.7%），并对人乳腺癌MCF-7细胞呈现出时间依赖性细胞毒性。此外，RK-33-PLGA纳米颗粒耐受性良好，在正常小鼠中RK-33的全身保留率显著提高。
PLGA纳米颗粒有潜力作为RK-33的肠胃外制剂。
