Zhang Chuanbo, Newsome Joseph T, Mewani Rajshree, Pei Jin, Gokhale Prafulla C, Kasid Usha N
Departments of Radiation Medicine and Biochemistry, Molecular and Cellular Biology, Georgetown University Medical Center, Washington D.C. 20057, USA.
Methods Mol Biol. 2009;480:65-83. doi: 10.1007/978-1-59745-429-2_5.
By virtue of their potential to selectively silence oncogenic molecules in cancer cells, antisense oligonucleotides (ASO) and small interfering RNAs (siRNAs) are powerful tools for development of tailored anti-cancer drugs. The clinical benefit of ASO/siRNA therapeutic is, however, hampered due to poor pharmacokinetics and biodistribution, and suboptimal suppression of the target in tumor tissues. Raf-1 protein serine/threonine kinase is a druggable signaling molecule in cancer therapy. Our laboratory has developed cationic liposomes for systemic delivery of raf ASO (LErafAON) and raf siRNA (LErafsiRNA) to human tumor xenografts grown in athymic mice. LErafAON is also the first ASO containing liposomal drug tested in humans. In this article, we primarily focus on a modified formulation of systemically delivered cationic liposomes containing raf antisense oligonucleotide (md-LErafAON). The cationic liposomes were prepared using dimyristoyl 1,2-diacyl-3-trimethylammonium-propane (DMTAP), phosphatidylcholine (PC), and cholesterol (CHOL). The toxicology, pharmacokinetics, biodistribution, target selectivity, and anti-tumor efficacy studies of md-LErafAON were conducted in mice. We demonstrate that md-LErafAON is the next generation of systemically delivered and well-tolerated antisense therapeutic suitable for clinical evaluation.
凭借其在癌细胞中选择性沉默致癌分子的潜力，反义寡核苷酸（ASO）和小干扰RNA（siRNA）是开发定制抗癌药物的有力工具。然而，由于药代动力学和生物分布不佳以及肿瘤组织中对靶点的抑制效果欠佳，ASO/siRNA治疗的临床益处受到阻碍。Raf-1蛋白丝氨酸/苏氨酸激酶是癌症治疗中一种可成药的信号分子。我们实验室已开发出阳离子脂质体，用于将raf ASO（LErafAON）和raf siRNA（LErafsiRNA）全身递送至无胸腺小鼠体内生长的人肿瘤异种移植模型。LErafAON也是首个在人体中进行测试的含脂质体药物的ASO。在本文中，我们主要聚焦于一种经改良的、全身递送的含raf反义寡核苷酸的阳离子脂质体配方（md-LErafAON）。阳离子脂质体是使用二肉豆蔻酰基1,2 - 二酰基 - 3 - 三甲基铵丙烷（DMTAP）、磷脂酰胆碱（PC）和胆固醇（CHOL）制备的。在小鼠中进行了md-LErafAON的毒理学、药代动力学、生物分布、靶点选择性和抗肿瘤疗效研究。我们证明md-LErafAON是适合临床评估的下一代全身递送且耐受性良好的反义治疗药物。
