Ramesh Rajagopal
Department of Thoracic and Cardiovascular Surgery, The University of Texas M.D.Anderson Cancer Center, Houston, TX, USA.
Methods Mol Biol. 2008;433:301-31. doi: 10.1007/978-1-59745-237-3_19.
Drug delivery, especially gene delivery to the lung, has been a challenge. Numerous gene delivery systems to the lung have been developed and tested in preclinical studies. However, only a few of them have been successfully tested in the clinic and shown promise. The reasons for failure to translate preclinical findings into clinical setting include inefficient gene delivery, toxicity, stability, and other factors related to scaling and manufacturing of the gene delivery vehicle. Therefore, there is a need for developing and testing of new gene delivery systems that can overcome some of the existing limitations. Preclinical studies from our laboratory using a cationic lipid (1,2-Dioleoyl-3-Trimethylammonium-Propane (DOTAP):cholesterol)-based nanoparticle have shown efficient and effective gene delivery to the lung especially to tumor-bearing lungs of mice. Based on the efficacy and toxicity studies observed in preclinical studies, we have recently initiated a Phase I clinical trial for systemic treatment of non-small cell lung cancer (NSCLC). In this clinical trial, a tumor suppressor gene encapsulated in the lipid-based nanoparticle will be delivered intravenously to determine the maximum-tolerated dose (MTD). The results from this clinical trial will provide a basis for conducting subsequent Phase II trial that will focus on determining toxicity and therapeutic efficacy. In this chapter, the details for the synthesis and testing of the lipid-based nanoparticle for systemic gene delivery to the lung with emphasis on lung cancer is provided.
药物递送，尤其是基因递送至肺部，一直是一项挑战。众多用于肺部的基因递送系统已在临床前研究中得到开发和测试。然而，其中只有少数在临床试验中成功进行了测试并显示出前景。临床前研究结果未能转化为临床应用的原因包括基因递送效率低下、毒性、稳定性以及与基因递送载体的放大和制造相关的其他因素。因此，需要开发和测试能够克服一些现有局限性的新基因递送系统。我们实验室使用基于阳离子脂质（1,2-二油酰基-3-三甲基铵丙烷（DOTAP）：胆固醇）的纳米颗粒进行的临床前研究表明，该纳米颗粒能够高效且有效地将基因递送至肺部，尤其是递送至荷瘤小鼠的肺部。基于临床前研究中观察到的疗效和毒性研究，我们最近启动了一项用于非小细胞肺癌（NSCLC）全身治疗的I期临床试验。在该临床试验中，封装在脂质纳米颗粒中的肿瘤抑制基因将通过静脉注射给药，以确定最大耐受剂量（MTD）。该临床试验的结果将为后续II期试验提供基础，后续试验将专注于确定毒性和治疗效果。在本章中，将详细介绍用于肺部全身基因递送（重点是肺癌）的脂质纳米颗粒的合成和测试。
