Department of Experimental Therapeutics, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030-4009, USA.
J Intern Med. 2010 Jan;267(1):44-53. doi: 10.1111/j.1365-2796.2009.02191.x.
Small interfering RNA (siRNA) technology holds great promise as a therapeutic intervention for targeted gene silencing in cancer and other diseases. However, in vivo systemic delivery of siRNA-based therapeutics to tumour tissues/cells remains a challenge. The major limitations against the use of siRNA as a therapeutic tool are its degradation by serum nucleases, poor cellular uptake and rapid renal clearance following systemic administration. Several siRNA-based loco-regional therapeutics are already in clinical trials. Further development of siRNAs for anti-cancer therapy depends on the development of safe and effective nanocarriers for systemic administration. To overcome these hurdles, nuclease-resistant chemically modified siRNAs and variety of synthetic and natural biodegradable lipids and polymers have been developed to systemically deliver siRNA with different efficacy and safety profiles. Cationic liposomes have emerged as one of the most attractive carriers because of their ability to form complexes with negatively charged siRNA and high in vitro transfection efficiency. However, their effectiveness as potential therapeutic carriers is limited by potential for pulmonary toxicity. Recently, our laboratories described the use of neutral 1,2-dioleoyl-sn-glycero-3-phosphatidylcholine based nanoliposomes in murine tumour models. We found this approach to be safe and 10- and 30-fold more effective than cationic liposomes and naked siRNA, respectively, for systemic delivery of siRNA into tumour tissues. Here, we review potential approaches for systemic delivery of siRNA for cancer therapy.
小干扰 RNA（siRNA）技术作为一种治疗性干预手段，在癌症和其他疾病的靶向基因沉默方面具有巨大的应用前景。然而，将基于 siRNA 的治疗剂系统地递送到肿瘤组织/细胞中仍然是一个挑战。将 siRNA 用作治疗工具的主要限制是其在血清核酸酶中的降解、细胞摄取能力差以及全身给药后快速肾清除。几种基于 siRNA 的局部治疗方法已经在临床试验中。进一步开发用于癌症治疗的 siRNA 取决于安全有效的纳米载体的开发，以便进行全身给药。为了克服这些障碍，已经开发了耐核酸酶的化学修饰 siRNA 以及各种合成和天然可生物降解的脂质和聚合物，以具有不同疗效和安全性的特征来系统地递送 siRNA。阳离子脂质体因其能够与带负电荷的 siRNA 形成复合物以及具有高体外转染效率而成为最有吸引力的载体之一。然而，它们作为潜在治疗载体的有效性受到潜在的肺毒性的限制。最近，我们实验室在小鼠肿瘤模型中描述了使用中性 1,2-二油酰基-sn-甘油-3-磷酸胆碱基纳米脂质体的方法。我们发现，与阳离子脂质体和裸 siRNA 相比，这种方法在将 siRNA 系统递送到肿瘤组织中的安全性分别提高了 10 倍和 30 倍。在这里，我们综述了用于癌症治疗的 siRNA 系统递送的潜在方法。
