Ozpolat Bulent, Sood Anil K, Lopez-Berestein Gabriel
Departments of Experimental Therapeutics, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA; Center for RNA Interference and Non-Coding RNA, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA.
Gynecologic Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA; Cancer Biology, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA; Center for RNA Interference and Non-Coding RNA, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA.
Adv Drug Deliv Rev. 2014 Feb;66:110-6. doi: 10.1016/j.addr.2013.12.008. Epub 2013 Dec 30.
Small interfering RNAs (siRNA) have recently emerged as a new class of therapeutics with a great potential to revolutionize the treatment of cancer and other diseases. A specifically designed siRNA binds and induces post-transcriptional silencing of target genes (mRNA). Clinical applications of siRNA-based therapeutics have been limited by their rapid degradation, poor cellular uptake, and rapid renal clearance following systemic administration. A variety of synthetic and natural nanoparticles composed of lipids, polymers, and metals have been developed for siRNA delivery, with different efficacy and safety profiles. Liposomal nanoparticles have proven effective in delivering siRNA into tumor tissues by improving stability and bioavailability. While providing high transfection efficiency and a capacity to form complexes with negatively charged siRNA, cationic lipids/liposomes are highly toxic. Negatively charged liposomes, on the other hand, are rapidly cleared from circulation. To overcome these problems we developed highly safe and effective neutral lipid-based nanoliposomes that provide robust gene silencing in tumors following systemic (intravenous) administration. This delivery system demonstrated remarkable antitumor efficacy in various orthotopic human cancer models in animals. Here, we briefly overview this and other lipid-based approaches with preclinical applications in different tumor models for cancer therapy and potential applications as siRNA-nanotherapeutics in human cancers.
小干扰RNA（siRNA）最近已成为一类新型治疗药物，极有可能彻底改变癌症和其他疾病的治疗方式。经过特殊设计的siRNA会结合并诱导靶基因（mRNA）的转录后沉默。基于siRNA的治疗药物的临床应用受到其快速降解、细胞摄取不佳以及全身给药后经肾脏快速清除的限制。为了递送siRNA，人们开发了多种由脂质、聚合物和金属组成的合成和天然纳米颗粒，它们具有不同的功效和安全性。脂质体纳米颗粒已被证明可通过提高稳定性和生物利用度，有效地将siRNA递送至肿瘤组织。虽然阳离子脂质/脂质体具有高转染效率以及与带负电荷的siRNA形成复合物的能力，但毒性很强。另一方面，带负电荷的脂质体在循环中会被迅速清除。为了克服这些问题，我们开发了高度安全有效的基于中性脂质的纳米脂质体，在全身（静脉）给药后能在肿瘤中实现强大的基因沉默。该递送系统在动物的各种原位人类癌症模型中显示出显著的抗肿瘤疗效。在此，我们简要概述这种以及其他基于脂质的方法，它们在不同肿瘤模型的癌症治疗临床前应用以及作为人类癌症中siRNA纳米治疗药物的潜在应用。
