在过去的几年中,基因医学从实验技术发展成为开发各种人类疾病治疗方法的可行策略。许多原型基于DNA的生物药物现在可以通过基因的诱导和/或抑制来控制疾病进展。这些有效的治疗剂包括含有转基因的质粒,寡核苷酸、适体,核酶,DNAzyme,和小干扰RNA。尽管只有2种基于DNA的药物(反义寡核苷酸制剂,Vitravene,(美国,1998),和腺病毒基因治疗治疗,基因医学(中国,2003),已获得监管机构的批准;许多候选人正处于人体临床试验的高级阶段。根据DNA序列和结构选择药物具有降低的潜在毒性,应该会导致更少的副作用,因此最终会产生比目前更安全的药物。这些预测基于此类分子识别其分子靶标的高选择性和特异性。然而,基于DNA的治疗剂的弱细胞摄取和快速体内降解需要使用递送系统以促进细胞内化并保持其活性。这篇综述讨论了结构设计的基础,行动模式,以及基于DNA的疗法的应用。研究了基于DNA的治疗剂的细胞摄取和细胞内运输的机制,并总结了这些运输过程对交付系统选择的限制。最后,讨论了一些目前最有前途的DNA递送平台的开发,并对每种方法的优缺点进行了评价。
The past several years have witnessed the evolution of gene medicine from an experimental technology into a viable strategy for developing therapeutics for a wide range of human disorders. Numerous prototype DNA-based biopharmaceuticals can now control disease progression by induction and/or inhibition of genes. These potent therapeutics include plasmids containing transgenes, oligonucleotides, aptamers, ribozymes, DNAzymes, and small interfering RNAs. Although only 2 DNA-based pharmaceuticals (an antisense oligonucleotide formulation, Vitravene, (USA, 1998), and an adenoviral gene therapy treatment, Gendicine (China, 2003), have received approval from regulatory agencies; numerous candidates are in advanced stages of human clinical trials. Selection of drugs on the basis of DNA sequence and structure has a reduced potential for toxicity, should result in fewer side effects, and therefore should eventually yield safer drugs than those currently available. These predictions are based on the high selectivity and specificity of such molecules for recognition of their molecular targets. However, poor cellular uptake and rapid in vivo degradation of DNA-based therapeutics necessitate the use of delivery systems to facilitate cellular internalization and preserve their activity. This
review discusses the basis of structural design, mode of action, and applications of DNA-based therapeutics. The mechanisms of cellular uptake and intracellular trafficking of DNA-based therapeutics are examined, and the constraints these transport processes impose on the choice of delivery systems are summarized. Finally, the development of some of the most promising currently available DNA delivery platforms is discussed, and the merits and drawbacks of each approach are evaluated.