Next generation gene delivery approaches: recent progress and hurdles.
Next generation gene delivery approaches: recent progress and hurdles.
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DOI：
10.1021/mp5008635
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发表时间：
2015-02
影响因子：
4.9
通讯作者：
D. Pan
中科院分区：
文献类型：
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作者：
D. Pan
这期《分子药剂学》专刊致力于下一代基因递送方法的主题，我们主要关注纳米结构作为安全有效的载体，用于递送包括治疗性多核苷酸在内的生物制剂。功能性DNA序列和RNA干扰（miRNAs、siRNAs等）的空前潜力，基础疗法在临床前已得到很好的确立。在这些治疗性多核苷酸中，功能性DNA序列以包含功能性基因、报道基因和共存的功能性和报道基因的各种质粒的形式使用，以遵循引入正确基因序列（基因治疗）或通过引入可诱导细胞凋亡的基因序列至相关细胞（自杀性基因治疗）的策略，其中MW从较低到较高kb变化。1− 4另一方面，RNAis是调节基因表达的小的非编码RNA，在癌症遗传学中发挥关键作用。随着帮助了解癌细胞中分子和遗传网络的敏感高通量技术的出现，反义药物的作用已被充分确定为靶基因表达的高度特异性抑制剂，以调节癌细胞对治疗策略的反应。5− 8生物制剂的递送受到无数障碍的限制，例如毒性、细胞摄取差、免疫原性、生物分布特征和肾清除率不明确、核酸酶降解、吞噬免疫细胞消除和内体释放差。各种物理和化学技术被用于生物制品的便捷运输。这些技术主要以两种方式占主导地位：使用病毒载体和非病毒载体。病毒颗粒具有渗透到细胞中以便于核酸运输的内在能力，而非病毒颗粒通过物理（电穿孔、基因枪）或化学（利用脂质复合物和聚合复合物）递送方式运输到细胞中。通常，从可以实现高转染效率的观点来看，病毒载体是有利的。然而，它们不能携带大的核酸片段使得它们不适合于许多生物学应用。此外，它们的高诱变潜力和诱导宿主免疫应答的能力是一些其他已知的瓶颈。病毒载体领域由核酸与阳离子脂质（lipoplex）和阳离子聚合物（polyplex）的复合物主导。基于纳米尺寸颗粒的非病毒载体由于其低免疫原性而显示出巨大的前景;然而，相对较低的转染率是一个挑战，必须通过合理设计递送载体来解决。尽管最近取得了进展，但这项技术的成功临床转化将需要大量的额外工作。重要的是要注意，更好地理解交付方法将有助于设计可翻译的平台。理想情况下，这些平台不会受到免疫反应的限制，也不会受到其不令人满意的效率、毒性和缺乏特异性的挑战。生物制剂的体内递送通常由于生物屏障而停滞，例如网状内皮系统（RES）清除、不良靶特异性和低的整体组织/细胞渗透。目前正在作出大量努力，设计和综合更好的输送系统，以克服这些障碍。虽然这些药物中的大多数仍处于临床前阶段，但有些已成功进入临床试验。在正在经历临床阶段的候选生物制剂（基于miRNA）中，LNA修饰的抗miR-122（Santaris...
This special issue of Molecular Pharmaceutics is dedicated to the topic of next generation gene delivery approaches where we mainly focus on the role of nanoarchitectures as safe and efficient carriers for the delivery of biologics including therapeutic polynucleotides. The unprecedented potential of functional DNA sequences and RNAis (miRNAs, siRNAs, etc.) based therapy is well established preclinically. Among these therapeutic polynucleotides, functional DNA sequences are used in the form of various plasmids comprising functional genes, reporter genes, and coexisting functional and reporter genes to follow the strategies of introducing correct gene sequence (gene therapy) or by introducing the gene sequence which can induce apoptosis to the concerned cells (suicidal gene therapy) with MW varying from lower to higher kb. 1− 4 On the other hand RNAis are small noncoding RNAs that regulate gene expression and play key features in cancer genetics. With the advent of sensitive high-throughput technologies to help understand the molecular and genetic network in cancer cells, the role of antisense agents is well established as highly specific inhibitors of the expression of target genes to modulate the response of cancer cells to therapeutic strategies. 5− 8 The delivery of biologics is restricted by countless barriers, such as toxicity, poor cellular uptake, immunogenicity, poorly defined biodistributive characteristics and renal clearance, degradation by nucleases, elimination by phagocytic immune cells, and poor endosomal release. Various physical and chemical techniques are employed for the facile transport of biologics. These techniques are dominated mainly in two ways: using viral vectors and nonviral vectors. Virus particles have intrinsic abilities to penetrate into the cells for the facile transport of nucleic acids, whereas nonviral particulates get transported to the cell by either physical (electroporation, gene gun) or chemical (utilizing lipoplexes and polyplexes) means for delivery. Typically viral vectors are advantageous from the standpoint that high transfection efficiencies can be achieved. However, their inability to carry large nucleic acid fragments makes them unsuitable for many biological applications. Also their high potential for mutagenesis and ability to induce host immune responses are some other known bottlenecks. The field of viral vectors is dominated by complexes of nucleic acids with cationic lipids (lipoplexes) and cationic polymers (polyplexes). Nonviral vectors based on nanometer-sized particles have shown great promise because of their low immunogenicity; however, a relatively lower transfection rate is a challenge that must be addressed through rational design of delivery vectors. 9, 10 Despite recent advances, successful clinical translation of this technology will require a significant amount of additional work. It is important to note that a better understanding of the delivery approaches will help to design translatable platforms. Ideally, these platforms will not be limited by immune responses and would not be challenged by their unsatisfying efficiency, toxicity, and lack of specificity. The delivery of biologics in vivo is usually stalled by biological barriers such as reticuloendothelial system (RES) clearance, poor target specificity, and low overall tissue/cell penetration. Numerous efforts are being devoted to design and synthesize better delivery systems to overcome these obstacles. Although the majority of these agents still remain in the preclinical stage, some have successfully entered clinical trials. Among the candidate biologics (miRNA-based) that are going through clinical phases, LNA-modified-anti-miR-122 (Santaris …