Abstract：
To overcome the biological barriers in the journey of systemic gene delivery, a multifaceted genomic synthetic nanomedicine was elaborated and strategically equipped with a multiple of intriguing responsiveness. Particularly, core-shell plasmid DNA condensates were created based on polyionic complexation with block copolymer of polyethylene glycol (PEG)-polylysine (PLys), namely, the nanoscaled PLys&pDNA nanoparticle tethered with the biocompatible PEG surroundings. Furthermore, redox-reversible disulfide crosslinking was introduced into PLys&pDNA nanoparticle to accomplish adequate structural stabilities, and thermal-responsive polypropylacrylamide (PNIPAM) was introduced as the secondary intermediate surroundings onto the pre-formulated PLys&pDNA nanoparticle with the aim of preventing the potential enzymatic degradation from the environmental nucleases. Hence, hundreds of times prolonged survival and retention was determined in pertinent to the blood circulation properties. Additionally, the installation of a guide ligand at the distal end of PEG segments was proposed to encourage selective tumor uptake. A linear peptide of GPLGVRG, which is selectively susceptible to digestion by the tumor-enriched matrix metalloproteinase 2 (MMP-2), was used as the linkage between the shell and core. This peptide has been shown to detach the bio-inert PEGylation, resulting in further facilitated cell endocytosis and intracellular trafficking activities. Hence, the precisely defined synthetic nanomedicine, which exhibits desirable characteristics, efficient expression of the therapeutic gene in the affected cells, and contributed to potent therapeutic efficacy in systemic treatment of intractable tumors by encapsulating the anti-angiogenic gene.
摘要：
为了克服系统性基因传递过程中的生物障碍，一个多方面的基因组合成纳米医学被精心设计和战略配备了多个有趣的反应能力。特别是,基于与聚乙二醇（PEG）-聚赖氨酸（PLys）的嵌段共聚物的聚离子络合，创建了核-壳质粒DNA缩合物，即,纳米级PLys和pDNA纳米颗粒与生物相容性PEG环境相连。此外，将氧化还原可逆的二硫化物交联引入PLys和pDNA纳米颗粒中，以实现足够的结构稳定性，将热响应性聚丙基丙烯酰胺(PNIPAM)作为第二中间体环境引入到预先配制的PLys&pDNA纳米颗粒上,目的是防止来自环境核酸酶的潜在酶降解。因此，与血液循环特性相关的数百倍延长的存活和保留时间被确定。此外,建议在PEG片段的远端安装引导配体以促进选择性肿瘤摄取.GPLGVRG的线性肽，它对富含肿瘤的基质金属蛋白酶2（MMP-2）的消化有选择性敏感性，用作壳和核之间的连接。该肽已被证明可以分离生物惰性聚乙二醇化，导致进一步促进细胞内吞和细胞内运输活动。因此，精确定义的合成纳米药物，表现出理想的特征，在受影响的细胞中有效表达治疗基因，并通过封装抗血管生成基因在难治性肿瘤的全身治疗中发挥了有效的治疗效果。
