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Nanoparticle depots for controlled and sustained gene delivery.
Journal of Controlled Release ( IF 10.8 ) Pub Date : 2020-03-16 , DOI: 10.1016/j.jconrel.2020.03.021
Zhongyu Li 1 , William Ho 1 , Xin Bai 2 , Fengqiao Li 1 , Yen-Jui Chen 1 , Xue-Qing Zhang 2 , Xiaoyang Xu 3
Affiliation  

Gene therapy is one of the most promising medical fields which holds the potential to rapidly advance the treatment of difficult ailments such as cancer as well as inherited genetic diseases. However, clinical translation is limited by several drug delivery hurdles including renal clearance, phagocytosis, enzymatic degradation, protein absorption, as well as cellular internalization barriers. Additionally, successful treatments require sustained release of drug payloads to maintain the effective therapeutic level. As such, controlled and sustained release is a significant concern as the localization and kinetics of nucleic acid therapeutics can significantly influence the therapeutic efficacy. This is an unmet need which calls for the development of controlled-release nanoparticle (NP) technologies to further improve the gene therapy efficacy by prolonging the release of nucleic acid drug payload for sustained, long-term gene expression or silencing. Herein, we present a polymeric NP system with sustained gene delivery properties, which can be synthesized using biodegradable and biocompatible polymers via self-assembly. The NP delivery system is composed of a polymeric NP which acts as a drug depot encapsulating cationic polymer/nucleic acid complexes, facilitating the enhanced retention and prolonged release of the gene payload. The NPs showed excellent cellular biocompatibility and gene delivery efficacy using the green fluorescent protein (GFP) encoded DNA plasmid (pGFP) as a reporter gene. Sustained release of the pGFP payload was shown over a period of 8 days. The physicochemical properties such as morphology, particle size, zeta potential, pGFP encapsulation efficiency and biological properties such as pGFP release profile, in vitro cytotoxicity and transfection efficacy in Hek 293 cells were characterized and evaluated. Importantly, the NP-mediated sustained release of pGFP generates enhanced GFP expression over time. We expect this NP-mediated gene delivery system to provide safe and sustained release of various nucleic acid-based therapeutics with applications in both fundamental biological studies and clinical translations.



中文翻译:

用于控制和持续基因递送的纳米颗粒贮库。

基因治疗是最有前途的医学领域之一,它具有迅速推进诸如癌症以及遗传性疾病等困难疾病治疗的潜力。但是,临床翻译受到几个药物传递障碍的限制,包括肾脏清除,吞噬作用,酶促降解,蛋白质吸收以及细胞内在化障碍。另外,成功的治疗需要持续释放药物有效载荷以维持有效的治疗水平。因此,由于核酸治疗剂的定位和动力学可显着影响治疗功效,因此控制释放和持续释放是一个重大问题。这是未满足的需求,需要开发控释纳米颗粒(NP)技术,以通过延长核酸药物有效载荷的释放来持续,长期的基因表达或沉默,从而进一步提高基因治疗功效。在本文中,我们提出了具有持续基因传递特性的聚合物NP系统,可以使用可生物降解和生物相容的聚合物通过自组装合成。NP递送系统由聚合物NP组成,其充当封装阳离子聚合物/核酸复合物的药物仓库,促进了基因有效载荷的增强的保留和延长的释放。使用绿色荧光蛋白(GFP)编码的DNA质粒(pGFP)作为报告基因,NP表现出出色的细胞生物相容性和基因传递功效。在8天的时间内显示出pGFP有效负载的持续释放。对Hek 293细胞的理化性质如形态,粒径,ζ电势,pGFP包封效率和生物学性质如pGFP释放曲线,体外细胞毒性和转染功效进行了表征和评估。重要的是,随着时间的流逝,NP介导的pGFP持续释放产生增强的GFP表达。我们希望这种NP介导的基因传递系统能够安全,持续地释放各种基于核酸的治疗药物,并应用于基础生物学研究和临床翻译。对Hek 293细胞的体外细胞毒性和转染功效进行了表征和评估。重要的是,随着时间的流逝,NP介导的pGFP持续释放产生增强的GFP表达。我们希望这种NP介导的基因传递系统能够安全,持续地释放各种基于核酸的治疗药物,并应用于基础生物学研究和临床翻译。对Hek 293细胞的体外细胞毒性和转染功效进行了表征和评估。重要的是,随着时间的流逝,NP介导的pGFP持续释放产生增强的GFP表达。我们希望这种NP介导的基因传递系统能够安全,持续地释放各种基于核酸的疗法,并在基础生物学研究和临床翻译中均得到应用。

更新日期:2020-04-21
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