a Assiut International Center of Nanomedicine , Al-Rajhy Liver Hospital, Assiut University , Assiut , Egypt.
b Department of Surgery, Faculty of Medicine , Assiut University , Assiut , Egypt.
Pharm Dev Technol. 2018 Apr;23(4):387-399. doi: 10.1080/10837450.2017.1312443. Epub 2017 Apr 7.
Nucleic acids therapeutic efficiency is generally limited by their low stability and intracellular bioavailability, and by the toxicity of the carriers used to deliver them to the target sites. Aminated poly(glycerol methacrylate) polymers are biodegradable and pH-sensitive polymers that have been used previously to deliver antisense oligonucleotide and show high transfection efficiency. The purpose of this study is to compare the efficiency and toxicity of aminated linear poly(glycerol methacrylate) (ALT) biodegradable polymer to the most commonly used cationic degradable (i.e. chitosan) and non-degradable (i.e. polyethylenimine (PEI)) polymers for delivery of short interfering RNA (siRNA). ALT, PEI and chitosan polymers were able to form nanosized particles with siRNA. Size, size-distribution and zeta-potential were measured over a wide range of nitrogen-to-phosphate (N/P) ratios, and the stability of the formed nanoparticles in saline and upon freeze-drying was also assessed. No significant cytotoxicity at the range of the tested concentrations of ALT and chitosan nanoparticles was observed, whereas the non-degradable PEI showed significant toxicity in huh-7 hepatocyte-derived carcinoma cell line. The safety profiles of the degradable polymers (ALT and chitosan) over non-degradable PEI were demonstrated in vitro and in vivo. In addition, ALT nanoparticles were able to deliver siRNA in vivo with significantly higher efficiency than chitosan nanoparticles. The results in the present study give evidence of the great implications of ALT nanoparticles in biomedical applications due to their biocompatibility, low cytotoxicity, high stability and simple preparation method.
核酸治疗的效率通常受到其低稳定性和细胞内生物利用度的限制，以及用于将其递送到靶部位的载体的毒性的限制。氨基化聚（甘油甲基丙烯酸酯）聚合物是可生物降解和 pH 敏感的聚合物，以前曾用于递送反义寡核苷酸，并显示出高转染效率。本研究的目的是比较氨基化线性聚（甘油甲基丙烯酸酯）（ALT）可生物降解聚合物与最常用的阳离子可降解（即壳聚糖）和不可降解（即聚乙烯亚胺（PEI））聚合物在递送短干扰 RNA（siRNA）方面的效率和毒性。ALT、PEI 和壳聚糖聚合物能够与 siRNA 形成纳米级颗粒。在广泛的氮-磷（N/P）比范围内测量了粒径、粒径分布和 zeta 电位，并评估了形成的纳米颗粒在盐水中和冷冻干燥时的稳定性。在测试浓度范围内，ALT 和壳聚糖纳米颗粒没有观察到明显的细胞毒性，而不可降解的 PEI 在 huh-7 肝癌衍生癌细胞系中表现出明显的毒性。可降解聚合物（ALT 和壳聚糖）在体外和体内的安全性概况均优于不可降解的 PEI。此外，ALT 纳米颗粒能够在体内以比壳聚糖纳米颗粒更高的效率递送 siRNA。本研究的结果证明了 ALT 纳米颗粒在生物医学应用中的重要意义，因为它们具有生物相容性、低细胞毒性、高稳定性和简单的制备方法。
