Institute of Pharmaceutics, College of Pharmaceutical Sciences , Zhejiang University , Hangzhou 310058 , China.
Center for Bionanoengineering and Key Laboratory of Biomass Chemical Engineering of the Ministry of Education, College of Chemical and Biological Engineering , Zhejiang University , Hangzhou 310027 , China.
Biomacromolecules. 2018 Jun 11;19(6):2308-2319. doi: 10.1021/acs.biomac.8b00440. Epub 2018 May 17.
Gene therapy has demonstrated effectiveness in many genetic diseases, as evidenced by recent clinical applications. Viral vectors have been extensively tested in clinical gene-therapy trials, but nonviral vectors such as cationic polymers or lipids are much less used due to their lower gene-transfection efficiencies. However, the advantages of nonviral vectors, such as easily tailored structures, nonimmunogenetics, and relatively low cost, still drive great efforts to improve their transfection efficiencies. A reverse question asks if nonviral vectors with current gene transfection efficiency can find application niches. Herein, we synthesized a cationic polymer, poly{ N-[2-(acryloyloxy)ethyl]- N-[ p-acetyloxyphenyl]- N, N-diethylammonium chloride} (PQDEA), as a gene-delivery carrier and compared it side by side with chemotherapy drugs for cancer treatment. PQDEA is rapidly hydrolyzed by intracellular esterases into anionic poly(acrylic acid) to give low cytotoxicity and fast release of DNA for expression. PQDEA formed stable complexes with DNA (PQDEA/DNA polyplexes), which were further coated with a lipid layer to make serum-stable lipidic polyplexes, LPQDEA/DNAs, for in vivo use. In an intraperitoneal tumor xenograft model mimicking late-stage metastatic cervical cancer, the LPQDEA/DNA vector with TRAIL suicide gene exerted strong tumor inhibition as effective as paclitaxel, the first-line anticancer drug, but gave much less tumor relapse and much longer survival than the clinical chemotherapy drugs, irinotecan and paclitaxel. Equally important, the gene therapy showed much fewer adverse effects than the chemotherapy drugs. This work shows that nonviral vectors with current transfection efficiencies may produce therapeutic advantages and may be safe and worthy of clinical translation in, for example, intraperitoneal cancer therapy.
基因治疗在许多遗传疾病中已被证明具有疗效，最近的临床应用也证明了这一点。病毒载体在临床基因治疗试验中得到了广泛的测试，但由于其基因转染效率较低，非病毒载体（如阳离子聚合物或脂质）的应用较少。然而，非病毒载体的优势，如易于定制的结构、非免疫遗传学和相对较低的成本，仍然促使人们努力提高其转染效率。一个相反的问题是，目前具有基因转染效率的非病毒载体是否能找到应用的切入点。在此，我们合成了一种阳离子聚合物，聚{ N-[2-(丙烯酰氧基)乙基]- N-[对乙酰氧基苯基]- N, N-二乙基氯化铵}（PQDEA），作为基因传递载体，并将其与化疗药物治疗癌症进行了平行比较。PQDEA 被细胞内酯酶迅速水解成阴离子聚（丙烯酸），从而产生低细胞毒性和快速释放 DNA 进行表达。PQDEA 与 DNA 形成稳定的复合物（PQDEA/DNA 多聚物），然后进一步用脂质层包覆，制成血清稳定的脂质多聚物 LPQDEA/DNAs，用于体内使用。在模拟晚期转移性宫颈癌的腹腔肿瘤异种移植模型中，携带 TRAIL 自杀基因的 LPQDEA/DNA 载体与一线抗癌药物紫杉醇一样具有强烈的肿瘤抑制作用，但肿瘤复发率和存活率均明显低于临床化疗药物伊立替康和紫杉醇。同样重要的是，基因治疗比化疗药物产生的副作用要少得多。这项工作表明，目前具有转染效率的非病毒载体可能具有治疗优势，并且在腹腔内癌症治疗等方面可能是安全且值得临床转化的。
