Key Laboratory of Drug Targeting and Drug Delivery Systems, Ministry of Education, West China School of Pharmacy, Sichuan University, Chengdu 610041, Sichuan, PR China.
Biomaterials. 2013 Apr;34(12):3020-30. doi: 10.1016/j.biomaterials.2012.12.051. Epub 2013 Jan 27.
Limitations of adenoviral (Ad) vectors for cancer gene therapy could be overcome by their combination with pharmaceutical technologies. Here we show that an enzyme-responsive liposomal formulation could significantly enhance the tumor cell transduction abilities and reduce the immunogenicity of Ad vectors. In the current research, the enzymatically cleavable PEG-lipids composed of a PEG/matrix metalloproteinase (MMP)-substrate peptide/cholesterol (PPC) were synthesized and characterized by (1)H NMR and TOF MS ES(+). The obtained MMP-cleavable lipids were inserted into the anionic liposomal Ad vectors (AL-Ad) by the post-insertion method. The results of in vitro infection assays indicated that the enzymatically cleavable formulation (PPC-AL-Ad) displayed a much higher gene expression than naked Ad5 and the non-cleavable PEG-lipid modified Ad vectors in tumor cells. More importantly, PPC-AL-Ad induces a lower production of neutralizing antibody and lower innate immune response, as well as significantly reduced liver toxicity in vivo. These findings suggest that PPC-AL-Ad is a promising system for gene delivery in tumor therapy.
腺病毒 (Ad) 载体在癌症基因治疗中的局限性可以通过与制药技术相结合来克服。在这里，我们展示了一种酶响应脂质体制剂可以显著提高肿瘤细胞转导能力并降低 Ad 载体的免疫原性。在目前的研究中，合成了由聚乙二醇/基质金属蛋白酶 (MMP)-底物肽/胆固醇 (PPC) 组成的酶切可裂解的 PEG 脂质，并通过 1H NMR 和 TOF MS ES(+)进行了表征。通过后插入法将所得 MMP 可裂解脂质插入阴离子脂质体 Ad 载体 (AL-Ad) 中。体外感染实验结果表明，酶切制剂 (PPC-AL-Ad) 在肿瘤细胞中的基因表达明显高于裸 Ad5 和不可裂解的 PEG 脂质修饰的 Ad 载体。更重要的是，PPC-AL-Ad 诱导产生的中和抗体和先天免疫反应较低，体内肝毒性也显著降低。这些发现表明，PPC-AL-Ad 是肿瘤治疗中基因传递的一种有前途的系统。
