Mohammed-Saeid Waleed, Chitanda Jackson, Al-Dulaymi Mays, Verrall Ronald, Badea Ildiko
Drug Design and Discovery Research Group, College of Pharmacy and Nutrition, University of Saskatchewan, 107 Wiggins Road, Health Sciences Building, Room 3D01.5, Saskatoon, Saskatchewan, S7N 5E5, Canada.
College of Pharmacy, Taibah University, Medina, Saudi Arabia.
Pharm Res. 2017 Sep;34(9):1886-1896. doi: 10.1007/s11095-017-2197-0. Epub 2017 Jun 22.
We have developed and evaluated novel peptide-targeted gemini surfactant-based lipoplexes designed for melanoma gene therapy.
Integrin receptor targeting peptide, cyclic-arginylglycylaspartic acid (cRGD), was either chemically coupled to a gemini surfactant backbone or physically co-formulated with lipoplexes. Several formulations and transfection techniques were developed. Transfection efficiency and cellular toxicity of the lipoplexes were evaluated in an in vitro human melanoma model. Physicochemical properties were examined using dynamic light scattering, zeta-potential, and small-angle X-ray scattering measurements.
RGD-modified gemini surfactant based lipoplexes showed significant enhancement in gene transfection activity in A375 cell lines compared to the standard non-targeted formulation, especially when RGD was chemically conjugated to the gemini surfactant (RGD-G). The RGD had no effect on the cell toxicity profile of the lipoplex systems. Targeting specificity was confirmed by using an excess of free RGD and negative control peptide (RAD) and was demonstrated by using normal human epidermal keratinocytes. Physicochemical characterization showed that all nanoparticles were in the optimal size range for cellular uptake and there were no significant differences between RGD-modified and standard lipoplexes.
These findings indicate the potential of RGD-modified gemini surfactant-based lipoplexes for use in melanoma gene therapy as an alternative to conventional chemotherapy.
我们研发并评估了用于黑色素瘤基因治疗的新型肽靶向 Gemini 表面活性剂基脂质体。
整合素受体靶向肽，环 - 精氨酰甘氨酰天冬氨酸（cRGD），要么化学偶联到 Gemini 表面活性剂主链上，要么与脂质体物理共配制。开发了几种制剂和转染技术。在体外人黑色素瘤模型中评估了脂质体的转染效率和细胞毒性。使用动态光散射、zeta 电位和小角 X 射线散射测量来检查物理化学性质。
与标准非靶向制剂相比，基于 RGD 修饰的 Gemini 表面活性剂的脂质体在 A375 细胞系中显示出基因转染活性的显著增强，特别是当 RGD 化学偶联到 Gemini 表面活性剂（RGD - G）时。RGD 对脂质体系统的细胞毒性特征没有影响。通过使用过量的游离 RGD 和阴性对照肽（RAD）证实了靶向特异性，并通过使用正常人表皮角质形成细胞进行了证明。物理化学表征表明，所有纳米颗粒都处于细胞摄取的最佳尺寸范围内，并且 RGD 修饰的脂质体和标准脂质体之间没有显著差异。
这些发现表明基于 RGD 修饰的 Gemini 表面活性剂的脂质体作为传统化疗的替代物用于黑色素瘤基因治疗的潜力。
