明胶—硅氧烷纳米颗粒作为基因载体的应用
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摘要
基因治疗的主要目的是研制安全有效的基因转染载体。在基因转染载体中,非病毒载体以其低毒性、低免疫原性、低致瘤性及易于制备等优点具有良好的应用前景。本文以新型有机-无机杂化材料——明胶.硅氧烷纳米颗粒作为基础,探讨了此种材料的合成机制,将其应用于基因治疗,并以活性多肽修饰表面增强功能性。取得的主要成果有:
1.以明胶、GPSM和氨水作为反应物,或以明胶、GPSM和APTMS作为反应物,通过溶胶.凝胶法,制得两种阳离子明胶.硅氧烷颗粒。探讨了两种纳米颗粒的合成机制,探索了一种全新材料的合成和表征方法。
2.利用明胶.硅氧烷纳米颗粒与质粒DNA的相互作用,系统地研究了明胶-硅氧烷纳米颗作为基因载体的理化性质。纳米颗粒/DNA复合物,能够稳定存在于血清、核酸酶DNaseⅠ、弱酸性和中性的环境中,对DNA具有很好的保护作用,是优良的非病毒基因载体。
3.从提高明胶.硅氧烷纳米颗粒的转染效率的角度出发,借助Tat多肽,对纳米颗粒表面进行修饰,系统地考察了多肽-明胶-硅氧烷载体作为非病毒载体的潜力。多肽修饰后的纳米颗粒,表面电位升高,纳米颗粒/DNA复合物,能够稳定存在于血清、核酸酶DNaseⅠ、弱酸性和中性的环境中,对DNA具有很好的保护作用,具有进行基因转染的巨大潜力。
The main objective in gene therapy is the development of efficient, non-toxic gene carriers. Non-viral vectors provide opportunities for improved lower toxicity, non-pathogenic and more facile manufacturing. In this work, the new hybrid nanoparticles with organic-inorganic contents of gelatin and siloxane were successfully synthesized. We described the synthesis of gelatin-siloxane nanoparticles and tested these vectors based on those NPs as vectors for gene therapy. The main results are as follows:
1. Preparing gelatin-siloxane nanoparticles by a sol-gel process in gelatin, GPSM, ammonia system or gelatin, GPSM, APTMS system. The synthetic scheme was also studied.
2. A systemic study of nanoparticles/DNA complexes in gene therapy was conducted. The complexes with nanosized diameters could protect DNA from digestion in phosphate buffer solution (pH 7.0 and pH 6.0), serum and DNase I solution.
3. The strategic to improve transfection ability of gelatin-siloxane nanoparticles comprise functionalizing the surface of the NPs with biofunctional peptide. A systemic study of peptide-NPs/DNA complexes in gene therapy was conducted. The peptide-NPs with higher surface charges and nanosized diameters could protect DNA from digestion in phosphate buffer solution (pH 7.0 and pH 6.0), serum and DNase I solution.
1.以明胶、GPSM和氨水作为反应物,或以明胶、GPSM和APTMS作为反应物,通过溶胶.凝胶法,制得两种阳离子明胶.硅氧烷颗粒。探讨了两种纳米颗粒的合成机制,探索了一种全新材料的合成和表征方法。
2.利用明胶.硅氧烷纳米颗粒与质粒DNA的相互作用,系统地研究了明胶-硅氧烷纳米颗作为基因载体的理化性质。纳米颗粒/DNA复合物,能够稳定存在于血清、核酸酶DNaseⅠ、弱酸性和中性的环境中,对DNA具有很好的保护作用,是优良的非病毒基因载体。
3.从提高明胶.硅氧烷纳米颗粒的转染效率的角度出发,借助Tat多肽,对纳米颗粒表面进行修饰,系统地考察了多肽-明胶-硅氧烷载体作为非病毒载体的潜力。多肽修饰后的纳米颗粒,表面电位升高,纳米颗粒/DNA复合物,能够稳定存在于血清、核酸酶DNaseⅠ、弱酸性和中性的环境中,对DNA具有很好的保护作用,具有进行基因转染的巨大潜力。
The main objective in gene therapy is the development of efficient, non-toxic gene carriers. Non-viral vectors provide opportunities for improved lower toxicity, non-pathogenic and more facile manufacturing. In this work, the new hybrid nanoparticles with organic-inorganic contents of gelatin and siloxane were successfully synthesized. We described the synthesis of gelatin-siloxane nanoparticles and tested these vectors based on those NPs as vectors for gene therapy. The main results are as follows:
1. Preparing gelatin-siloxane nanoparticles by a sol-gel process in gelatin, GPSM, ammonia system or gelatin, GPSM, APTMS system. The synthetic scheme was also studied.
2. A systemic study of nanoparticles/DNA complexes in gene therapy was conducted. The complexes with nanosized diameters could protect DNA from digestion in phosphate buffer solution (pH 7.0 and pH 6.0), serum and DNase I solution.
3. The strategic to improve transfection ability of gelatin-siloxane nanoparticles comprise functionalizing the surface of the NPs with biofunctional peptide. A systemic study of peptide-NPs/DNA complexes in gene therapy was conducted. The peptide-NPs with higher surface charges and nanosized diameters could protect DNA from digestion in phosphate buffer solution (pH 7.0 and pH 6.0), serum and DNase I solution.
引文
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