Lower Rim Guanidinocalix[4]arenes: Macrocyclic Nonviral Vectors for Cell Transfection
Lower Rim Guanidinocalix[4]arenes: Macrocyclic Nonviral Vectors for Cell Transfection
复制标题
DOI：
10.1021/bc2006829
复制
发表时间：
2012-05-01
影响因子：
4.7
通讯作者：
Ungaro, Rocco
中科院分区：
文献类型：
--
作者：
Bagnacani, Valentina;Franceschi, Valentina;Ungaro, Rocco
在杯[4]芳烃的锥形构象下，通过间隔区引入胍基，得到了新的潜在的非病毒基因载体。探索了几种结构修饰，例如大环支架的存在或不存在、骨架的亲油性、间隔子的长度和带电基团的性质，以便更好地理解影响这些衍生物的DNA缩合能力和转染效率的因素。最令人感兴趣的化合物是杯[4]芳烃，其上边缘未被取代，并且具有通过三个碳原子间隔物在下边缘连接的四个胍基。当与DOPE一起配制时，该化合物在治疗人横纹肌肉瘤和Vero细胞中显示出低毒性和高于市售的lipofectamine LTX的转染效率。大多数研究的化合物显示出在纯水中或在盐的存在下自聚集的趋势，如通过NMR和AFM研究所证明的，并且发现在纳米球中凝聚DNA质粒的能力是转染的必要但不是充分条件。大环载体的线性Gemini型类似物和胍相比，其他铵头组在确定载体的生物活性的优越性也被确定。
Guanidinium groups were introduced through a spacer at the lower rim of calix[4]arenes in the cone conformation to give new potential nonviral vectors for gene delivery. Several structural modifications were explored, such as the presence or absence of a macrocyclic scaffold, lipophilicity of the backbone, length of the spacer, and nature of the charged groups, in order to better understand the factors which affect the DNA condensation ability and transfection efficiency of these derivatives. The most interesting compound was a calix[4]arene unsubstituted at the upper rim and having four guanidinium groups linked at the lower rim through a three carbon atom spacer. This compound, when formulated with DOPE, showed low toxicity and transfection efficiency higher than the commercially available lipofectamine LTX in the treatment of human Rhabdomiosarcoma and Vero cells. Most of the investigated compounds showed a tendency to self-aggregate in pure water or in the presence of salts, as evidenced by NMR and AFM studies, and it was found that the ability to condense DNA plasmids in nanometric globules is a necessary but not sufficient condition for transfection. The superiority of macrocyclic vectors over linear Gemini-type analogues and of guanidinium compared to other ammonium head groups in determining the biological activity of the vectors was also ascertained.