Third-generation poly(amidoamine) dendrimer (PAMAM) was modified by stepwise primary amine group amidation with d-glucoheptono-1,4-lactone. The physicochemical properties of the conjugates—size, ζ potential in lysosomal pH 5 and in neutral aqueous solutions, as well as intramolecular dynamics by differential scanning calorimetry—were determined. Internalization and toxicity of the conjugates against normal human fibroblasts BJ were monitored in vitro in order to select an appropriate carrier for a drug delivery system. It was found that initial glucoheptoamidation (up to 1/3 of amine groups of neat dendrimers available) resulted in increase of conjugate size and ζ potential. Native or low substituted dendrimer conjugates accumulated efficiently in fibroblast cells at nontoxic 1 µM concentration. Further substitution of dendrimer caused consistent decrease of size and ζ potential, cell accumulation, and toxicity. All dendrimers are amorphous at 36.6 °C as determined by differential scanning calorimetry (DSC). The optimized dendrimer, half-filled with glucoheptoamide substituents, was applied as carrier bearing two covalently attached cytisine molecules: a rigid and hydrophobic alkaloid. The conjugate with 2 cytisine and 16 glucoheptoamide substituents showed fast accumulation and no toxicity up to 200 µM concentration. The half-glucoheptoamidated PAMAM dendrimer was selected as a promising anticancer drug carrier for further applications.

中文翻译：

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聚（酰胺基胺）树状大分子G3的逐步葡庚酰胺化以调节潜在药物载体的理化性质：对胱氨酸结合物的体外测试。

第三代聚（酰胺基胺）树状聚合物（PAMAM）是通过逐步将伯胺基团与d-葡萄糖庚基-1,4-内酯酰胺化而改性的。确定了缀合物的物理化学性质-大小，溶酶体pH 5和中性水溶液中的ζ电位，以及通过差示扫描量热法的分子内动力学。在体外监测缀合物对正常人成纤维细胞BJ的内在化和毒性，以选择用于药物递送系统的合适载体。发现初始的葡萄糖庚酰胺化（最多可使用纯树状聚合物的胺基的1/3）导致缀合物尺寸和ζ电位增加。天然或低取代的树状聚合物结合物在成纤维细胞中以无毒1 µM浓度有效积累。树枝状聚合物的进一步取代引起尺寸和ζ电势，细胞积累和毒性的持续降低。通过差示扫描量热法（DSC）测定，所有树枝状聚合物在36.6°C下均为无定形。最优化的树枝状聚合物半填充了葡萄糖庚酰胺取代基，被用作带有两个共价连接的胞嘧啶分子的载体：刚性和疏水生物碱。具有2个半胱氨酸和16个糖基庚酰胺取代基的缀合物显示出快速积累，在浓度高达200 µM时无毒性。选择了半葡萄糖庚酰胺化的PAMAM树状大分子作为有前途的抗癌药物载体。将半填充葡糖庚酰胺取代基的化合物用作带有两个共价连接的胱氨酸分子的载体：刚性和疏水性生物碱。具有2个胱氨酸和16个糖基庚酰胺取代基的缀合物显示出快速积累，在浓度高达200 µM时无毒性。选择了半葡萄糖庚酰胺化的PAMAM树状大分子作为有前途的抗癌药物载体。将半填充葡糖庚酰胺取代基的化合物用作带有两个共价连接的胱氨酸分子的载体：刚性和疏水性生物碱。具有2个胱氨酸和16个糖基庚酰胺取代基的缀合物显示出快速积累，并且在浓度高达200 µM时没有毒性。选择了半葡萄糖庚酰胺化的PAMAM树状大分子作为有前途的抗癌药物载体。