Department of Biopharmaceutics, Kyoto Pharmaceutical University, Kyoto 607-8414, Japan.
J Pharm Sci. 2011 May;100(5):1866-78. doi: 10.1002/jps.22428. Epub 2010 Dec 28.
The absorption-enhancing effects of polyamidoamine (PAMAM) dendrimers with various generations (G0-G3) and concentrations [0.1%-1.0% (w/v)] on the pulmonary absorption of peptide and protein drugs were studied in rats. Insulin and calcitonin were chosen as models of peptide and protein drugs, and their pulmonary absorption with or without PAMAM dendrimers was examined by in vivo pulmonary absorption studies. PAMAM dendrimers significantly increased the pulmonary absorption of insulin and calcitonin in rats, and their absorption-enhancing effects were generation dependent. The rank order of absorption enhancement effect of these PAMAM dendrimers was G3 > G2 > G1 > G0. For the same generation, the absorption-enhancing effects of PAMAM dendrimers were shown to be concentration dependent. The toxicity of these PAMAM dendrimers in the lung tissues was evaluated by measuring the release of protein and the activities of lactate dehydrogenase (LDH) in bronchoalveolar lavage fluid (BALF). The PAMAM dendrimers with various generations and concentrations did not significantly increase the release of protein and the activities of LDH in BALF, indicating that these dendrimers did not cause any membrane damage to the lung tissues. The zeta potentials of insulin and calcitonin solutions changed to positive by the addition of PAMAM dendrimers, and the degree of positive charge as determined by the zeta potentials was linearly correlated with the absorption-enhancing effects of the PAMAM dendrimers. This positive charge of the PAMAM dendrimers might be related to their absorption-enhancing mechanisms for improving the pulmonary absorption of insulin and calcitonin in rats. In conclusion, the PAMAM dendrimers are suitable absorption enhancers to improve the pulmonary absorption of insulin and calcitonin without any membrane damage to the respiratory tissues.
聚酰胺-胺（PAMAM）树枝状聚合物的各代数（G0-G3）和浓度[0.1%-1.0%（w/v）]对肽类和蛋白质类药物在肺部的吸收增强作用在大鼠中进行了研究。选择胰岛素和降钙素作为肽类和蛋白质类药物的模型，通过体内肺部吸收研究考察了有无 PAMAM 树枝状聚合物时它们的肺部吸收情况。PAMAM 树枝状聚合物显著增加了胰岛素和降钙素在大鼠肺部的吸收，且其吸收增强作用具有代际依赖性。这些 PAMAM 树枝状聚合物的吸收增强效果的顺序为 G3>G2>G1>G0。对于相同的代际，PAMAM 树枝状聚合物的吸收增强效果呈现浓度依赖性。通过测量支气管肺泡灌洗液（BALF）中蛋白质的释放和乳酸脱氢酶（LDH）的活性来评估这些 PAMAM 树枝状聚合物在肺组织中的毒性。不同代际和浓度的 PAMAM 树枝状聚合物并未显著增加 BALF 中蛋白质的释放和 LDH 的活性，表明这些树枝状聚合物未对肺组织造成任何膜损伤。胰岛素和降钙素溶液的 ζ 电位因添加 PAMAM 树枝状聚合物而变为正，ζ 电位确定的正电荷量与 PAMAM 树枝状聚合物的吸收增强效果呈线性相关。这些 PAMAM 树枝状聚合物的正电荷可能与其吸收增强机制有关，该机制可改善胰岛素和降钙素在大鼠肺部的吸收。总之，PAMAM 树枝状聚合物是合适的吸收增强剂，可改善胰岛素和降钙素的肺部吸收，而不会对呼吸组织造成任何膜损伤。
