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首页> 外文期刊>Journal of Pharmacy and Pharmacology >Poly(L-lysine) as a model drug macromolecule with which to investigate secondary structure and microporous membrane transport, part 2: diffusion studies.
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Poly(L-lysine) as a model drug macromolecule with which to investigate secondary structure and microporous membrane transport, part 2: diffusion studies.

机译：聚（L-赖氨酸）作为模型药物大分子，用于研究二级结构和微孔膜转运，第2部分：扩散研究。

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Peptide drugs are hydrophilic in nature and so their preferred pathway of membrane transport is by the paracellular route, which primarily involves passive diffusion across intercellular pores. The objective of the present study was to investigate the effect of secondary structure on the aqueous diffusion of a model polypeptide, poly(L-lysine), through a microporous membrane. The primary aim was to systematically evaluate the variables (e.g. viscosity and/or hydrodynamic radius) that may contribute to the difference, if any, in the calculated values of the aqueous diffusion coefficient (D(aq)) for each conformer of poly(L-lysine). Variations in pH and temperature of the medium were used to induce secondary structural changes in poly(L-lysine). Transport studies were conducted for 3 h at 25 or 37 degrees C using side-by-side diffusion cells. Hydrophilic microporous polyester membranes with a 1-microm pore diameter were used to measure the free diffusion of each conformer. The values for the apparent permeability (P(app)) and D(aq) were calculated using standard equations. The viscosity of each conformer solution was determined and the hydrodynamic radius of each conformer was then estimated. At 25 degrees C, both P(app) and D(aq) of the alpha-helix conformer were approximately the same as those of the random coil conformer. In contrast, at 37 degrees C, the P(app) and the D(aq) of the beta-sheet conformer were significantly (P < 0.05) less than those of the random coil conformer. At 25 degrees C, the solutions containing primarily either the random coil or the-helix conformers had approximately the same viscosity. On the other hand, at 37 degrees C, the solutions containing the beta-sheet conformer had a significantly (P < 0.05) higher viscosity than when this conformer was absent. The random coil and the alpha-helix conformers appeared to have comparable sizes, whereas the hydrodynamic radius estimated for the beta-sheet conformer was significantly (P < 0.05) larger than those for the other two conformers. In summary, changing the secondary structure of poly(L-lysine) from the random coil to the alpha-helix did not affect its P(app) and intrinsic D(aq). On the other hand, appearance of the beta-sheet conformer significantly decreased the values of P(app) and D(aq). The differences appeared to result from the significantly higher solution viscosity as well as the extended structure associated with the beta-sheet conformer of poly(L-lysine). This strategy may represent a potential mechanism to sustain the delivery of therapeutic peptide drugs from a controlled drug delivery device.
机译：肽类药物本质上是亲水性的，因此它们的膜运输首选途径是细胞旁途径，该途径主要涉及细胞间孔的被动扩散。本研究的目的是研究二级结构对模型多肽聚（L-赖氨酸）通过微孔膜的水扩散的影响。主要目的是系统地评估变量（例如粘度和/或流体动力学半径），这些变量可能会导致聚（L）每个构象异构体的水扩散系数（D（aq））的计算值产生差异（如果有的话） -赖氨酸）。培养基的pH和温度的变化用于诱导聚（L-赖氨酸）的二级结构变化。使用并排扩散池在25或37摄氏度下进行了3小时的运输研究。使用孔径为1微米的亲水性微孔聚酯膜来测量每个构象异构体的自由扩散。使用标准方程式计算表观渗透率（P（app））和D（aq）的值。确定每种构象剂溶液的粘度，然后估算每种构象剂的流体力学半径。在25摄氏度时，α-螺旋构象异构体的P（app）和D（aq）均与随机线圈构象异构体的P（app）和D（aq）大致相同。相反，在37摄氏度时，β-sheet构象异构体的P（app）和D（aq）显着（P <0.05）小于随机线圈构象异构体的P（app）和D（aq）。在25℃下，主要含有无规卷曲或螺旋构象的溶液的粘度大致相同。另一方面，在37℃下，与没有该β-片状构象体的溶液相比，具有显着（P ＜0.05）的粘度。随机线圈和α-螺旋构象异构体似乎具有可比较的尺寸，而β-折叠构象异构体的流体力学半径估计值明显大于其他两个构象异构体（P <0.05）。总之，将聚（L-赖氨酸）的二级结构从无规卷曲变为α-螺旋不会影响其P（app）和固有D（aq）。另一方面，β-折叠构象异构体的出现显着降低了P（app）和D（aq）的值。差异似乎是由明显更高的溶液粘度以及与聚（L-赖氨酸）的β-折叠构象异构体相关的延伸结构引起的。该策略可以代表维持从受控药物递送装置递送治疗性肽药物的潜在机制。

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