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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

Montakarn Chittchang, Nazila Salamat-Miller, Hemant H Alur, David G Vander Velde, Ashim K Mitra, Thomas P Johnston

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Abstract 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 (Daq) 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°C using side-by-side diffusion cells. Hydrophilic microporous polyester membranes with a 1-μm pore diameter were used to measure the free diffusion of each conformer. The values for the apparent permeability (Papp) and Daq 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°C, both Papp and Daq of the α-helix conformer were approximately the same as those of the random coil conformer. In contrast, at 37°C, the Papp and the Daq of the β-sheet conformer were significantly (P < 0.05) less than those of the random coil conformer. At 25°C, the solutions containing primarily either the random coil or the α-helix conformers had approximately the same viscosity. On the other hand, at 37°C, the solutions containing the β-sheet conformer had a significantly (P < 0.05) higher viscosity than when this conformer was absent. The random coil and the α-helix conformers appeared to have comparable sizes, whereas the hydrodynamic radius estimated for the β-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 α-helix did not affect its Papp and intrinsic Daq. On the other hand, appearance of the β-sheet conformer significantly decreased the values of Papp and Daq. The differences appeared to result from the significantly higher solution viscosity as well as the extended structure associated with the β-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.