caa a22 4500 477128092 CHVBK 20180405111655.0 cr unu---uuuuu 170330e19970201xx s 000 0 eng 10.1023/A:1012040425146 doi (NATIONALLICENCE)springer-10.1023/A:1012040425146 Effect of Size and Charge on the Passive Diffusion of Peptides Across Caco-2 Cell Monolayers via the Paracellular Pathway [Elektronische Daten] [Giovanni Pauletti, Franklin Okumu, Ronald Borchardt] Purpose. To evaluate the effect of size and charge on the permeation characteristics of peptides across the intestinal mucosa. Methods. The lipophilicities of neutral, positively and negatively charged capped amino acids (Asn, Lys, Asp), tripeptides (Ac-Gly-X-Ala-NH2; X = Asn, Lys, Asp) and hexapeptides (Ac-Tip-Ala-Gly-Gly-X-Ala-NH2; X = Asn, Lys, Asp) were estimated using an immobilized artificial membrane. The diffusion coefficients used to calculate the molecular radii were measured by NMR. The transport characteristics of the model peptides were determined across Caco-2 cell monolayers. Results. When model compounds having the same charge were compared, permeation was highly size-dependent (capped amino acids > tripeptides > hexapeptides), suggesting transport predominantly via the paracellular route. For example, the flux of the negatively charged Asp amino acid (Papp = 10.04 ± 0.43 × 10−8 cm/s) was 3 times greater than that observed for the Asp-containing hexapeptide (Papp = 3.19 ± 0.27 × 10−8 cm/s). When model compounds of the same size were compared, permeation across the cell monolayer was charge-dependent (negative < positive ≤ neutral). For example, the neutral, Asn-containing tripeptide (Papp = 25.79 ± 4.86 × 10−8 cm/s) was substantially more able to permeate the Caco-2 cell monolayer than the negatively charged Asp-containing tripeptide (Papp = 7.95 ± 1.03 × 10−8 cm/s) and the positively charged Lys-containing tripeptide (Papp = 9.86 ± 0.18 × 10−8 cm/s). The permeability of the cell monolayer to peptides became less sensitive to net charge as the size of the peptides increased. Conclusions. A positive net charge of hydrophilic peptides enhances their permeation across the intestinal mucosa via the paracellular pathway. With increasing molecular size, molecular sieving of the epithelial barrier dominates the transport of peptides, and the effect of the net charge becomes less significant. Plenum Publishing Corporation, 1997 peptide delivery nationallicence size nationallicence charge nationallicence Caco-2 cells nationallicence membrane permeability nationallicence Pauletti Giovanni aut Okumu Franklin aut Borchardt Ronald aut Pharmaceutical Research Kluwer Academic Publishers-Plenum Publishers 14/2(1997-02-01), 164-168 0724-8741 14:2<164 1997 14 11095 https://doi.org/10.1023/A:1012040425146 text/html Onlinezugriff via DOI 1 research-article jats NATIONALLICENCE 856 40 https://doi.org/10.1023/A:1012040425146 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Pauletti Giovanni aut NATIONALLICENCE 700 1- Okumu Franklin aut NATIONALLICENCE 700 1- Borchardt Ronald aut NATIONALLICENCE 773 0- Pharmaceutical Research Kluwer Academic Publishers-Plenum Publishers 14/2(1997-02-01), 164-168 0724-8741 14:2<164 1997 14 11095 Metadata rights reserved Springer special CC-BY-NC licence nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-springer