Increased Carrier Peptide Stability through pH Adjustment Improves Insulin and PTH(1-34) Delivery In Vitro and In Vivo Rather than by Enforced Carrier Peptide-Cargo Complexation
Oral delivery of therapeutic peptides is hampered by their large molecular size and labile nature, thus limiting their permeation across the intestinal epithelium. Promising approaches to overcome the latter include co-administration with carrier peptides. In this study, the cell-penetrating peptide...
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MDPI AG
2020-10-01
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| Series: | Pharmaceutics |
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| Online Access: | https://www.mdpi.com/1999-4923/12/10/993 |
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| author | Mie Kristensen Ragna Guldsmed Diedrichsen Valeria Vetri Vito Foderà Hanne Mørck Nielsen |
| author_facet | Mie Kristensen Ragna Guldsmed Diedrichsen Valeria Vetri Vito Foderà Hanne Mørck Nielsen |
| author_sort | Mie Kristensen |
| collection | DOAJ |
| description | Oral delivery of therapeutic peptides is hampered by their large molecular size and labile nature, thus limiting their permeation across the intestinal epithelium. Promising approaches to overcome the latter include co-administration with carrier peptides. In this study, the cell-penetrating peptide penetratin was employed to investigate effects of co-administration with insulin and the pharmacologically active part of parathyroid hormone (PTH(1-34)) at pH 5, 6.5, and 7.4 with respect to complexation, enzymatic stability, and transepithelial permeation of the therapeutic peptide in vitro and in vivo. Complex formation between insulin or PTH(1-34) and penetratin was pH-dependent. Micron-sized complexes dominated in the samples prepared at pH-values at which penetratin interacts electrostatically with the therapeutic peptide. The association efficiency was more pronounced between insulin and penetratin than between PTH(1-34) and penetratin. Despite the high degree of complexation, penetratin retained its membrane activity when applied to liposomal structures. The enzymatic stability of penetratin during incubation on polarized Caco-2 cell monolayers was pH-dependent with a prolonged half-live determined at pH 5 when compared to pH 6.5 and 7.4. Also, the penetratin-mediated transepithelial permeation of insulin and PTH(1-34) was increased in vitro and in vivo upon lowering the sample pH from 7.4 or 6.5 to 5. Thus, the formation of penetratin-cargo complexes with several molecular entities is not prerequisite for penetratin-mediated transepithelial permeation a therapeutic peptide. Rather, a sample pH, which improves the penetratin stability, appears to optimize the penetratin-mediated transepithelial permeation of insulin and PTH(1-34). |
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| language | English |
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| publishDate | 2020-10-01 |
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| spelling | doaj.art-6b9c20a68dc44310a4511acacfb549fb2023-11-20T17:46:26ZengMDPI AGPharmaceutics1999-49232020-10-01121099310.3390/pharmaceutics12100993Increased Carrier Peptide Stability through pH Adjustment Improves Insulin and PTH(1-34) Delivery In Vitro and In Vivo Rather than by Enforced Carrier Peptide-Cargo ComplexationMie Kristensen0Ragna Guldsmed Diedrichsen1Valeria Vetri2Vito Foderà3Hanne Mørck Nielsen4Department of Pharmacy, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, DK-2100 Copenhagen, DenmarkDepartment of Pharmacy, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, DK-2100 Copenhagen, DenmarkDipartimento di Fisica e Chimica, Università Degli Studi di Palermo, Viale delle Scienze ed. 18, IT-90128 Palermo, ItalyDepartment of Pharmacy, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, DK-2100 Copenhagen, DenmarkDepartment of Pharmacy, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, DK-2100 Copenhagen, DenmarkOral delivery of therapeutic peptides is hampered by their large molecular size and labile nature, thus limiting their permeation across the intestinal epithelium. Promising approaches to overcome the latter include co-administration with carrier peptides. In this study, the cell-penetrating peptide penetratin was employed to investigate effects of co-administration with insulin and the pharmacologically active part of parathyroid hormone (PTH(1-34)) at pH 5, 6.5, and 7.4 with respect to complexation, enzymatic stability, and transepithelial permeation of the therapeutic peptide in vitro and in vivo. Complex formation between insulin or PTH(1-34) and penetratin was pH-dependent. Micron-sized complexes dominated in the samples prepared at pH-values at which penetratin interacts electrostatically with the therapeutic peptide. The association efficiency was more pronounced between insulin and penetratin than between PTH(1-34) and penetratin. Despite the high degree of complexation, penetratin retained its membrane activity when applied to liposomal structures. The enzymatic stability of penetratin during incubation on polarized Caco-2 cell monolayers was pH-dependent with a prolonged half-live determined at pH 5 when compared to pH 6.5 and 7.4. Also, the penetratin-mediated transepithelial permeation of insulin and PTH(1-34) was increased in vitro and in vivo upon lowering the sample pH from 7.4 or 6.5 to 5. Thus, the formation of penetratin-cargo complexes with several molecular entities is not prerequisite for penetratin-mediated transepithelial permeation a therapeutic peptide. Rather, a sample pH, which improves the penetratin stability, appears to optimize the penetratin-mediated transepithelial permeation of insulin and PTH(1-34).https://www.mdpi.com/1999-4923/12/10/993intestinal peptide deliveryinsulinPTH(1-34)cell-penetrating peptidepenetratincarrier peptide |
| spellingShingle | Mie Kristensen Ragna Guldsmed Diedrichsen Valeria Vetri Vito Foderà Hanne Mørck Nielsen Increased Carrier Peptide Stability through pH Adjustment Improves Insulin and PTH(1-34) Delivery In Vitro and In Vivo Rather than by Enforced Carrier Peptide-Cargo Complexation Pharmaceutics intestinal peptide delivery insulin PTH(1-34) cell-penetrating peptide penetratin carrier peptide |
| title | Increased Carrier Peptide Stability through pH Adjustment Improves Insulin and PTH(1-34) Delivery In Vitro and In Vivo Rather than by Enforced Carrier Peptide-Cargo Complexation |
| title_full | Increased Carrier Peptide Stability through pH Adjustment Improves Insulin and PTH(1-34) Delivery In Vitro and In Vivo Rather than by Enforced Carrier Peptide-Cargo Complexation |
| title_fullStr | Increased Carrier Peptide Stability through pH Adjustment Improves Insulin and PTH(1-34) Delivery In Vitro and In Vivo Rather than by Enforced Carrier Peptide-Cargo Complexation |
| title_full_unstemmed | Increased Carrier Peptide Stability through pH Adjustment Improves Insulin and PTH(1-34) Delivery In Vitro and In Vivo Rather than by Enforced Carrier Peptide-Cargo Complexation |
| title_short | Increased Carrier Peptide Stability through pH Adjustment Improves Insulin and PTH(1-34) Delivery In Vitro and In Vivo Rather than by Enforced Carrier Peptide-Cargo Complexation |
| title_sort | increased carrier peptide stability through ph adjustment improves insulin and pth 1 34 delivery in vitro and in vivo rather than by enforced carrier peptide cargo complexation |
| topic | intestinal peptide delivery insulin PTH(1-34) cell-penetrating peptide penetratin carrier peptide |
| url | https://www.mdpi.com/1999-4923/12/10/993 |
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