Systemic delivery of proteins using novel peptides via the sublingual route

• Published in: Journal of controlled release Vol. 368; pp. 290 - 302
• Main Authors: Wu, Jiamin, Jones, Natalie, Hohenwarter, Lukas, Zhao, Feng, Chan, Vanessa, Tan, Zheng, Carlaw, Tiffany, Morin, Tessa, Li, Jing, Kaur, Tejinder, Andrew, Lucas J., Ross, Colin J.D., Hedtrich, Sarah, Li, Shyh-Dar
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.04.2024
• Subjects: Administration, Sublingual; Animals; Cell-penetrating peptides; Humans; Immunoglobulin G; Inuslin; Mice; Peptides; Protamine; Protamines; Proteins and peptides; Semaglutide; Sublingual delivery; Semaglutide; Proteins and peptides; Inuslin; Cell-penetrating peptides; Protamine; Sublingual delivery
• ISSN: 0168-3659; 1873-4995
• DOI: 10.1016/j.jconrel.2024.02.042

Therapeutic proteins often require needle-based injections, which compromise medication adherence especially for those with chronic diseases. Sublingual administration provides a simple and non-invasive alternative. Herein, two novel peptides (lipid-conjugated protamine and a protamine dimer) were synthesized to enable sublingual delivery of proteins through simple physical mixing with the payloads. It was found that the novel peptides promoted intracellular delivery of proteins via increased pore formation on the cell surface. Results from in vitro models of cell spheroids and human sublingual tissue substitute indicated that the novel peptides enhanced protein penetration through multiple cell layers compared to protamine. The novel peptides were mixed with insulin or semaglutide and sublingually delivered to mice for blood glucose (BG) control. The effects of these sublingual formulations were comparable to the subcutaneous preparations and superior to protamine. In addition to peptide drugs, the novel peptides were shown to enable sublingual absorption of larger proteins with molecular weights from 22 to 150 kDa in mice, including human recombinant growth hormone (rhGH), bovine serum albumin (BSA) and Immunoglobulin G (IgG). The novel peptides given sublingually did not induce any measurable toxicities in mice. [Display omitted] •Two novel derivatives of protamine were synthesized to facilitate sublingual delivery of proteins.•These protamine derivatives enable delivery of proteins up to 150 KDa by simple mixing.•The protamine derivatives promoted transcellular delivery by forming nanopores on cell surface.•These protamine derivatives were safe in mice.