UBCが開発した経口インスリン製剤が糖尿病患者を救う(UBC-developed oral insulin drops offer relief for diabetes patients)

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2024-06-05 カナダ・ブリティッシュコロンビア大学(UBC)

カナダでは1170万人が糖尿病または前糖尿病を患っており、UBCの科学者たちは、痛みのない薬物投与方法を開発しました。Li研究室の研究者たちは、舌下に置くと迅速かつ効率的に体内に吸収される経口インスリンドロップを開発しました。このドロップは、インスリンと細胞浸透ペプチド(CPP)を混合したもので、インスリン注射の代替となる可能性があります。CPPは魚の副産物から得られ、インスリンが血流に到達するのを助けます。プレ臨床試験では、ペプチドとインスリンの混合物が効果的に血流に到達することが示されました。UBCチームは、この技術を商業パートナーにライセンス供与することを目指しています。

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新規ペプチドを用いた舌下ルートによるタンパク質の全身送達 Systemic delivery of proteins using novel peptides via the sublingual route

Jiamin Wu, Natalie Jones, Lukas Hohenwarter, Feng Zhao, Vanessa Chan, Zheng Tan, Tiffany Carlaw, Tessa Morin, Jing Li, Tejinder Kaur, Lucas J. Andrew, Colin J.D. Ross, Sarah Hedtrich, Shyh-Dar Li
Journal of Controlled Release  Available online: 4 March 2024
DOI:https://doi.org/10.1016/j.jconrel.2024.02.042

Highlights

  • 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.

Abstract

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.

Graphical abstract

UBCが開発した経口インスリン製剤が糖尿病患者を救う(UBC-developed oral insulin drops offer relief for diabetes patients)

タンパク質の経粘膜デリバリーのための細胞透過性ペプチド Cell-penetrating peptides for transmucosal delivery of proteins

Jiamin Wu, Sophie Roesger, Natalie Jones, Che-Ming J. Hu, Shyh-Dar Li
Journal of Controlled Release  Available online: 27 January 2024
DOI:https://doi.org/10.1016/j.jconrel.2024.01.038

Highlights

  • Cell-penetrating peptides (CPPs) enhance biological drug permeation across various mucosal barriers.
  • CPPs use endocytosis, direct translocation, and membrane destabilization to mediate intracellular transport.
  • Local administration of CPPs is a preferable route with clinical successes.

Abstract

Enabling non-invasive delivery of proteins across the mucosal barriers promises improved patient compliance and therapeutic efficacies. Cell-penetrating peptides (CPPs) are emerging as a promising and versatile tool to enhance protein and peptide permeation across various mucosal barriers. This review examines the structural and physicochemical attributes of the nasal, buccal, sublingual, and oral mucosa that hamper macromolecular delivery. Recent development of CPPs for overcoming those mucosal barriers for protein delivery is summarized and analyzed. Perspectives regarding current challenges and future research directions towards improving non-invasive transmucosal delivery of macromolecules for ultimate clinical translation are discussed.

Graphical abstract

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有機化学・薬学
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