Peptide permeation enhancers for improving oral bioavailability of macromolecules

Kim, Dohyun; Liu, Jin; Park, Eun Ji; Na, Dong Hee

doi:10.1007/s40005-022-00609-4

Cited by 10 publications

(5 citation statements)

References 69 publications

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“…[55][56][57] Despite the distinct potential of various peptides, there are several challenges that exist, with penetration being one of the most prominent issues. [27][28][29][30] Typically, peptides have poor skin absorption and permeability, thus various modifications or formulations of peptide are required.…”

Section: Screening and Selection Of Anti-inflammatory Peptides By Int...mentioning

confidence: 99%

“…These properties can significantly enhance the therapeutic efficacy of peptides as a treatment option. 27–30…”

Section: Introductionmentioning

confidence: 99%

“…These properties can significantly enhance the therapeutic efficacy of peptides as a treatment option. [27][28][29][30] In this study, we utilized the IDDT platform developed by REMEDI to identify the sequences of several peptides derived from human proteins that possess CPP properties. Through the assignment of CPP scores using the IDDT platform, over 1000 peptides were obtained which could have CPP properties.…”

Section: Introductionmentioning

confidence: 99%

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Development and application of novel peptide-formulated nanoparticles for treatment of atopic dermatitis

Lim,

Lee,

Shin

et al. 2023

J. Mater. Chem. B

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Section: Screening and Selection Of Anti-inflammatory Peptides By Int...mentioning

confidence: 99%

“…These properties can significantly enhance the therapeutic efficacy of peptides as a treatment option. 27–30…”

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Development and application of novel peptide-formulated nanoparticles for treatment of atopic dermatitis

Lim,

Lee,

Shin

et al. 2023

J. Mater. Chem. B

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“… 18 While chemical-based medications integrated with such derivatives can pass through the intestinal epithelium via the apical sodium-dependent bile acid transporter (ASBT) pathway, applying them to macromolecule therapeutics becomes daunting, primarily due to their extensive size, often exceeding 1000 Da. 19 , 20 Previous research has highlighted the role of ASBT in the transcytosis mechanism underlying macromolecule transit. In this process, ASBT induces cell membrane invagination into vesicles, which then bind with ileal bile acid-binding proteins for transport through the organic anion transporter system to the basolateral face.…”

Section: Introductionmentioning

confidence: 99%

Coordinated ASBT and EGFR Mechanisms for Optimized Liraglutide Nanoformulation Absorption in the GI Tract

Kweon,

Park,

Lee

et al. 2024

IJN

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Background For maintenance therapy in type 2 diabetes, glucagon-like peptide-1 agonist (GLP-1A), which exhibits low cardiovascular risk and high efficacy, is a promising peptide therapeutic. However, developing an oral GLP-1A presents challenges due to the analog’s poor cellular permeability and gastrointestinal (GI) stability. Methods To mitigate such limitations, an oral nanoformulation of liraglutide (LG) was designed and achieved by combining LG with bile acid derivatives using the nanoprecipitation method. This strategy allowed the bile acid moieties to localize at the nanoparticle surface, enhancing the binding affinity for apical sodium-dependent bile acid transporter (ASBT) and improving GI stability. The in vitro characteristics, cellular permeability, and absorption mechanisms of the LG nanoformulation (LG/TD-NF) were thoroughly investigated. Furthermore, the in vivo oral absorption in rats and the glucose-lowering effects in a diabetic ( db/db ) mouse model were evaluated. Results The LG/TD-NF produced neutral nanoparticles with a diameter of 58.7 ± 4.3 nm and a zeta potential of 4.9 ± 0.4 mV. Notably, when exposed to simulated gastric fluid, 65.7 ± 3.6% of the LG/TD-NF remained stable over 120 min, while free LG was fully degraded. Relative to unformulated LG, the Caco-2 cellular permeability of the nanoformulation improved, measuring 10.9 ± 2.1 (× 10 −6 cm/s). The absorption mechanism prominently featured endocytosis simultaneously mediated by both ASBT and epidermal growth factor receptor (EGFR). The oral bioavailability of the LG/TD-NF was determined to be 3.62% at a dosage of 10 mg/kg, which is 45.3 times greater than that of free LG. In a diabetes model, LG/TD-NF at 10 mg/kg/day exhibited commendable glucose sensitivity and reduced HbA1c levels by 4.13% within 28 days, similar to that of subcutaneously administered LG at a dosage of 0.1 mg/kg/day. Conclusion The oral LG/TD-NF promotes ASBT/EGFR-mediated transcytosis and assures cellular permeability within the GI tract. This method holds promise for the development of oral GLP-1A peptides as an alternative to injections, potentially enhancing patient adherence to maintenance therapy.

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“…However, because of the hydrophilic and macromolecular properties of GLP-1A, penetration of the intestinal mucous and cellular layers remains difficult. To address this issue, drug delivery systems for oral peptides have been developed to improve the cellular permeability of peptides using absorption enhancers [e.g., sodium N-[8-(2-hydroxybenzoyl)amino]caprylate (SNAC), bile acids, β-cyclodextrin, and cell-penetrating peptides] and ingestible devices [e.g., self-orienting millimeter-scale applicator (SOMA), liquid-injecting SOMA, luminal unfolding microneedle injector, and magnetic-controlled microneedle robots] [ 22 – 28 ]. However, these therapeutic systems use a paracellular pathway or nonspecific passive transcellular pathway, resulting in a low peptide absorption rate and high variability in absorption.…”

Section: Introductionmentioning

confidence: 99%

Design of chimeric GLP-1A using oligomeric bile acids to utilize transporter-mediated endocytosis for oral delivery

Kweon,

Lee,

Yang

et al. 2023

Biomater Res

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Background Despite the effectiveness of glucagon-like peptide-1 agonist (GLP-1A) in the treatment of diabetes, its large molecular weight and high hydrophilicity result in poor cellular permeability, thus limiting its oral bioavailability. To address this, we developed a chimeric GLP-1A that targets transporter-mediated endocytosis to enhance cellular permeability to GLP-1A by utilizing the transporters available in the intestine, particularly the apical sodium-dependent bile acid transporter (ASBT). Methods In silico molecular docking and molecular dynamics simulations were used to investigate the binding interactions of mono-, bis-, and tetra-deoxycholic acid (DOCA) (monoDOCA, bisDOCA, and tetraDOCA) with ASBT. After synthesizing the chimeric GLP-1A-conjugated oligomeric DOCAs (mD-G1A, bD-G1A, and tD-G1A) using a maleimide reaction, in vitro cellular permeability and insulinotropic effects were assessed. Furthermore, in vivo oral absorption in rats and hypoglycemic effect on diabetic db/db mice model were evaluated. Results In silico results showed that tetraDOCA had the lowest interaction energy, indicating high binding affinity to ASBT. Insulinotropic effects of GLP-1A-conjugated oligomeric DOCAs were not different from those of GLP-1A-Cys or exenatide. Moreover, bD-G1A and tD-G1A exhibited improved in vitro Caco-2 cellular permeability and showed higher in vivo bioavailability (7.58% and 8.63%) after oral administration. Regarding hypoglycemic effects on db/db mice, tD-G1A (50 μg/kg) lowered the glucose level more than bD-G1A (50 μg/kg) compared with the control (35.5% vs. 26.4%). Conclusion GLP-1A was conjugated with oligomeric DOCAs, and the resulting chimeric compound showed the potential not only for glucagon-like peptide-1 receptor agonist activity but also for oral delivery. These findings suggest that oligomeric DOCAs can be used as effective carriers for oral delivery of GLP-1A, offering a promising solution for enhancing its oral bioavailability and improving diabetes treatment. Graphical Abstract

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Peptide permeation enhancers for improving oral bioavailability of macromolecules

Cited by 10 publications

References 69 publications

Development and application of novel peptide-formulated nanoparticles for treatment of atopic dermatitis

Development and application of novel peptide-formulated nanoparticles for treatment of atopic dermatitis

Coordinated ASBT and EGFR Mechanisms for Optimized Liraglutide Nanoformulation Absorption in the GI Tract

Design of chimeric GLP-1A using oligomeric bile acids to utilize transporter-mediated endocytosis for oral delivery

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