Barriers to the Intestinal Absorption of Four Insulin-Loaded Arginine-Rich Nanoparticles in Human and Rat

Lundquist, Patrik; Khodus, Georgiy; Niu, Zhigao; Thwala, Lungile Nomcebo; McCartney, Fiona; Simoff, Ivailo; Andersson, Ellen; Beloqui, Ana; Mabondzo, Aloı̈se; Robla, Sandra; Webb, Dominic-Luc; Hellström, Per M.; Keita, Åsa V.; Sima, Eduardo; Csaba, Nœmi; Sundbom, Magnus; Préat, Véronique; Brayden, David J.; Alonso, Marı́a José; Artursson, Per

doi:10.1021/acsnano.2c04330

Cited by 13 publications

(6 citation statements)

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“…[96b] As suggested in a recent study, a biointeractive structure underneath a bioinert one may increase both mucus penetration and cell uptake. [97] Regardless of whether LNPs or preformed complexes are considered, in vivo evidence for the potency of biodegradable cationic and ionizable cationic lipids that can be metabolized into natural or even endogenous metabolites, is limited. The few available in vivo studies (Table 3) lack data on the elimination of the lipid and its metabolites, as well as a comparison with the lead compounds ALC-0315 and SM-102.…”

Section: Complexation Of Nucleic Acidsmentioning

confidence: 99%

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Biodegradable Cationic and Ionizable Cationic Lipids: A Roadmap for Safer Pharmaceutical Excipients

Jörgensen

Wibel

Bernkop‐Schnürch

2023

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The use of cationic and ionizable cationic lipids in pharmaceutical products, however, is a double-edged sword, as these excipients are of considerable safety concerns. Because of their permanent or pHdependent cationic nature, they perturbate cellular and nuclear membranes, trigger the release of degrading enzymes from lysosomes, cause mitochondrial permeabilization and dysfunction, generate reactive oxygen species (ROS), alter cytoplasmatic enzyme functions, and damage DNA. [3] To address this substantial shortcoming of cationic and ionizable cationic lipids, biodegradable alternatives have been introduced that are rapidly degraded in vivo to preferably endogenous metabolites. The design of such lipids is inspired by natural cationic or ionizable cationic compounds like arginine, lysine or betaine that are generally regarded as safe. Their conjugation to endogenous lipids like fatty acids or cholesterol results in amphiphilic lipids. As ester and amide bonds are cleaved in vivo by numerous enzymes such as lipases, esterases, and proteases, they are the preferred linkages between these natural building blocks.Since the FDA approved ethyl Nα-lauroyl-l-arginate as biodegradable food preservative being effective against a broad range of Gram-positive and Gram-negative bacteria, yeasts, and molds in 2005, [4] the potential use of biodegradable cationic and ionizable cationic lipids as pharmaceutical excipients has been evaluated by numerous research groups. As these excipients exhibit the same properties as their non-biodegradable counterparts but causing relatively low adverse effects, they will likely substitute currently used non-biodegradable lipids in the future. Within this review, we provide an overview on the different types of biodegradable cationic and ionizable cationic lipids, their synthesis and cleavage by endogenous enzymes. Applications in drug delivery systems and as antimicrobial agents are discussed. A guideline on their design and application is provided and an outlook on future developments is given. Building Blocks and Formation of Cationic and Ionizable Cationic LipidsGenerally, biodegradable cationic and ionizable cationic lipids are composed of biocompatible building blocks that are conjugated via a linkage such as an ester or amide bond. [5] Representative building blocks and linkages are depicted in Figure 1. Endogenous enzymes can break these linkages and degrade Cationic and ionizable cationic lipids are broadly applied as auxiliary agents, but their use is associated with adverse effects. If these excipients are rapidly degraded to endogenously occurring metabolites such as amino acids and fatty acids, their toxic potential can be minimized. So far, synthesized and evaluated biodegradable cationic and ionizable cationic lipids already showed promising results in terms of functionality and safety. Within this review, an overview about the different types of such biodegradable lipids, the available building blocks, their synthesis and cleavage by endogenous enzymes is provided. Moreover, ...

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Section: Complexation Of Nucleic Acidsmentioning

confidence: 99%

“…[ 96b ] As suggested in a recent study, a biointeractive structure underneath a bioinert one may increase both mucus penetration and cell uptake. [ 97 ]…”

Section: Use As Complexing Agents For Drug Deliverymentioning

confidence: 99%

Biodegradable Cationic and Ionizable Cationic Lipids: A Roadmap for Safer Pharmaceutical Excipients

Jörgensen

Wibel

Bernkop‐Schnürch

2023

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“…Arginine-rich peptides, nanoparticles, or polymers are widely used as delivery carriers in various biomedical applications due to their enhanced cell uptake property. − Arginine-rich cell-penetrating peptides are generally cationic in nature with less than 40 amino acids and can penetrate the plasma membrane of cells and tissues. , They are widely used as delivery carriers via electrostatic or covalent conjugation with various cargos (e.g., nucleic acids, polymers, liposomes, drugs, SiRNA, genes) with high efficiency. − Due to the high and specific delivery efficiency of these cell-penetrating peptides, they have potential use in different therapeutics such as for cancer, neurodegenerative diseases, cardiological issues, viral, and bacterial infections. ,, Generally, arginine-rich peptides/polymers/nanoparticle follow an energy-dependent endocytic uptake pathway for cellular entry. , In this endocytic uptake, the cell membrane wraps around the nanomaterial and is then engulfed by the endocytic vesicle. , Endocytotic uptake of nanomaterial is slow and energy-dependent as it is associated with the cell surface receptors’ mobility and clustering for their interaction with nanomaterials followed by endosomal/lysosomal trafficking . This slower uptake can be avoided if nanomaterials follow the nonendocytic and direct membrane penetration pathway.…”

Section: Introductionmentioning

confidence: 99%

Arginine Surface Density of Nanoparticles Controls Nonendocytic Cell Uptake and Autophagy Induction

Ray,

Ghosh,

Maity

et al. 2024

ACS Appl. Mater. Interfaces

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Nonendocytic cell uptake of nanomaterials is challenging, which requires specific surface chemistry and smaller particle size. Earlier works have shown that an arginine-terminated nanoparticle of <10−20 nm size shows nonendocytic uptake via direct membrane penetration. However, the roles of surface arginine density and the argininearginine distance at the nanoparticle surface in controlling such nonendocytic uptake mechanism is not yet explored. Here we show that a higher arginine density at the nanoparticle surface with an arginine-arginine distance of <3 nm is the most critical aspect for such nonendocytic uptake. We have used quantum dot (QD)-based nanoparticles as a model for fluorescent tracking inside cells and for quantitative estimation of cellular uptake. We found that arginine-terminated nanoparticles of 10 nm size can opt for the energydependent endocytosis pathway if the arginine-arginine distance is >3 nm. In contrast, nanoparticles with <3 nm arginine-arginine distance rapidly enter into the cell via the nonendocytic approach, are freely available in the cytosol in large amounts to capture the cellular adenosine triphosphate (ATP), generate oxidative stress, and induce ATP-deficient cellular autophagy. This work shows that arginine-arginine distance at the nanoparticle surface is another fundamental parameter, along with the particle size, for the nonendocytic cell uptake of foreign materials and to control intracellular activity. This approach may be utilized in designing nanoprobes and nanocarriers with more efficient biomedical performances.

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“…Oral absorption of GLP-1 RAs mimics the physiological route of endogenous GLP-1 [ 6 ], which is secreted by L-cells in the distal ileum and then enters the blood circulation [ 7 ]. However, owing to the hostile environment of the gastrointestinal tract (GIT) and the challenges from molecules’ size and polarity, the oral delivery of proteins and peptides is hampered by enzyme degradation and low permeability [ 8 ].…”

Section: Introductionmentioning

confidence: 99%

Intestinal epithelium penetration of liraglutide via cholic acid pre-complexation and zein/rhamnolipids nanocomposite delivery

et al. 2023

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Background Oral administration offered a painless way and improved compliance for diabetics. However, the emerging GLP-1 analog peptide drugs for diabetes primarily rely on the injection route, and the development of oral dosage forms was hampered by the low oral bioavailability due to the structural vulnerability to digestive enzymes and molecule impermeability in the gastrointestinal tract. Results In this study, the non-covalent interaction between cholic acid (CA) and liraglutide (LIRA) was found and theoretically explained by molecular docking simulation. Formation of this physical complex of liraglutide and cholic acid (LIRA/CA Complex) reduced the self-aggregation of LIRA and accelerated intestinal epithelium penetration. By the anti-solvent method, LIRA/CA Complex was loaded into zein/rhamnolipids nanoparticles (LIRA/CA@Zein/RLs) with a loading efficiency of 76.8%. LIRA was protected from fast enzymatic degradation by the hydrophobic zein component. Meanwhile, Rhamnolipids, a glycolipid with surface activity, promoted endocytosis while also stabilizing the nanoparticles. The two components worked synergistically to ensure the delivery of LIRA/CA Complex to intestinal villi and improved oral absorption without disrupting tight junctions. LIRA/CA@Zein/RLs demonstrated a considerable intestinal epithelium absorption in mouse gastrointestinal section and a retention in vivo over 24 h, resulting in a significant and long-lasting hypoglycemic effect in Type 2 diabetes mice. Conclusion This study provided a promising oral delivery approach for LIRA and exhibited the potential for further translation into clinical application.

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Barriers to the Intestinal Absorption of Four Insulin-Loaded Arginine-Rich Nanoparticles in Human and Rat

Cited by 13 publications

References 68 publications

Biodegradable Cationic and Ionizable Cationic Lipids: A Roadmap for Safer Pharmaceutical Excipients

Biodegradable Cationic and Ionizable Cationic Lipids: A Roadmap for Safer Pharmaceutical Excipients

Arginine Surface Density of Nanoparticles Controls Nonendocytic Cell Uptake and Autophagy Induction

Intestinal epithelium penetration of liraglutide via cholic acid pre-complexation and zein/rhamnolipids nanocomposite delivery

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