Lipid-based nanoparticles: Enhanced cellular uptake via surface thiolation

Knoll, Patrick; Racaniello, Giuseppe Francesco; Laquintana, Valentino; Veider, Florina; Saleh, Ahmad; Seybold, Anna; Denora, Nunzio; Bernkop‐Schnürch, Andreas

doi:10.1016/j.ijpharm.2023.122753

Cited by 16 publications

(7 citation statements)

References 46 publications

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“…CAXs undergo dynamic covalent exchanges with membrane-bound protein thiols (or disulfides), where each exchange produces a new (or offers another) covalently tethered exchanger, that can continue exchanging until they are delivered into the cytosol . TMU has been realized with many classes of CAX for the cytosolic delivery of small molecules, , antibodies and other proteins, − genome editing machinery and other oligonucleotides, − polymers, liposomes, and nanoparticles ,, into various cellular targets including deep tissue, , living animals, , plant cells, and bacteria . Proteomics data, heatmap patterns, , and literature on oligonucleotide phosphorothioate , and viral uptake ,− all support that multipartner exchange networks are involved in how TMU brings matter into cells .…”

mentioning

confidence: 99%

Inhibition of Cell Motility by Cell-Penetrating Dynamic Covalent Cascade Exchangers: Integrins Participate in Thiol-Mediated Uptake

Coelho

Saidjalolov

Moreau

et al. 2023

JACS Au

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Integrins are cell surface proteins responsible for cell motility. Inspired by the rich disulfide exchange chemistry of integrins, we show here the inhibition of cell migration by cascade exchangers (CAXs), which also enable and inhibit cell penetration by thiol-mediated uptake. Fast-moving CAXs such as reversible Michael acceptor dimers, dithiabismepanes, and bioinspired epidithiodiketopiperazines are best, much better than Ellman's reagent. The implication that integrins participate in thiol-mediated uptake is confirmed by reduced uptake in integrin-knockdown cells. Although thiol-mediated uptake is increasingly emerging as a unifying pathway to bring matter into cells, its molecular basis is essentially unknown. These results identify the integrin superfamily as experimentally validated general cellular partners in the dynamic covalent exchange cascades that are likely to account for thiolmediated uptake. The patterns identified testify to the complexity of the dynamic covalent networks involved. This work also provides chemistry tools to explore cell motility and expands the drug discovery potential of CAXs from antiviral toward antithrombotic and antitumor perspectives.

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mentioning

confidence: 99%

Inhibition of Cell Motility by Cell-Penetrating Dynamic Covalent Cascade Exchangers: Integrins Participate in Thiol-Mediated Uptake

Coelho

Saidjalolov

Moreau

et al. 2023

JACS Au

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“…Cytotoxicity Studies: The cytotoxic effect of SEDDS on a Caco-2 cell line was evaluated via the resazurin reduction assay. [39] To reach a monolayer, Caco-2 cells were seeded on 96-well plates in a density of 5 × 10 5 Caco-2 cells•mL −1 per well several days before the experiment. Cells were supplemented with 10% (v/v) heat-inactivated fetal calf serum (FCS) and a penicillin/streptomycin solution (100 units/0.1 mg•L −1 ) at 95% humidity and 37 °C in an atmosphere of 5% CO 2 during this period.…”

Section: Development Of Dry Reverse Micellesmentioning

confidence: 99%

Self‐Emulsifying Drug Delivery Systems (SEDDS) Containing Reverse Micelles: Advanced Oral Formulations for Therapeutic Peptides

Jörgensen,

Steinbring,

Stengel

et al. 2023

Adv Healthcare Materials

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Alternative methods to hydrophobic ion pairing for the formation of lipophilic complexes of peptide drugs to incorporate them in lipid‐based nanocarriers such as self‐emulsifying drug delivery systems (SEDDS) for oral administration are highly on demand. Such an alternative might be reverse micelles. Within this study, SEDDS containing dry reverse micelles (dRMsPMB) formed with an anionic (sodium docusate; AOT), cationic (dimethyl‐dioctadecyl‐ammonium bromide; DODAB), amphoteric (soy lecithin; SL), or non‐ionic (polysorbate 85; P85) surfactant loaded with the model peptide drug polymyxin B (PMB) are developed. They are characterized regarding size, payload, release kinetics, cellular uptake, and peptide activity.SEDDS exhibit sizes from 22.2 ± 1.7 (AOT‐SEDDS‐dRMsPMB) to 61.7 ± 3.2 nm (P85‐SEDDS‐dRMsPMB) with payloads up to 2% that are approximately sevenfold higher than those obtained via hydrophobic ion pairing. Within 6 h P85‐SEDDS‐dRMsPMB and AOT‐SEDDS‐dRMsPMB show no release of PMB in aqueous medium, whereas DODAB‐SEDDS‐dRMsPMB and SL‐SEDDS‐dRMsPMB show a sustained release. DODAB‐SEDDS‐dRMsPMB improves uptake by Caco‐2 cells most efficiently reaching even ≈100% within 4 h followed by AOT‐SEDDS‐dRMsPMB with ≈20% and P85‐/SL‐SEDDS‐dRMsPMB with ≈5%. The peptide drug maintains its antimicrobial activity in all SEDDS‐dRMsPMB.According to these results, SEDDS containing dRMs might be a game changing strategy for oral peptide drug delivery.

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“…Thiol-mediated uptake (TMU) refers to the cell-penetrating activity acquired by the attachment of thiol-reactive motifs to the substrates of interest (SOI), − such as probes, , drugs, proteins, ,,,− oligonucleotides, − liposomes, ,− quantum dots, nanoparticles, ,, and so on (Figure ). Since this process appears to operate with dynamic covalent exchange reactions with cellular thiols and disulfides, e.g., cysteine and cystine residues, it can be inhibited by other thiol-reactive agents, which is the hallmark of TMU.…”

Section: Introductionmentioning

confidence: 99%

Inclusive Pattern Generation Protocols to Decode Thiol-Mediated Uptake

Saidjalolov,

Coelho,

Mercier

et al. 2024

ACS Cent. Sci.

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Thiol-mediated uptake (TMU) is an intriguing enigma in current chemistry and biology. While the appearance of cell-penetrating activity upon attachment of cascade exchangers (CAXs) has been observed by many and is increasingly being used in practice, the molecular basis of TMU is essentially unknown. The objective of this study was to develop a general protocol to decode the dynamic covalent networks that presumably account for TMU. Uptake inhibition patterns obtained from the removal of exchange partners by either protein knockdown or alternative inhibitors are aligned with original patterns generated by CAX transporters and inhibitors and patterns from alternative functions (here cell motility). These inclusive TMU patterns reveal that the four most significant CAXs known today enter cells along three almost orthogonal pathways. Epidithiodiketopiperazines (ETP) exchange preferably with integrins and protein disulfide isomerases (PDIs), benzopolysulfanes (BPS) with different PDIs, presumably PDIA3, and asparagusic acid (AspA), and antisense oligonucleotide phosphorothioates (OPS) exchange with the transferrin receptor and can be activated by the removal of PDIs with their respective inhibitors. These findings provide a solid basis to understand and use TMU to enable and prevent entry into cells.

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Lipid-based nanoparticles: Enhanced cellular uptake via surface thiolation

Cited by 16 publications

References 46 publications

Inhibition of Cell Motility by Cell-Penetrating Dynamic Covalent Cascade Exchangers: Integrins Participate in Thiol-Mediated Uptake

Inhibition of Cell Motility by Cell-Penetrating Dynamic Covalent Cascade Exchangers: Integrins Participate in Thiol-Mediated Uptake

Self‐Emulsifying Drug Delivery Systems (SEDDS) Containing Reverse Micelles: Advanced Oral Formulations for Therapeutic Peptides

Inclusive Pattern Generation Protocols to Decode Thiol-Mediated Uptake

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