Thiolated α-cyclodextrin: The likely smallest drug carrier providing enhanced cellular uptake and endosomal escape

Carbohydrate Polymers, Journal Year: 2023, Volume and Issue: 316, P. 121070 - 121070

Published: May 31, 2023

This study aimed to evaluate the effect of thiolated α-cyclodextrin (α-CD-SH) on cellular uptake its payload. For this purpose, α-CD was using phosphorous pentasulfide. Thiolated characterized by FT-IR and 1H NMR spectroscopy, differential scanning calorimetry (DSC), powder X-ray diffractometry (PXRD). Cytotoxicity α-CD-SH evaluated Caco-2, HEK 293, MC3T3 cells. Dilauryl fluorescein (DLF) coumarin-6 (Cou) serving as surrogates for a pharmaceutical payload were incorporated in α-CD-SH, analyzed flow cytometry confocal microscopy. Endosomal escape investigated microscopy hemolysis assay. Results showed no cytotoxic within 3 h, while dose-dependent cytotoxicity observed 24 h. The DLF Cou up 20- 11-fold enhanced compared native α-CD, respectively. Furthermore, provided an endosomal escape. According these results, is promising carrier shuttle drugs into cytoplasm target

Language: Английский

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Cell-Surface-Retained Peptide Additives for the Cytosolic Delivery of Functional Proteins

Journal of the American Chemical Society, Journal Year: 2023, Volume and Issue: unknown

Published: Oct. 31, 2023

The delivery of functional proteins remains a major challenge in advancing biological and pharmaceutical sciences. Herein, we describe powerful, simple, highly effective strategy for the intracellular cargoes. Previously, demonstrated that cell-penetrating peptide (CPP) additives equipped with electrophilic thiol-reactive moieties temporarily attach to cellular membrane, thereby facilitating uptake protein- antibody-CPP cargoes through direct membrane transduction at low concentrations. Now, hypothesize CPP-additives an increased retention on will further enhance uptake. We discovered adding small hydrophobic sequence arginine-rich CPP-additive improved protein-CPP conjugates, whereas larger anchors showed cytotoxicity. Cell viability integrity measurements, structure-activity relationship studies, quantitative evaluation revealed important design principles cell-surface-retained CPP-additives. These investigations allowed us identify nontoxic, containing ILFF sequence, which can deliver fluorescent model micromolar This addition protein after initial additive incubation. Time-lapse fluorescence microscopy tension analysis cells treated ILFF-CPP-additives supported claim cell surface suggested enter mechanism involving lowered tension. Finally, our newly engineered enabled macrocyclic peptidic MDM2-inhibitor recombinant genome editing protein. indicates developed holds promise as tool

Language: Английский

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Self-assembled porphyrin–peptide cages for photodynamic therapy

Organic & Biomolecular Chemistry, Journal Year: 2024, Volume and Issue: 22(7), P. 1484 - 1494

Published: Jan. 1, 2024

Dynamic covalent chemistry affords porphyrin–peptide cages which are found to be active photosensitizers for photodynamic therapy using green-light irradiation.

Language: Английский

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Organ/Cell-Selective Intracellular Delivery of Biologics via N-Acetylated Galactosamine-Functionalized Polydisulfide Conjugates

Journal of the American Chemical Society, Journal Year: 2024, Volume and Issue: 146(6), P. 3974 - 3983

Published: Feb. 1, 2024

Biologics, including proteins and antisense oligonucleotides (ASOs), face significant challenges when it comes to achieving intracellular delivery within specific organs or cells through systemic administrations. In this study, we present a novel approach for delivering ASOs liver cells, both in vitro vivo, using conjugates that tether N-acetylated galactosamine (GalNAc)-functionalized, cell-penetrating polydisulfides (PDSs). The method involves the thiol-bearing cargo-mediated ring-opening polymerization of GalNAc-functionalized lipoamide monomers so-called aggregation-induced polymerization, leading formation site-specific protein/ASO-PDS with narrow dispersity. hepatocyte-selective arises from combination factors, first GalNAc binding ASGPR receptors on cell immobilization, subsequent thiol–disulfide exchange occurring surface, promoting internalization. Our findings emphasize critical role close proximity PDS backbone as governs success and, consequently, penetration. These hold tremendous potential overcoming various biological barriers encountered during cell-specific biomacromolecular cargos, opening up new avenues diagnosis treatment range liver-targeting diseases.

Language: Английский

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Non-covalent delivery of native proteins and peptides by phenylboronic cell-penetrating poly(disulfide)s

Nano Today, Journal Year: 2024, Volume and Issue: 56, P. 102283 - 102283

Published: April 30, 2024

Language: Английский

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