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Encapsulation of Gold-Based Anticancer Agents in Protease-Degradable Peptide Nanofilaments Enhances Their Potency

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    Encapsulation of Gold-Based Anticancer Agents in Protease-Degradable Peptide Nanofilaments Enhances Their Potency
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    • Yaron Marciano
      Yaron Marciano
      Nanoscience Initiative, Advanced Science Research Center at The Graduate Center of the City University of New York (CUNY), 85 Saint Nicholas Terrace, New York, New York10031, United States
      Department of Chemistry, Brooklyn College, CUNY, 2900 Bedford Avenue, Brooklyn, New York11210, United States
      Ph.D. Program in Chemistry, The Graduate Center of CUNY, 365 Fifth Avenue, New York, New York10016, United States
      More by Yaron Marciano
    • Virginia del Solar
      Virginia del Solar
      Department of Chemistry, Brooklyn College, CUNY, 2900 Bedford Avenue, Brooklyn, New York11210, United States
      More by Virginia del Solar
    • Nazia Nayeem
      Nazia Nayeem
      Department of Chemistry, Brooklyn College, CUNY, 2900 Bedford Avenue, Brooklyn, New York11210, United States
      Ph.D. Program in Biology, The Graduate Center of CUNY, 365 Fifth Avenue, New York, New York10016, United States
      More by Nazia Nayeem
    • Dhwanit Dave
      Dhwanit Dave
      Nanoscience Initiative, Advanced Science Research Center at The Graduate Center of the City University of New York (CUNY), 85 Saint Nicholas Terrace, New York, New York10031, United States
      Ph.D. Program in Chemistry, The Graduate Center of CUNY, 365 Fifth Avenue, New York, New York10016, United States
      Department of Chemistry, Hunter College, CUNY, 695 Park Avenue, New York, New York10065, United States
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      Orcidhttps://orcid.org/0000-0002-6218-4584
    • Jiye Son
      Jiye Son
      Nanoscience Initiative, Advanced Science Research Center at The Graduate Center of the City University of New York (CUNY), 85 Saint Nicholas Terrace, New York, New York10031, United States
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      Orcidhttps://orcid.org/0000-0003-3482-9813
    • María Contel*
      María Contel
      Department of Chemistry, Brooklyn College, CUNY, 2900 Bedford Avenue, Brooklyn, New York11210, United States
      Ph.D. Program in Chemistry,  Ph.D. Program in Biochemistry  and  Ph.D. Program in Biology, The Graduate Center of CUNY, 365 Fifth Avenue, New York, New York10016, United States
      *Email: [email protected]
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      Orcidhttps://orcid.org/0000-0002-9825-4441
    • Rein V. Ulijn*
      Rein V. Ulijn
      Nanoscience Initiative, Advanced Science Research Center at The Graduate Center of the City University of New York (CUNY), 85 Saint Nicholas Terrace, New York, New York10031, United States
      Ph.D. Program in Chemistry  and  Ph.D. Program in Biochemistry, The Graduate Center of CUNY, 365 Fifth Avenue, New York, New York10016, United States
      Department of Chemistry, Hunter College, CUNY, 695 Park Avenue, New York, New York10065, United States
      *Email: [email protected]
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      Orcidhttps://orcid.org/0000-0002-7138-1213
    Other Access OptionsSupporting Information (5)

    Journal of the American Chemical Society

    Cite this: J. Am. Chem. Soc. 2023, 145, 1, 234–246
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    https://doi.org/10.1021/jacs.2c09820
    Published December 21, 2022
    Copyright © 2022 American Chemical Society
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    Abstract

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    We investigated the use of amphiphilic, protease-cleavable peptides as encapsulation moieties for hydrophobic metallodrugs, in order to enhance their bioavailability and consequent activity. Two hydrophobic, gold-containing anticancer agents varying in aromatic ligand distribution (Au(I)-N-heterocyclic carbene compounds 1 and 2) were investigated. These were encapsulated into amphiphilic decapeptides that form soluble filamentous structures with hydrophobic cores, varying supramolecular packing arrangements and surface charge. Peptide sequence strongly dictates the supramolecular packing within the aromatic core, which in turn dictates drug loading. Anionic peptide filaments can effectively load 1, and to a lesser extent 2, while their cationic counterparts could not, collectively demonstrating that loading efficiency is dictated by both aromatic and electrostatic (mis)matching between drug and peptide. Peptide nanofilaments were nontoxic to cancerous and noncancerous cells. By contrast, those loaded with 1 and 2 displayed enhanced cytotoxicity in comparison to 1 and 2 alone, when exposed to Caki-1 and MDA-MB-231 cancerous cell lines, while no cytotoxicity was observed in noncancerous lung fibroblasts, IMR-90. We propose that the enhanced in vitro activity results from the enhanced proteolytic activity in the vicinity of the cancer cells, thereby breaking the filaments into drug-bound peptide fragments that are taken up by these cells, resulting in enhanced cytotoxicity toward cancer cells.

    Copyright © 2022 American Chemical Society

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    Supporting Information

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    The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/jacs.2c09820.

    • MD simulations, peptide stability, drug loading, characterization using ζ-potential, AFM, TEM, MMP-9 expression and activity, cell viability, enzyme kinetics and drug release, cellular uptake, cell death (PDF)

    • Movie S1: 5000 ns coarse-grained molecular dynamics trajectory of 950 copies of the PD peptide with water and ion beads removed for clarity; Snapshots were saved every nanosecond, and the peptide beads are color coded with purple for FF beads, green for PLGLAG beads, and red for the DD beads (MPG)

    • Movie S2: 5000 ns coarse-grained molecular dynamics trajectory of 950 copies of the PK peptide with water and ion beads removed for clarity; Snapshots were saved every nanosecond, and the peptide beads are color coded with purple for FF beads, green for PLGLAG beads, and blue for the KK beads (MPG)

    • Movie S3: 5000 ns coarse-grained molecular dynamics trajectory of 950 copies of the AD peptide with water and ion beads removed for clarity; Snapshots were saved every nanosecond, and the peptide beads are color coded with purple for FF beads, green for ALGLAG beads, and red for the DD beads (MPG)

    • Movie S4: 5000 ns coarse-grained molecular dynamics trajectory of 950 copies of the AK peptide with water and ion beads removed for clarity; Snapshots were saved every nanosecond, and the peptide beads are color coded with purple for FF beads, green for ALGLAG beads, and blue for the KK beads (MPG)

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    Cite this: J. Am. Chem. Soc. 2023, 145, 1, 234–246
    Click to copy citationCitation copied!
    https://doi.org/10.1021/jacs.2c09820
    Published December 21, 2022
    Copyright © 2022 American Chemical Society
    Request reuse permissions

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