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Open AccessOpen Access JUSTC Chemistry ; Life Sciences 06 April 2023

Synthesis of pH-responsive supramolecular polypeptide nanoparticles from α-amino acids for combined chemo-photothermal therapy

  • 1.

    Department of Chemical Physics, University of Science and Technology of China, Hefei 230026, China

  • 2.

    Department of Hepatobiliary Surgery, the First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230001, China

Cite this:
https://doi.org/10.52396/JUSTC-2022-0154
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  • Author Bio:

    Hongyun Qian obtained her master’s degree at the School of Chemistry and Materials Science, University of Science and Technology of China, under the supervision of Prof. Lifeng Yan. Her research mainly focuses on biomaterials

    Lifeng Yan received his Ph.D. degree in Chemistry from the University of Science and Technology of China. He is currently a Professor at the University of Science and Technology of China. His research interests include nanomedicine, polymeric science, and green chemistry

  • Corresponding author: E-mail: lfyan@ustc.edu.cn
  • Received Date: 28 October 2022
  • Accepted Date: 28 November 2022
    • Available Online: 06 April 2023
    Abstract

  • Abstract

    A new smart supramolecular polypeptide copolymer P(Glu-co-Lys) was synthesized by the polymerization of α-amino acids using the N-thiocarboxylic acid anhydride (NTA) method, using the pH dynamic response peptide of L-glutamic acid and L-lysine as a carrier for tumor cells. The drug delivery system activated by external acid can self-assemble (pH 7.4) and disassemble (pH 5.5) under the adjustment of pH to load the drug and control its release. Doxycycline (DOX) and the photothermal reagent hydrophilic quanternary stereo-cyanine (HQS-Cy) were loaded into the peptide copolymer to obtain HQS-Cy/DOX nanoparticles (NPs) for chemo-photothermal therapy. Gentle photothermal heating can enhance the absorption of drugs by cells and enhance the efficacy of chemotherapy. In addition, chemo-photothermal therapy can solve the defect of easy recurrence after single photothermal therapy. The ingenious nanodrug delivery system of HQS-Cy/DOX NPs provides great potential for the improvement of chemo-photothermal therapy and will achieve excellent therapeutic effects in cancer treatment.

    Graphical abstract

      pH-switchable polypeptide nanoparticles for chemo-photothermal therapy.

    Abstract

    A new smart supramolecular polypeptide copolymer P(Glu-co-Lys) was synthesized by the polymerization of α-amino acids using the N-thiocarboxylic acid anhydride (NTA) method, using the pH dynamic response peptide of L-glutamic acid and L-lysine as a carrier for tumor cells. The drug delivery system activated by external acid can self-assemble (pH 7.4) and disassemble (pH 5.5) under the adjustment of pH to load the drug and control its release. Doxycycline (DOX) and the photothermal reagent hydrophilic quanternary stereo-cyanine (HQS-Cy) were loaded into the peptide copolymer to obtain HQS-Cy/DOX nanoparticles (NPs) for chemo-photothermal therapy. Gentle photothermal heating can enhance the absorption of drugs by cells and enhance the efficacy of chemotherapy. In addition, chemo-photothermal therapy can solve the defect of easy recurrence after single photothermal therapy. The ingenious nanodrug delivery system of HQS-Cy/DOX NPs provides great potential for the improvement of chemo-photothermal therapy and will achieve excellent therapeutic effects in cancer treatment.

    • Public Summary

    • A new polypeptide copolymer, P(Glu-co-Lys), was synthesized by the polymerization of α-amino acids via the N-thiocarboxylic acid anhydride (NTA) method.
    • Both drugs and organic dyes can be efficiently encapsulated by the self-assembly of the copolymer, and the drug delivery system shows pH-sensitive performance.
    • In vitro experiments reveal that the nanoparticles show efficient smart combined chemo-photothermal therapy.

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    • References(17)
  • [1]
    Fan L, Jin B Q, Zhang S L, et al. Stimuli-free programmable drug release for combination chemo-therapy. Nanoscale, 2016, 8: 12553–12559. doi: 10.1039/C5NR06305A
    [2]
    Suo A L, Qian J M, Zhang Y P, et al. Comb-like amphiphilic polypeptide-based copolymer nanomicelles for co-delivery of doxorubicin and P-gp siRNA into MCF-7 cells. Mat. Sci. Eng. C-Mater., 2016, 62: 564–573. doi: 10.1016/j.msec.2016.02.007
    [3]
    Xu W J, Qian J M, Hou G H, et al. Hyaluronic Acid-functionalized gold nanorods with pH/NIR dual responsive drug release for synergetic targeted photothermal chemotherapy of breast cancer. ACS Appl. Mater. Inter., 2017, 9: 36533–36547. doi: 10.1021/acsami.7b08700
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    [5]
    Aubert P, Knott E B. Synthesis of thiazolid-2:5-dione. Nature, 1950, 166: 1039–1040. doi: 10.1038/1661039b0
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    Higashimura T, Kato H, Suzuoki K, et al. Condensation polymerization of N-dithiocarbonyl alkoxycarbonyl-amino acids. Part I. Synthesis and condensation polymerization of N-dithiocarbonyl ethoxycarbonyl-amino acids. Makromolekul Chem., 1966, 90: 243–248. doi: 10.1002/macp.1966.020900123
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    [8]
    Kricheldorf H R, Bösinger K. Mechanismus der NCA-polymerisation, 3. Über die amin-katalysierte polymerisation von sarkosin-NCA und-NTA. Makromol. Chem., 1976, 177: 1243–1258. doi: 10.1002/macp.1976.021770502
    [9]
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    [11]
    Li J G, Wang T, Wu D L, et al. Stimuli-responsive zwitterionic block copolypeptides: Poly(N-isopropylacrylamide)-block-poly(lysine-co-glutamic acid). Biomacromolecules, 2008, 9: 2670–2676. doi: 10.1021/bm800394p
    [12]
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    Frisch H, Unsleber J P, Lüdeker D, et al. pH-switchable ampholytic supramolecular copolymers. Angew. Chem. Int. Ed., 2013, 52: 10097–10101. doi: 10.1002/anie.201303810
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    Behanna H A, Donners J J J M, Gordon A C, et al. Coassembly of amphiphiles with opposite peptide polarities into nanofibers. J. Am. Chem. Soc., 2005, 127: 1193–1200. doi: 10.1021/ja044863u
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    1.  (a) Chemical structure of P(Glu-co-Lys) under neutral and acidic conditions. (b) Conceptual illustration of pH-switchable HQS-Cy/DOX NPs for chemo-photothermal therapy.

    2.  Synthesis of P(Glu-co-Lys) by the NTA method.

    Figure  1.  1H NMR spectra of (a) XAA, (b) BLG-NTA, (c) ZLys-NTA, (d) P(BLG-co-Zlys), (e) P(Glu-co-Lys), and (f) the NIR dye HQS-Cy.

    Figure  2.  (a) TEM and (b) DLS methods to determine the nanoparticle size distribution of HQS-Cy/DOX NPs.

    Figure  3.  Determination of pKa of peptide copolymer P(Glu-co-Lys).

    Figure  4.  DOX release from HQS-Cy/DOX NPs at pH 7.4 or 5.5 and 37 °C (triplicate).

    Figure  5.  Cytotoxicity assays of (a) HQS-Cy@P(Glu-co-Lys) and (b) DOX@P(Glu-co-Lys) against HepG2 cells under dark conditions.

    Figure  6.  MTT method to test the therapeutic effect of HQS-Cy/DOX NPs on HepG2 cells.

    Figure  7.  Cell death staining method to test the therapeutic effect of HQS-Cy/DOX NPs on HepG2 cells.

    [1]
    Fan L, Jin B Q, Zhang S L, et al. Stimuli-free programmable drug release for combination chemo-therapy. Nanoscale, 2016, 8: 12553–12559. doi: 10.1039/C5NR06305A
    [2]
    Suo A L, Qian J M, Zhang Y P, et al. Comb-like amphiphilic polypeptide-based copolymer nanomicelles for co-delivery of doxorubicin and P-gp siRNA into MCF-7 cells. Mat. Sci. Eng. C-Mater., 2016, 62: 564–573. doi: 10.1016/j.msec.2016.02.007
    [3]
    Xu W J, Qian J M, Hou G H, et al. Hyaluronic Acid-functionalized gold nanorods with pH/NIR dual responsive drug release for synergetic targeted photothermal chemotherapy of breast cancer. ACS Appl. Mater. Inter., 2017, 9: 36533–36547. doi: 10.1021/acsami.7b08700
    [4]
    Wang Z Z, Chen Z W, Liu Z, et al. A multi-stimuli responsive gold nanocage-hyaluronic platform for targeted photothermal and chemotherapy. Biomaterials, 2014, 35: 9678–9688. doi: 10.1016/j.biomaterials.2014.08.013
    [5]
    Aubert P, Knott E B. Synthesis of thiazolid-2:5-dione. Nature, 1950, 166: 1039–1040. doi: 10.1038/1661039b0
    [6]
    Higashimura T, Kato H, Suzuoki K, et al. Condensation polymerization of N-dithiocarbonyl alkoxycarbonyl-amino acids. Part I. Synthesis and condensation polymerization of N-dithiocarbonyl ethoxycarbonyl-amino acids. Makromolekul Chem., 1966, 90: 243–248. doi: 10.1002/macp.1966.020900123
    [7]
    Dewey R S, Schoenewaldt E F, Joshua H, et al. Synthesis of peptides in aqueous medium. V. Preparation and use of 2, 5-thiazolidinediones (NTA’s). Use of 13C-H nuclear magnetic resonance signal as internal standard for quantitative studies. J. Am. Chem. Soc., 1968, 90: 3254–3255. doi: 10.1021/ja01014a059
    [8]
    Kricheldorf H R, Bösinger K. Mechanismus der NCA-polymerisation, 3. Über die amin-katalysierte polymerisation von sarkosin-NCA und-NTA. Makromol. Chem., 1976, 177: 1243–1258. doi: 10.1002/macp.1976.021770502
    [9]
    Deming T J. Synthetic polypeptides for biomedical applications. Prog. Polym. Sci., 2007, 32: 858–875. doi: 10.1016/j.progpolymsci.2007.05.010
    [10]
    Choe U J, Sun V Z, Tan J K Y, et al. Self-assembled polypeptide and polypeptide hybrid vesicles: From synthesis to application. In: Deming T, editor. Peptide-Based Materials. Berlin, Heidelberg: Springer, 2011: 117–134.
    [11]
    Li J G, Wang T, Wu D L, et al. Stimuli-responsive zwitterionic block copolypeptides: Poly(N-isopropylacrylamide)-block-poly(lysine-co-glutamic acid). Biomacromolecules, 2008, 9: 2670–2676. doi: 10.1021/bm800394p
    [12]
    Rodríguez-Hernández J, Lecommandoux S. Reversible inside-out micellization of pH-responsive and water-soluble vesicles based on polypeptide diblock copolymers. J. Am. Chem. Soc., 2005, 127: 2026–2027. doi: 10.1021/ja043920g
    [13]
    Frisch H, Unsleber J P, Lüdeker D, et al. pH-switchable ampholytic supramolecular copolymers. Angew. Chem. Int. Ed., 2013, 52: 10097–10101. doi: 10.1002/anie.201303810
    [14]
    Behanna H A, Donners J J J M, Gordon A C, et al. Coassembly of amphiphiles with opposite peptide polarities into nanofibers. J. Am. Chem. Soc., 2005, 127: 1193–1200. doi: 10.1021/ja044863u
    [15]
    Wang C, Xu H, Liang C, et al. Iron oxide @ polypyrrole nanoparticles as a multifunctional drug carrier for remotely controlled cancer therapy with synergistic antitumor effect. ACS Nano, 2013, 7: 6782–6795. doi: 10.1021/nn4017179
    [16]
    Liu T, Wang C, Cui W, et al. Combined photothermal and photodynamic therapy delivered by PEGylated MoS2 nanosheets. Nanoscale, 2014, 6: 11219–11225. doi: 10.1039/C4NR03753G
    [17]
    Qian H Y, Cheng Q, Tian Y L, et al. An anti-aggregation NIR-II heptamethine-cyanine dye with a stereo-specific cyanine for imaging-guided photothermal therapy. J. Mater. Chem. B, 2021, 9: 2688–2696. doi: 10.1039/D1TB00018G
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