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Bottlebrush Polymer-Conjugated Melittin Exhibits Enhanced Antitumor Activity and Better Safety Profile

  • Fei Jia
    Fei Jia
    Departments of Chemistry and Chemical Biology, Chemical Engineering, and Bioengineering, Northeastern University, Boston, Massachusetts 02115, United States
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  • Peiru Chen
    Peiru Chen
    Departments of Chemistry and Chemical Biology, Chemical Engineering, and Bioengineering, Northeastern University, Boston, Massachusetts 02115, United States
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  • Dali Wang
    Dali Wang
    Departments of Chemistry and Chemical Biology, Chemical Engineering, and Bioengineering, Northeastern University, Boston, Massachusetts 02115, United States
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  • Yehui Sun
    Yehui Sun
    Departments of Chemistry and Chemical Biology, Chemical Engineering, and Bioengineering, Northeastern University, Boston, Massachusetts 02115, United States
    More by Yehui Sun
  • Mengqi Ren
    Mengqi Ren
    Departments of Chemistry and Chemical Biology, Chemical Engineering, and Bioengineering, Northeastern University, Boston, Massachusetts 02115, United States
    More by Mengqi Ren
  • Yuyan Wang
    Yuyan Wang
    Departments of Chemistry and Chemical Biology, Chemical Engineering, and Bioengineering, Northeastern University, Boston, Massachusetts 02115, United States
    More by Yuyan Wang
  • Xueyan Cao
    Xueyan Cao
    Departments of Chemistry and Chemical Biology, Chemical Engineering, and Bioengineering, Northeastern University, Boston, Massachusetts 02115, United States
    More by Xueyan Cao
  • Lei Zhang
    Lei Zhang
    Departments of Chemistry and Chemical Biology, Chemical Engineering, and Bioengineering, Northeastern University, Boston, Massachusetts 02115, United States
    More by Lei Zhang
  • Yang Fang
    Yang Fang
    Departments of Chemistry and Chemical Biology, Chemical Engineering, and Bioengineering, Northeastern University, Boston, Massachusetts 02115, United States
    More by Yang Fang
  • Xuyu Tan
    Xuyu Tan
    Departments of Chemistry and Chemical Biology, Chemical Engineering, and Bioengineering, Northeastern University, Boston, Massachusetts 02115, United States
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  • Hao Lu
    Hao Lu
    Departments of Chemistry and Chemical Biology, Chemical Engineering, and Bioengineering, Northeastern University, Boston, Massachusetts 02115, United States
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  • Jiansong Cai
    Jiansong Cai
    Departments of Chemistry and Chemical Biology, Chemical Engineering, and Bioengineering, Northeastern University, Boston, Massachusetts 02115, United States
    More by Jiansong Cai
  • Xueguang Lu*
    Xueguang Lu
    David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States
    *Email: [email protected]
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  • , and 
  • Ke Zhang*
    Ke Zhang
    Departments of Chemistry and Chemical Biology, Chemical Engineering, and Bioengineering, Northeastern University, Boston, Massachusetts 02115, United States
    *Email: [email protected]
    More by Ke Zhang
Cite this: ACS Appl. Mater. Interfaces 2021, 13, 36, 42533–42542
Publication Date (Web):September 2, 2021
https://doi.org/10.1021/acsami.1c14285
Copyright © 2021 American Chemical Society

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    Abstract

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    Despite potency against a variety of cancers in preclinical systems, melittin (MEL), a major peptide in bee venom, exhibits non-specific toxicity, severe hemolytic activity, and poor pharmacological properties. Therefore, its advancement in the clinical translation system has been limited to early-stage trials. Herein, we report a biohybrid involving a bottlebrush-architectured poly(ethylene glycol) (PEG) and MEL. Termed pacMEL, the conjugate consists of a high-density PEG arrangement, which provides MEL with steric inhibition against protein access, while the high molecular weight of pacMEL substantially enhances plasma pharmacokinetics with a ∼10-fold increase in the area under the curve (AUC) compared to free MEL. pacMEL also significantly reduces hepatic damage and unwanted innate immune response and all but eliminated hemolytic activities of MEL. Importantly, pacMEL passively accumulates at subcutaneously inoculated tumor sites and exhibits stronger tumor-suppressive activity than molecular MEL. Collectively, pacMEL makes MEL a safer and more appealing drug candidate.

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    The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsami.1c14285.

    • Synthesis and characterization of PEGylated MELs; enzymatic degradation of MEL-containing samples; in vitro experiments; in vivo antitumor activity; and initial biocompatibility evaluation of MEL-containing samples (PDF)

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    Cited By

    This article is cited by 4 publications.

    1. Yang Fang, Jiansong Cai, Mengqi Ren, Tongtong Zhong, Dali Wang, Ke Zhang. Inhalable Bottlebrush Polymer Bioconjugates as Vectors for Efficient Pulmonary Delivery of Oligonucleotides. ACS Nano 2024, 18 (1) , 592-599. https://doi.org/10.1021/acsnano.3c08660
    2. Ruonan Wang, Panpan Xiao, Bo Yu, Ying Sun, Jia Li, Ling’e Zhang, Xiqun Jiang, Wei Wu. Fluorination Effects on the Drug Delivery Property of Cylindrical Polymer Brushes. ACS Applied Bio Materials 2022, 5 (12) , 5924-5932. https://doi.org/10.1021/acsabm.2c00870
    3. Catarina Pacheco, Ana Baião, Tao Ding, Wenguo Cui, Bruno Sarmento. Recent advances in long-acting drug delivery systems for anticancer drug. Advanced Drug Delivery Reviews 2023, 194 , 114724. https://doi.org/10.1016/j.addr.2023.114724
    4. Markus Müllner. Molecular polymer bottlebrushes in nanomedicine: therapeutic and diagnostic applications. Chemical Communications 2022, 58 (38) , 5683-5716. https://doi.org/10.1039/D2CC01601J

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