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Impact of Zwitterionic Polymers on the Tumor Permeability of Molecular Bottlebrush-Based Nanoparticles

  • Shota Fujii*
    Shota Fujii
    Department of Chemistry and Biochemistry, University of Kitakyushu, 1-1 Hibikino, Kitakyushu, Fukuoka 808-0135, Japan
    *Email: [email protected]
    More by Shota Fujii
    Orcidhttps://orcid.org/0000-0002-6594-5211
  • , 
  • Shin Takano
    Shin Takano
    Department of Chemistry and Biochemistry, University of Kitakyushu, 1-1 Hibikino, Kitakyushu, Fukuoka 808-0135, Japan
    More by Shin Takano
  • , 
  • Kohji Nakazawa
    Kohji Nakazawa
    Department of Chemistry and Biochemistry, University of Kitakyushu, 1-1 Hibikino, Kitakyushu, Fukuoka 808-0135, Japan
    More by Kohji Nakazawa
  • , and 
  • Kazuo Sakurai
    Kazuo Sakurai
    Department of Chemistry and Biochemistry, University of Kitakyushu, 1-1 Hibikino, Kitakyushu, Fukuoka 808-0135, Japan
    More by Kazuo Sakurai
    Orcidhttps://orcid.org/0000-0002-9737-0061
Cite this: Biomacromolecules 2022, 23, 7, 2846–2855
Publication Date (Web):April 29, 2022
https://doi.org/10.1021/acs.biomac.2c00216
Copyright © 2022 American Chemical Society
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    Abstract

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    Biocompatible polymers possessing antifouling properties for biomolecules are necessary to be combined with nanoparticles for cancer chemotherapy to improve their retention in blood and subsequent tumor accumulation. However, these properties simultaneously lead to poor affinity to cells, and low tumor tissue permeability subsequently, which is one of the major barriers in achieving efficient anticancer efficacy. To address this, we try to elucidate the tumor permeability of nanoparticles using molecular bottlebrushes (MBs) as model polymeric nanoparticles composed of various biocompatible polymers. An MB comprising nonionic poly[(ethylene glycol) methyl ether methacrylate] (PEGMA) shows no tumor permeability at all, whereas zwitterionic MBs composed of poly(phosphobetaine methacrylate), poly(sulfobetaine methacrylate), or poly(carboxybetaine methacrylate) penetrate deeply into tumor tissues. The carboxybetaine-based MBs showed an efficient cellular uptake into cancer cells while the other MBs did not, which enable them to penetrate into tumor tissues via the transcytosis pathway. Additionally, their permeability is based on intercellular or intracellular pathways, which might be related to the zwitterionic betaine properties that recognize protein transporters on cancer cells. Surprisingly, incorporating only 10 mol % of the zwitterionic betaine polymers into PEGMA-based MBs significantly enhances their tissue permeability. This platform technology enables us to redesign the PEG-based nanoparticles developed for cancer chemotherapy in clinical applications.

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    The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.biomac.2c00216.

    • Polymer synthesis procedure; 1H-NMR and FTIR spectra; concentration dependence of refractive index increment for MBs; analysis of SEC-MALS results; DLS autocorrelation functions; DLS results for QAMB; Guinier plots for MBs; summary of SAXS fitting parameters; spheroid permeability of Cy5-labeled PEG, PEGMA, and pCBMA observed by CLSM; spheroid permeability of Cy5-labeled MBs into the HCT tumor cell spheroids observed by CLSM; fluorescence spectra of Cy5-labeled MBs; comparison of the cellular uptake of CBMB, QAMB, and pCBMA when incubated at 37 and 4 °C; SIM images for CT26 cells incubated with QAMB; cellular uptake of Cy5-labeled MBs for the HCT116 cell; analysis of interactions between CBMB and a liposome as a model cellular membrane using the ITC study; cellular uptake of CBMB and pCBMA for CT26 cells in the presence of α-CHA; time dependence of the cellular uptake of CBMB, QAMB, and pCBMA for CT26 cells; structural characterization of SBL-MB and CBL-MB; effect of endocytic inhibitors for the cellular uptake of CBL-MB for CT26 cells; synthesis scheme of PEG-based MBs incorporating 10 mol % of betaine polymers; characterization of PEG-based MBs incorporating 10 mol % of betaine polymers and the summary of the results; comparison of the cellular uptake of PEG-based MBs incorporating 10 mol % of betaine polymers for CT26 cells and HCT116 cells; and spheroid permeability of Cy5-labeled PEG-based MBs incorporating 10 mol % of betaine polymers observed by CLSM (PDF)

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    Cited By

    This article is cited by 7 publications.

    1. Jennifer A. Clark, Vivek M. Prabhu, Jack F. Douglas. Molecular Dynamics Simulation of the Influence of Temperature and Salt on the Dynamic Hydration Layer in a Model Polyzwitterionic Polymer PAEDAPS. The Journal of Physical Chemistry B 2023, 127 (38) , 8185-8198. https://doi.org/10.1021/acs.jpcb.3c03654
    2. Shin Takano, Yusuke Miyashima, Shota Fujii, Kazuo Sakurai. Molecular Bottlebrushes for Immunostimulatory CpG ODN Delivery: Relationship among Cation Density, Complex Formation Ability, and Cytotoxicity. Biomacromolecules 2023, 24 (3) , 1299-1309. https://doi.org/10.1021/acs.biomac.2c01348
    3. Subhrajit Mohanty, Binita Tirkey, Soumya Ranjan Jena, Luna Samanta, Usharani Subuddhi. Exploring Steroidal Surfactants as Potential Drug Carriers for an Anticancer Drug Curcumin: An Insight into the Effect of Surfactants’ Structure on the Photophysical Properties, Stability, and Activity of Curcumin. Langmuir 2023, 39 (5) , 1852-1869. https://doi.org/10.1021/acs.langmuir.2c02797
    4. Changshun Zhao, Suchen Wen, Jingfang Pan, Ke Wang, Yicheng Ji, Dechun Huang, Bingbing Zhao, Wei Chen. Robust Construction of Supersmall Zwitterionic Micelles Based on Hyperbranched Polycarbonates Mediates High Tumor Accumulation. ACS Applied Materials & Interfaces 2023, 15 (2) , 2725-2736. https://doi.org/10.1021/acsami.2c20056
    5. Shota Fujii, Kazuo Sakurai. Zwitterionic Amino Acid Polymer-Grafted Core-Crosslinked Particle toward Tumor Delivery. Biomacromolecules 2022, 23 (9) , 3968-3977. https://doi.org/10.1021/acs.biomac.2c00803
    6. Meike N. Leiske, Bruno G. De Geest, Richard Hoogenboom. Impact of the polymer backbone chemistry on interactions of amino-acid-derived zwitterionic polymers with cells. Bioactive Materials 2023, 24 , 524-534. https://doi.org/10.1016/j.bioactmat.2023.01.005
    7. Nazende Nur Bayram, Gizem Tuğçe Ulu, Nusaibah Abdulsalam Abdulhadi, Seda Gürdap, İsmail Alper İşoğlu, Yusuf Baran, Sevil Dinçer İşoğlu. HER2-Specific Peptide (LTVSPWY) and Antibody (Herceptin) Targeted Core Cross-Linked Micelles for Breast Cancer: A Comparative Study. Pharmaceutics 2023, 15 (3) , 733. https://doi.org/10.3390/pharmaceutics15030733
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