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Folate–Gold–Bilirubin Nanoconjugate Induces Apoptotic Death in Multidrug-Resistant Oral Carcinoma Cells

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European Journal of Drug Metabolism and Pharmacokinetics Aims and scope Submit manuscript

Abstract

Background

Gold nanoparticles (GNPs) are receiving increasing attention as drug delivery carriers due to their high surface-to-volume ratio, hydrophilicity, and functionality. Drug delivery by nanocarriers has the potential to bypass P-glycoprotein (P-gp)-mediated multidrug resistance (MDR) by altering the drug internalization mechanism and/or intracellular release pattern, inhibiting the activity of ABC-transporter efflux pumps, or downregulating the expression of genes responsible for the activity of efflux pumps.

Objective

We developed a folate–gold–bilirubin (FGB) nanoconjugate to reverse MDR in P-expressing KB-ChR-8-5 cells.

Methods

The P-gp overexpressing KB-ChR-8-5 cells were incubated with the FGB nanoconjugate, bilirubin, or GNPs. Various cellular endpoints, such as cytotoxicity, ROS generation, DNA damage, and apoptosis, were analyzed using analytical methods. Further, a KB-ChR-8-5 cell-bearing tumor xenograft was developed and the anticancer potential of the prepared FGB nanoparticles was compared to that of bilirubin or GNPs in this preclinical model.

Results

The FGB nanoconjugate was found to be a stronger inhibitor of the viability of multidrug-resistant KB-ChR-8-5 cells than bilirubin and GNPs treatment alone. The nanoconjugate induced reactive oxygen species (ROS) formation, DNA strand breaks, and apoptotic morphological changes in the P-gp-overexpressing drug-resistant cells to a greater degree than bilirubin treatment alone. Also, the FGB nanoparticles led to stronger suppression of tumor development in the KB-ChR-8-5 xenograft mouse model than achieved with bilirubin treatment alone. Thus, the present results suggest that the FGB nanoconjugate suppresses tumor growth in drug-resistant tumor cells by inducing apoptotic cell death.

Conclusion

FGB nanoparticles significantly inhibit tumor growth, probably through the folate receptor, which is highly expressed in KB cells. Hence, folate–gold–bilirubin nanoparticles could be a promising agent for inducing apoptosis in P-gp-overexpressing drug-resistant cancer cells.

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Funding

This project work was supported by the Centre for International Research and Innovation—Waikato Institute of Technology, Hamilton, New Zealand.

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Authors and Affiliations

  1. Centre for International Research and Internships, Waikato Institute of Technology, Hamilton, New Zealand

    Pierson Rathinaraj

  2. Department of Biochemistry and Biotechnology, Annamalai University, Annamalainagar, Tamil Nadu, India

    Ganesan Muthusamy, Nagarajan Rajendra Prasad & Srithar Gunaseelan

  3. Department of Chemical Engineering, Kyungpook National University, Daegu, Republic of Korea

    Boeun Kim

  4. Department of Mechanical Engineering, Jinhua Polytechnic, Jinhua, People’s Republic of China

    Suhang Zhu

Authors
  1. Pierson Rathinaraj
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  2. Ganesan Muthusamy
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  3. Nagarajan Rajendra Prasad
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  4. Srithar Gunaseelan
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  5. Boeun Kim
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  6. Suhang Zhu
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Contributions

PR and NRP conceived and designed all experiments. PR, MG, SG, SZ, and BH performed all of the experiments. PR and NRP wrote the manuscript.

Corresponding author

Correspondence to Pierson Rathinaraj.

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Rathinaraj, P., Muthusamy, G., Prasad, N.R. et al. Folate–Gold–Bilirubin Nanoconjugate Induces Apoptotic Death in Multidrug-Resistant Oral Carcinoma Cells. Eur J Drug Metab Pharmacokinet 45, 285–296 (2020). https://doi.org/10.1007/s13318-019-00600-9

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  • DOI: https://doi.org/10.1007/s13318-019-00600-9

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