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Novel Meta-iodobenzylguanidine and Etoposide Complex: Physicochemical Characterization and Mathematical Modeling of Anticancer Activity

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Abstract

It is hypothesized that meta-iodobenzylguanidine (MIBG) complexation with etoposide (VP-16) will improve drug solubility and specificity towards BE(2)C neuroblastoma (NB) cells, 90% of which are known to be MIBG avid. After MIBG and VP-16 interaction, the dry complex was analyzed for crystalline structure, surface morphology, solubility, and size distribution by X-ray powder diffraction (P-XRD), scanning electron microscopy (SEM), infrared (FTIR) and UV spectroscopy, and dynamic light scattering. After exposure to the complex, the cell viability and decay rates were assessed by the MTS assay and estimated using exponential decay models (EDM). Multi-factorial ANOVA and an independent t-test were used to assess for cell viability and solubility data, respectively. The resulting (1: 3 w/w) VP-16: MIBG complex had a mean diameter and zeta potential of 458.5 nm and 0.951 mV, respectively. It dramatically increased the drug apparent water solubility (~ 12-folds). This was ascribed to the formation of a VP-16/MIBG nanocrystalline state mainly governed by cation-π interactions, evidenced by FTIR, SEM, and P-XRD data following the complexation. The EDM relating percent cell viability to drug concentration yielded an excellent fit (r2 > 0.95) and enabled to estimate the IC50 values of both native drug and its complex: 6.2 μM and 5.23 μM, respectively (indicating a conservation of drug anticancer activity). The statistical results were consistent with those of the exponential decay models, indicating that MIBG does not inhibit the anticancer activity of VP-16. This study indicates that the VP-16/MIBG complexation improves VP-16 solubility without antagonizing its anticancer activity. Moreover, the efficiency of the EDM for drug IC50 estimation provides alternative mathematical method for such in vitro cytotoxicity studies.

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Abbreviations

ANOVA:

Analysis of variance

EDM:

Exponential decay models

EDTA:

Ethylenediaminetetraacetic acid

FTIR:

Fourier transformed infrared

MIBG:

Meta-iodobenzylguanidine

MTS:

3-(4,5-Dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium

NAD + :

Nicotinamide adenine dinucleotide

NB:

Neuroblastoma

NE:

Norepinephrine

NET:

Norepinephrine transporter

P-XRD:

Powder X-ray diffraction

SEM:

Scanning electron microscopy

SPSS:

Statistical Product and Service Solutions

VP-16:

Etoposide

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Acknowledgements

The authors would like to thank Dr. James Murowchick (University of Missouri Kansas City, Department of Geosciences) and Dr. Donggao Zhao, Research Professor & Director of Electron Microscope Laboratory (UMKC School of Dentistry), for supporting and assistance with the XRD and SEM analysis, respectively. The authors would also like to thank Sarah Christian at the University of Missouri-Kansas City Graduate writing initiative, for thorough proof-read and English language editing of the entire manuscript.

Funding

This work was supported by the University of Missouri—Kansas City (UMKC) Collaborative Data Science Grant (March 2020) administered by the UMKC Institute of Data Education, Analytics and Science (IDEAS) Grant Program.

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Authors and Affiliations

  1. Laboratory of Future Nanomedicines and Theoretical Chronopharmaceutics, Division of Pharmaceutical Sciences, School of Pharmacy, University of Missouri, 2464 Charlotte, Kansas City, Missouri, 64108, USA

    Omowumi Akinjole & Bi-Botti Celestin Youan

  2. Division of Computing, Analytics and Mathematics, School of Science and Engineering, University of Missouri, Kansas City, USA

    Kathryn Menta & Majid Bani-Yaghoub

  3. Department of Pharmaceutics, College of Pharmacy, Jazan University, Jazan, Saudi Arabia

    Abdullah Alsalhi

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  1. Omowumi Akinjole
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  2. Kathryn Menta
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  3. Abdullah Alsalhi
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Contributions

Omowumi and Abdullah performed all wet laboratory experiments under Prof. Youan’s guidance at UMKC School of Pharmacy. Kathryn performed all statistical analysis and mathematical modeling under Prof. Bani-Yagoub’s guidance at UMKC.

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Correspondence to Bi-Botti Celestin Youan.

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Akinjole, O., Menta, K., Alsalhi, A. et al. Novel Meta-iodobenzylguanidine and Etoposide Complex: Physicochemical Characterization and Mathematical Modeling of Anticancer Activity. AAPS PharmSciTech 24, 174 (2023). https://doi.org/10.1208/s12249-023-02599-4

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