Selection of the Parameters in the Synthesis of Ethylenediamine-Folate Using the Plackett Burman Design

Erianti Siska Purnamasari; Linda Septiana; Ari Hardianto; Ukun Mochammad Syukur Soedjanaatmadja; Anni Anggraeni; Husein Hernadi Bahti

doi:10.22146/ijc.68313

Selection of the Parameters in the Synthesis of Ethylenediamine-Folate Using the Plackett Burman Design

https://doi.org/10.22146/ijc.68313

Erianti Siska Purnamasari⁽¹⁾, Linda Septiana⁽²⁾, Ari Hardianto⁽³⁾, Ukun Mochammad Syukur Soedjanaatmadja⁽⁴⁾, Anni Anggraeni⁽⁵⁾, Husein Hernadi Bahti^(6*)

(1) Department of Chemistry, Faculty of Mathematics and Natural Sciences, Universitas Padjadjaran, Jl. Raya Bandung-Sumedang km 21, Jatinangor 45363, West Java, Indonesia
(2) Department of Chemistry, Faculty of Mathematics and Natural Sciences, Universitas Padjadjaran, Jl. Raya Bandung-Sumedang km 21, Jatinangor 45363, West Java, Indonesia
(3) Department of Chemistry, Faculty of Mathematics and Natural Sciences, Universitas Padjadjaran, Jl. Raya Bandung-Sumedang km 21, Jatinangor 45363, West Java, Indonesia
(4) Department of Chemistry, Faculty of Mathematics and Natural Sciences, Universitas Padjadjaran, Jl. Raya Bandung-Sumedang km 21, Jatinangor 45363, West Java, Indonesia
(5) Department of Chemistry, Faculty of Mathematics and Natural Sciences, Universitas Padjadjaran, Jl. Raya Bandung-Sumedang km 21, Jatinangor 45363, West Java, Indonesia
(6) Department of Chemistry, Faculty of Mathematics and Natural Sciences, Universitas Padjadjaran, Jl. Raya Bandung-Sumedang km 21, Jatinangor 45363, West Java, Indonesia
(*) Corresponding Author

Abstract

This study is concerned with synthesizing ethylenediamine-folate (EDA-Folate), which will then be used as a precursor in synthesizing Gd-PEG-DOTA-Folate, a novel targeted-contrast agent for the diagnosis of cancer, employing the Magnetic Resonance Imaging method. This study aims to determine all the parameters affecting the synthesis of EDA-Folate using the Plackett Burman design. The synthesis method included activation of folic acid using dicyclohexylcarbodiimide and N-Hydroxysuccinimide to result in NHS-Folate, followed by conjugation of ethylenediamine with NHS-Folate to produce EDA-Folate. Analysis of the reaction product confirmed that the reaction product was EDA-Folate. From the resulted data, it can also be concluded that there were four significant parameters (out of the ten parameters studied) in the synthesis of EDA-Folate (with its value presented in the bracket), i.e., time inactivation of NHS-Folate (24 h), stirring rate inactivation of NHS-Folate (300 rpm), the mole of EDA (12 moles), and time of EDA-Folate (12 h). Moreover, the value or desirability of the experimental design was found to be 0.875 (which is < 1.0), meaning that the design will produce optimal conditions and thus the optimal yield of the reaction.

Keywords

ethylenediamine-folate; Plackett-Burman design; yield; contrast agent; Gd-PEG-DOTA-Folate

Full Text:

Full Text PDF

References

[1] Stoja, E., Konstandin, S., Philipp, D., Wilke, R.N., Betancourt, D., Bertuch, T., Jenne, J., Umathum, R., and Günther, M., 2021, Improving magnetic resonance imaging with smart and thin metasurface, Sci. Rep., 11, 16179.

[2] Wald, L.L., McDaniel, P.C., Witzel, T., Stockmann, J.P., and Cooley, C.Z., 2019, Low-cost and portable MRI, J. Magn. Reson. Imaging, 52 (3), 686–696.

[3] Fernandez, M., Javaid, F., and Chudasama, V., 2017, Advances in targeting the folate receptor in the treatment/imaging of cancers, Chem. Sci., 9 (4), 790–810.

[4] Zwicke, G.L., Mansoori, G.A., and Jeffery, C.J., 2012, Utilizing folate receptor for active targeting of cancer nanotherapeutics, Nano Rev., 3 (1), 18496.

[5] Arnaud, C.H., 2013, Structure of folic acid bound to folate receptor is solved, Chem. Eng. News, 91 (29).

[6] Fauzia, R.P., Mutalib, A., Soedjanaatmadja, R.U.M.S., Bahti, H.H., Anggraeni, A., Gunawan, A.H., Pujiastuti, H., and Hidayati, Y., 2015, Synthesis and characterization of gadolinium diethylenetriamine pentaacetate-folate, Procedia Chem., 17, 139–146.

[7] Kusuma, Y.N.W., Mutalib, A., Anggraeni, A., Martalena, R., Fauzia, R.P., and Bahti, H.H., 2018, Analysis and characterization of complex compound cadolinium-(1,4,7,10-Tetraazacyclododecane,1-4-7-10- tetraacetic acid)n-poliamidoamine generation 3- trastuzumab as a novel contrast agent for magnetic resonance imaging, Res. J. Chem. Environ, 22, 249–254.

[8] Hsu, Y.I., Mahara, A., and Yamaoka, T., 2018, Influence of molecular mobility on contrast efficiency of branched polyethylene glycol contrast agent, Contrast Media Mol. Imaging, 2018, 1259325.

[9] Fauzia, R.P., Maolana, I., Mutalib, A., Nafisah, Z., Soedjanaatmadja, R.U.M.S., Anggraeni, A., and Bahti, H.H., 2017, Comparison characteristics of different synthesis methods for production of gadolinium diethylenetriaminepentaacetate-folate, 7^th Int'l Conf. on Innovations in Chemical, Biological, Environmental and Food Sciences, (ICBEFS-17), Pattaya, Thailand, August 3-4, 2017, 60–63.

[10] Gunawan, A.H., Yono, S., and Maskur, M., 2012, Sintesis Gd-DTPA-Folat untuk magnetic resonance imaging contrast agent dan karakterisasinya menggunakan perunut radioaktif ¹⁵³Gd-DTPA-Folat, JUSAMI, 13 (4), 1–6.

[11] Ndaliman, M.B., Khan, A.A., Ali, M.Y., and Wahid, Z., 2013, Determination of influential factors on EDMed surface properties using Plackett-Burman design, World Appl. Sci. J., 21, 88–93.

[12] Fauzia, R.P., Soedjanaatmadja, A.U., Anggraeni, A., Yusuf, M., and Bahti, H., 2017, Aplikasi desain eksperimen Plackett-Burman dan response surface methodology Box-Behnken pada produksi senyawa pengontras magnetic resonance imaging gadolinium dietilentriaminpentaasetat-folat, JCNA, 1–8.

[13] Li, X., McTaggart, M., and Malardier-Jugroot, C., 2016, Synthesis and characterization of pH responsive folic acid functionalized polymeric drug delivery system, Biophys. Chem., 214-215, 17–26.

[14] Singh, R., Kesharwani, P., Mehra, N.K., Singh, S., Banerjee, S., and Jain, N.K., 2015, Development and characterization of folate anchored Saquinavir entrapped PLGA nanoparticles for anti-tumor activity, Drug Dev. Ind. Pharm., 41 (11), 1888–1901.

[15] Razjouyan, J., Zolata, H., Khayat, O., Nowshiravan, F., Shadanpour N., and Mohammadnia, M., 2015, Synthesis and evaluation of radiolabeled, folic acid-PEG conjugated, amino silane coated magnetic nanoparticles in tumor-bearing Balb/C mice, NUCLEONIKA, 60 (3), 497–502.

[16] Li, X., Yang, X., Lin, Z., Wang, D., May, D., He, B., Wang, X., Wang, X., Zhang, Q., and Gao, W., 2015, A folate modified pH-sensitive targeted polymeric micelle alleviated systemic toxicity of doxorubicin (DOX) in multi-drug resistant tumor-bearing mice, Eur. J. Pharm. Sci., 76, 95–101.

[17] Nurmiah, S., Syarief, R., Sukarno, Peranginangin, R., and Nurtama, B., 2013, Aplikasi response surface methodology pada optimalisasi kondisi proses pengolahan alkali treated cottonii (ATC), JPBKP, 8 (1), 9–22.

[18] Hermanson, G.T., 2013, Bioconjugate Techniques, 3^rd Ed., Academic Press, Boston,United States.

[19] Effendi, S., Mutalib, A., Anggraeni, A., and Bahti, H.H., 2020, Penggunaan desain Plackett Burman untuk seleksi parameter pemisahan logam tanah jarang kelompok sedang dari logam tanah jarang kelompok lainnya dengan metode pengendapan, al-Kimiya, 7 (1), 1–6.

[20] Yatim, N.M., Shaaban, A., Dimin, M.F., and Yusof, F., 2015, Statistical evaluation of the production of urea fertilizer-multiwalled carbon nanotubes using Plackett Burman experimental design, Procedia Soc. Behav. Sci., 195, 315–323.

DOI: https://doi.org/10.22146/ijc.68313