Synthesis, characterization, and cytotoxicity analyses of ABA-type block copolymer bearing p-xylene-bis(2-mercaptoethyloxy) core

Year 2024, Volume: 13 Issue: 3, 271 - 283, 31.12.2024

Murat Mısır , Serap Yalçın Azarkan

https://doi.org/10.54187/jnrs.1590655

Abstract

ABA–type amphiphilic novel poly(N-vinyl pyrrolidone)-block-poly(D,L-lactide)-block-poly(N-vinyl pyrrolidone) (PNVP-b-PDLLA-b-PNVP), triblock copolymer was synthesized via combination of ring-opening polymerization (ROP) and reversible addition-fragmentation chain transfer (RAFT) polymerization using novel bifunctional PDLLA based RAFT macro chain transfer agent (CTA) bearing p-xylene-bis(2-mercaptoethyloxy) core. For this goal, bifunctional initiator p-xylene-bis-(1-hydroxy-3-thia-propane) (1) was synthesized by the reaction of α,α'-dibromo-p-xylene with 2-mercaptoethanol in the presence of KOH in ethanol. PDLLA-diol was synthesized by metal-free organocatalyzed ROP of D, L-lactide (D,L-LA) in presence of 4-(dimethylamino) pyridine (DMAP) as catalyst using (1) as initiator Dibromoester end-functionalized PDLLA-based macroinitiator (3) was prepared by esterification of hydroxyl end groups of PDLLA-diol (2). PDLLA macro-CTA (4) was then synthesized via a substitution reaction of (3) with potassium ethylxanthate (KEX). Finally, PNVP-b-PDLLA-b-PNVP triblock copolymer (5) was synthesized RAFT polymerization of NVP using (4). Characterization of the molecular structures for synthesized novel polymers was made by spectroscopic (FTIR, 1H NMR) methods. In this study's application phase, polymers' effectiveness was examined on cervical cancer cells. Cytotoxicity and metastatic effects were evaluated in vitro on HeLa cell lines. In our study, we observed no toxic effect of the block copolymer below 600 µg/mL on the HeLa cervical cancer cell line and in future studies on drug delivery studies of cancer treatments.

Keywords

Amphiphilic block copolymer, Cytotoxicity, Cancer cells

Project Number

MMF.A3.24.005

Thanks

This study was supported by Kırşehir Ahi Evran University Scientific Research Projects Unit, Grant number: MMF.A3.24.005.

References

• S. Rawal, M. M. Patel, Threatening cancer with nanoparticle aided combination oncotherapy, Journal of Controlled Release. 301 (2019) 76-109.
• L. Zhao, N. Li, K. Wang, C. Shi, L. Zhang, Y. Luan, A review of polypeptide-based polymersomes, Biomaterials 35 (4) (2014) 1284-1301.
• T. Biela, A. Kowalski, J. Libiszowski, A. Duda, S. Penczek, Progress in polymerization of cyclic esters: mechanisms and synthetic applications, Macromolecular symposia 240 (1) (2006) 47-55.
• D. Babikova, R. Kalinova, I. Zhelezova, D. Momekova, S. Konstantinov, G. Momekov, D. Ivaylo, Functional block copolymer nanocarriers for anticancer drug delivery, RSC Advances 6 (88) (2016) 84634-84644.
• T. K. Dash, V. B. Konkimalla, Polymeric modification and its implication in drug delivery: Poly-ε-caprolactone (PCL) as a model polymer, Molecular Pharmaceutics 9 (9) (2012) 2365-2379.
• M. Hussain, S. M. Khan, M. Shafiq, N. Abbas, A review on PLA-based biodegradable materials for biomedical applications, Giant 18 (2024) Article Number 100261 31 pages.
• C-F. Yu, S-P. Rwei, S-J. Yang, W-C. Tsen, L-H. Lin, Synthesis and characterization of poly (DL-lactide) containing fluorene structures, Polymers 15 (11) (2023) Article Number 2555 16 pages.
• P. Franco, I. De Marco, The use of poly (N-vinyl pyrrolidone) in the delivery of drugs: A review, Polymers 12 (5) (2020) Article Number 1114 29 pages.
• D. Gigmes, T. Trimaille, Advances in amphiphilic polylactide/vinyl polymer based nano-assemblies for drug delivery, Advances in Colloid and Interface Science 294 (2021) Article Number 102483 13 pages.
• D. Le Garrec, S. Gori, L. Luo, D. Lessard, D. C. Smith, M.-A. Yessine, M. Ranger, J-C. Leroux, Poly (N-vinylpyrrolidone)-block-poly (D, L-lactide) as a new polymeric solubilizer for hydrophobic anticancer drugs: in vitro and in vivo evaluation, Journal of Controlled Release 99 (1) 2004 83-101.
• X. Liu, Y. Xu, Z. Wu, H. Chen, Poly (N‐vinylpyrrolidone)‐modified surfaces for biomedical applications, Macromolecular Bioscience 13 (2) (2013) 147-154.
• R. K. Mishra, M. Datt, A. K. Banthia. Synthesis and characterization of pectin/PVP hydrogel membranes for drug delivery system. Aaps Pharmscitech 9 (2008) 395-403.
• G. Gaucher, M. Poreba, F. Ravenelle, J-C Leroux, Poly (N‐vinyl‐pyrrolidone)‐block‐poly (D, L‐lactide) as polymeric emulsifier for the preparation of biodegradable nanoparticles, Journal of Pharmaceutical Sciences 96 (7) (2007) 1763-1775.
• F. Ravenelle, S. Gori, D. Le Garrec, D. Lessard, L. Luo, D. Palusova, J. R. Sneyd, D. Smith, Novel lipid and preservative-free propofol formulation: properties and pharmacodynamics, Pharmaceutical Research 23 (2008) 313-319.
• H. Feng, X. Lu, W. Wang, N-G. Kang, J. W. Mays, Block copolymers: Synthesis, self-assembly, and applications, Polymers 9 (10) (2017) Article Number 494 31 pages.
• K. Ramesh, R. K. Gundampati, S. Singh, K. Mitra, A. Shukla, M. V. Jagannadham, D. Chattopadhyay, Self-assembly, doxorubicin-loading and antibacterial activity of well-defined ABA-type amphiphilic poly (N-vinylpyrrolidone)-b-poly (d, l-lactide)-b-poly (N-vinyl pyrrolidone) triblock copolymers. RSC Advances 2016 6 (31) 25864-25876.
• N. Kang, J-C. Leroux, Triblock and star-block copolymers of N-(2-hydroxypropyl) methacrylamide or N-vinyl-2-pyrrolidone and d, l-lactide: synthesis and self-assembling properties in water, Polymer 45 (26) (2004) 8967-8980.
• L. Xiong, H. W. Jiang, D. Z. Wang, Synthesis, characterization and degradation of poly (dl-lactide)-block-polyvinylpyrrolidone-block-poly (dl-lactide) copolymers, Journal of Polymer Research 2009 16:191-197.
• S. K. Hira, K. Ramesh, U. Gupta, K. Mitra, N. Misra, B. Ray, P. P. Manna, Methotrexate-loaded four-arm star amphiphilic block copolymer elicits CD8+ T cell response against a highly aggressive and metastatic experimental lymphoma, ACS Applied Materials & Interfaces 7 (36) (2015) 20021-20033.
• D. D. Perrin, W. L. Armarego, Purification of laboratory chemicals, 2nd Edition, Pergamon Press, Oxford, 1988.
• M. Mısır, S. S. Yılmaz, A. Bilgin, Synthesis and characterization of ABA-type triblock copolymers using novel bifunctional PS, PMMA, and PCL macroinitiators bearing p-xylene-bis (2-mercaptoethyloxy) core, Polymers 15 (18) (2023) Article Number 3813 25 pages.
• K. Kamenova, E. Haladjova, G. Grancharov, M. Kyulavska, V. Tzankova, D. Aluani, K. Yoncheva, S. Pispas, P.Petrov, Co-assembly of block copolymers as a tool for developing novel micellar carriers of insulin for controlled drug delivery, European Polymer Journal 104 (2018) 1-9.
• L. M. Shaw, Tumor cell invasion assays, Vol 294 of Cell Migration. Methods in Molecular Biology, 2005, Humana Press, pp. 97-105.
• F. Nederberg, E. F. Connor, M. Möller, T. Glauser, J. L. Hedrick, New paradigms for organic catalysts: The first organocatalytic living polymerization. Angewandte Chemie (International ed in English). 40 (14) (2001) 2712-2715.
• J. Burke, R. Donno, R. d'Arcy, S. Cartmell, N. Tirelli, The effect of branching (star architecture) on poly (D, L-lactide)(PDLLA) degradation and drug delivery, Biomacromolecules 18 (3) (2017) 728-739.
• A. Ali, R. Bhadane, A. A. Asl, C-E. Wilén, O. Salo-Ahen, J. M. Rosenholm, K.K. Bansal, Functional block copolymer micelles based on poly (jasmine lactone) for improving the loading efficiency of weakly basic drugs, RSC Advances 12 (41) (2022) 26763-26775.
• M. Stanković, C. Hiemstra, H. de Waard, J. Zuidema, R. Steendam, H.W. Frijlink, W. L. Hinrichs, Protein release from water-swellable poly(D,L-lactide-PEG)-b-poly(ϵ-caprolactone) implants, International Journal of Pharmaceutics 480 (1-2) (2015) 73–83.
• K. Khodadust, P. Mutlu, S. Yalcın, G. Unsoy, U. Gunduz, Doxorubicin loading, release, and stability of polyamidoamine dendrimer-coated magnetic nanoparticles. Journal of Pharmaceutical Sciences 102 (6) (2013) 1825-1835.
• K. Khodadust, G. Unsoy, S. Yalcın, G. Gunduz, U. Gunduz, PAMAM dendrimer-coated iron oxide nanoparticles: synthesis and characterization of different generations, Journal of Nanoparticle Research 15 (2013) 1-13.
• C. Yuan, J. Gao, J. Guo, L. Bai, C. Marshall, Z. Cai, L. Wang, M. Xiao, Dimethyl sulfoxide damages mitochondrial integrity and membrane potential in cultured astrocytes, PloS One 9 (9) (2014) Article Number e107447.
• F. Hajighasemi, S. Tajic, Assessment of cytotoxicity of dimethyl sulfoxide in human hematopoietic tumor cell lines. Iranian Journal of Blood and Cancer 9 (2) (2017) 48-53.