Liposome-coated metal-organic frameworks as the efficient drug delivery system for therapeutic applications

Abstract

Zeolitic imidazole framework-8 (ZIF-8) particles, composed of zinc ions (Zn²⁺) and 2-methylimidazolate, were used as carriers for incorporating iron oxide (Fe₃O₄) nanoparticles, resulting in Fe₃O₄@ZIF-8 particles. Due to the toxicity of Zn²⁺ to cell membranes, liposomes were employed to reduce this toxicity. Fluorescent dyes were loaded into ZIF-8 or Fe₃O₄@ZIF-8 nanoparticles as the mock drugs to facilitate tracking during cellular studies. The encapsulation efficiency of fluorescein (Flu) and nile red (NiR) in the MOFs was calculated to be around 40%-60%. A burst release of Flu was observed under acidic conditions within 30 min, while natural PBS was significantly release in 6 h. The release kinetic of the whole platform was fixed as the Higuchi equation which referred to diffusion release. Liposome coating significantly decreased the toxicity of the MOFs, as evidenced by an increase in IC₅₀ values from approximately 30 to 120 µg/mL. The LDH release from L929 cells was confirmed when particles were used at exceeding 100 µg/mL. The cellular uptake of the liposome-coated dye-loaded MOFs was confirmed after 3 hour-incubation. These findings suggested that liposome-coated MOFs could be served as an alternative carrier in biomedical engineering field.

Keywords

Liposome / Metal-organic frameworks (MOFs) / Cellular uptake / Drug delivery system (DDS) / Fluorescent dyes

Declaration of Competing Interest

The authors declare that they have no competing financial interests or personal relationships that may have influenced the work reported in this study.

CRediT authorship contribution statement

Natchanon Ratanapun: Writing - original draft, Visualization, Software, Methodology, Investigation, Formal analysis. Komgrit Eawsakul: Writing - review & editing, Methodology, Formal analysis. Naruemon Setthaya: Writing - review & editing, Methodology, Investigation, Formal analysis. Chakkresit Chindawong: Writing - review & editing, Methodology, Investigation, Formal analysis. Wei Guo Song: Writing - review & editing. Chawan Manaspon: Writing - review & editing, Validation, Supervision, Software, Methodology, Investigation, Conceptualization. Pagasukon Mekrattanachai: Writing - review & editing, Validation, Supervision, Software, Methodology, Investigation, Funding acquisition, Conceptualization.

Acknowledgements

The authors are grateful for the fundamental fund from the University of Phayao (FF67-1848/2567). The authors would like to thank the Unit of Excellence on Advanced Nanomaterials which was supported by the Thailand Science Research and Innovation Fund and the University of Phayao. This research work was supported by Chiang Mai University.

Supplementary materials

Supplementary material associated with this article can be found, in the online version, at doi:10.1016/j.chphma.2025.08.004.

References

[1] S. Bamrungsap, Z. Zhao, T. Chen, L. Wang, C. Li, T. Fu, W. Tan, Nanotechnology in therapeutics: A focus on nanoparticles as a drug delivery system, Nanomed. (Lond.) 7 (2012) 1253-1271, doi:10.2217/nnm.12.87.

[2] L. Sun, H. Liu, Y. Ye, Y. Lei, R. Islam, S. Tan, R. Tong, Y.B. Miao, L. Cai, Smart nanoparticles for cancer therapy, Sig. Transduct. Target. Ther. 8 (2023) 418, doi:10.1038/s41392-023-01642-x.

[3] J. Halder, D. Pradhan, P. Biswasroy, V.K. Rai, B. Kar, G. Ghosh, G. Rath, Trends in iron oxide nanoparticles: A nano-platform for theranostic application in breast cancer, J. Drug. Target. 30 (2022) 1055-1075, doi:10.1080/1061186X.2022.2095389.

[4] H. Park, A. Otte, K. Park, Evolution of drug delivery systems: From 1950 to 2020 and beyond, J. Controll. Release 342 (2022) 53-65, doi:10.1016/j.jconrel.2021.12.030.

[5] A.M. Wright, M.T. Kapelewski, S. Marx, O.K. Farha, W. Morris, Transitioning metalorganic frameworks from the laboratory to market through applied research, Nat. Mater. 24 (2025) 178-187, doi:10.1038/s41563-024-01947-4.

[6] C. Li, J. Wang, Y. Wang, H. Gao, G. Wei, Y. Huang, H. Yu, Y. Gan, Y. Wang, L. Mei, Recent progress in drug delivery, Acta Pharm. Sin. B 9 (2019) 1145-1162, doi:10.1016/j.apsb.2019.08.003.

[7] J. Cao, X. Li, H. Tian, Metal-organic framework (MOF)-based drug delivery, Curr. Med. Chem. 27 (2020) 5949-5969, doi:10.2174/0929867326666190618152518.

[8] H. Kaur, G.C. Mohanta, V. Gupta, D. Kukkar, S. Tyagi, Synthesis and characterization of ZIF-8 nanoparticles for controlled release of 6-mercaptopurine drug, J. Drug Deliv. Sci. Technol. 41 (2017) 106-112, doi:10.1016/j.jddst.2017.07.004.

[9] J.A. Greathouse, M.D. Allendorf, The interaction of water with MOF-5 simulated by molecular dynamics, J. Am. Chem. Soc. 128 (2006) 10678-10679, doi:10.1021/ja063506b.

[10] F. Demir Duman, A. Monaco, R. Foulkes, C.R. Becer, R.S. Forgan, Glycopolymerfunctionalized MOF-808 nanoparticles as a cancer-targeted dual drug delivery system for carboplatin and floxuridine, ACS Appl. Nano Mater. 5 (2022) 13862-13873, doi:10.1021/acsanm.2c01632.

[11] Y. Dai, Q. Tang, Z. Zhang, C. Yu, H. Li, L. Xu, S. Zhang, Z. Zou, Enhanced mechanical, thermal, and UV-shielding properties of poly (vinyl alcohol)/metal-organic framework nanocomposites, RSC Adv. 8 (2018) 3868138688, doi:10.1039/C8RA07143H.

[12] A. Ma, R. Zhang, Facile synthesis of redox-responsive paclitaxel drug release platform using metal-organic frameworks (ZIF-8) for gastric cancer treatment, Mater. Res. Express 7 (2020) 095402, doi:10.1088/2053-1591/abb2ce.

[13] Y. Wang, M. Zeng, T. Fan, M. Jia, R. Yin, J. Xue, L. Xian, P. Fan, M. Zhan, Biomimetic ZIF-8 nanoparticles: A novel approach for biomimetic drug delivery systems, Int. J. Nanomed. 19 (2024) 5523-5544, doi:10.2147/IJN.S462480.

[14] X. Sun, F. Li, L. Yuan, Z. Bing, X. Li, K. Yang, pH-responsive resveratrol-loaded ZIF-8 nanoparticles modified with tannic acid for promoting colon cancer cell apoptosis, J. Biomed. Mater. Res. B 112 (2024) e35320, doi:10.1002/jbm.b.35320.

[15] M. Alizadeh, P.A. Azar, S.A. Mozaffari, H. Karimi-Maleh, A.M. Tamaddon, A DNA based biosensor amplified with ZIF-8/ionic liquid composite for determination of mitoxantrone anticancer drug: An experimental/docking investigation, Front. Chem. 8 (2020) 814, doi:10.3389/fchem.2020.00814.

[16] P. Chen, M. He, B. Chen, B. Hu, Size-and dose-dependent cytotoxicity of ZIF8 based on single cell analysis, Ecotoxicol. Environ. Saf. 205 (2020) 111110, doi:10.1016/j.ecoenv.2020.111110.

[17] P. Mekrattanachai, N. Setthaya, C. Chindawong, B. Yotnoi, W.G. Song, C. Manaspon, Synthesis of hydrogels incorporating core-shell structured Fe₃O₄@ZIF-8 as bio-nanocomposite carriers for drug delivery, Aust. J. Chem. 76 (2023) 201-208, doi:10.1071/CH22224.

[18] P. Mekrattanachai, N. Setthaya, C. Chindawong, B. Yotnoi, W.G. Song, N. Ratanapun, S. Tambunlertchai, C. Manaspon, Zeolitic imidazolate framework-8-loaded hydrogels as a highly biocompatible carrier for drug delivery applications, J. Biomim. Biomater. Biomed. Eng. 60 (2023) 29-42, doi:10.4028/p-268hc7.

[19] R.S. Chouhan, M. Horvat, J. Ahmed, N. Alhokbany, S.M. Alshehri, S. Gandhi, Magnetic nanoparticles-A multifunctional potential agent for diagnosis and therapy, Cancers 13 (2021) 2213, doi:10.3390/cancers13092213.

[20] R. Ghazi, T.K. Ibrahim, J.A. Nasir, S. Gai, G. Ali, I. Boukhris, Z. Rehman, Iron oxide based magnetic nanoparticles for hyperthermia, MRI and drug delivery applications: A review, RSC Adv. 15 (2025) 11587-11616, doi:10.1039/D5RA00728C.

[21] Y. Wu, Q. Huang, J. Wang, Y. Dai, M. Xiao, Y. Li, H. Zhang, W. Xiao, The feasibility of targeted magnetic iron oxide nanoagent for noninvasive IgA nephropathy diagnosis, Front. Bioeng. Biotechnol. 9 (2021) 755692, doi:10.3389/fbioe.2021.755692.

[22] J. Nowak-Jary, B. Machnicka, Comprehensive analysis of the potential toxicity of magnetic iron oxide nanoparticles for medical applications: Cellular mechanisms and systemic effects, Int. J. Mol. Sci. 25 (2024) 12013, doi:10.3390/ijms252212013.

[23] A. Samad, Y. Sultana, M. Aqil, Liposomal drug delivery systems: An update review, Curr. Drug. Deliv. 4 (2007) 297-305, doi:10.2174/156720107782151269.

[24] E. Zingale, A. Romeo, S. Rizzo, C. Cimino, A. Bonaccorso, C. Carbone, T. Musumeci, R. Pignatello, Fluorescent nanosystems for drug tracking and theranostics: Recent applications in the ocular field, Pharmaceutics 14 (2022) 955, doi:10.3390/pharmaceutics14050955.

[25] E. Jaradat, E. Weaver, A. Meziane, D.A. Lamprou, Microfluidic paclitaxel-loaded lipid nanoparticle formulations for chemotherapy, Int. J. Pharm. 628 (2022) 122320, doi:10.1016/j.ijpharm.2022.122320.

[26] M. Askarizadeh, N. Esfandiari, B. Honarvar, S.A. Sajadian, A. Azdarpour, Kinetic modeling to explain the release of medicine from drug delivery systems, ChemBioEng Rev. 10 (2023) 1006-1049, doi:10.1002/cben. 202300027.

[27] W.M. Saltzman, Drug delivery:Engineering principles For Drug Therapy, Oxford University Press, New York, 2001.

[28] D. Guimarães, A. Cavaco-Paulo, E. Nogueira, Design of liposomes as drug delivery system for therapeutic applications, Int. J. Pharm. 601 (2021) 120571, doi:10.1016/j.ijpharm.2021.120571.

[29] H. Nsairat, A.A. Ibrahim, A.M. Jaber, S. Abdelghany, R. Atwan, N. Shalan, H. Abdelnabi, F. Odeh, M. El-Tanani, W. Alshaer, Liposome bilayer stability: Empha-sis on cholesterol and its alternatives, J. Liposom. Res. 34 (2024) 178-202, doi:10.1080/08982104.2023.2226216.

[30] J. Huang, X. Mo, H. Fu, Y. Sun, Q. Gao, X. Chen, J. Zou, Y. Yuan, J. Nie, Y. Zhang, Tyndall-effect-enhanced supersensitive naked-eye determination of mercury (II) ions with silver nanoparticles, Sens. Actuators B-Chem. 344 (2021) 130218, doi:10.1016/j.snb.2021.130218.

[31] N.V.N. Jyothi, P.M. Prasanna, S.N. Sakarkar, K.S. Prabha, P.S. Ramaiah, G. Srawan, Microencapsulation techniques, factors influencing encapsulation efficiency, J. Microencapsul. 27 (2010) 187-197, doi:10.3109/02652040903131301.

[32] C. Adhikari, A. Das, A. Chakraborty, Zeolitic imidazole framework (ZIF) nanospheres for easy encapsulation and controlled release of an anticancer drug doxorubicin under different external stimuli: A way toward smart drug delivery system, Mol. Pharm. 12 (2015) 3158-3166, doi:10.1021/acs.molpharmaceut.5b00043.

[33] N.A. Soomro, Q. Wu, S.A. Amur, H. Liang, A.U. Rahman, Q. Yuan, Y. Wei, Natural drug physcion encapsulated zeolitic imidazolate framework, and their application as antimicrobial agent, Colloid. Surf. B Biointerfaces 182 (2019) 110364, doi:10.1016/j.colsurfb.2019.110364.

[34] S. Mohammadkhah, M. Ramezanzadeh, H.E. Mohammadloo, B. Ramezanzadeh, R. Ghamsarizade, Construction of a nano-micro nacre-inspired 2D-MoS₂ -MOFglutamate carrier toward designing a high-performance smart epoxy composite, J. Ind. Eng. Chem. 121 (2023) 358-377, doi:10.1016/j.jiec.2023.01.039.

[35] L.R. de Moura Ferraz, A.É.G.A. Tabosa, D.D.S. da Silva Nascimento, A.S. Ferreira, V. de Albuquerque Wanderley Sales, J.Y.R. Silva, S.A. Júnior, L.A. Rolim, J.J. de Souza Pereira, P.J. Rolim-Neto,ZIF-8 as a promising drug delivery system for benznidazole: Development, characterization, in vitro dialysis release and cytotoxicity, Sci. Rep. 10 (2020) 16815, doi:10.1038/s41598-020-73848-w.

[36] L.R. de Moura Ferraz, A.É.G.A. Tabosa, D.D.S. da Silva Nascimento, A.S. Ferreira, J.Y.R. Silva, S.A. Junior, L.A. Rolim, P.J. Rolim-Neto, Benznidazole in vitro dissolution release from a pH -sensitive drug delivery system using Zif-8 as a carrier, J. Mater. Sci.: Mater. Med. 32 (2021) 59, doi:10.1007/s10856-021-06530-w.

[37] M. Chen, F. Song, N. Wu, H. Luo, X. Cai, Y. Li, Corn-like mSiO₂@ZIF-8 composite load with curcumin for target cancer drug-delivery system, ChemistrySelect 7 (2022) e202204213, doi:10.1002/slct.202204213.

[38] M.U. Amin, S. Ali, M.Y. Ali, I. Tariq, U. Nasrullah, S.R. Pinnapreddy, C. Wölk, U. Bakowsky, J. Brüßler, Enhanced efficacy and drug delivery with lipid coated mesoporous silica nanoparticles in cancer therapy, Eur. J. Pharm. Biopharm. 165 (2021) 31-40, doi:10.1016/j.ejpb.2021.04.020.