Biocompatibility of cucurbit[n]urils
Abstract
This review considers the biological properties of nitrogen-containing macrocyclic glycoluryl derivatives – cucurbit[n]urils (CB[n]). Currently, the use of biomaterials that come into contact with the internal environment of the body is widespread in medicine. Of particular interest is the possibility of giving biocompatible biomaterials new properties by impregnating them with various chemical compounds, fine-tuning these properties for each specific task. One example of such customization is the use of cucurbit[n]urils. Cucurbit[n]urils are a class of macrocyclic organic compounds that are hollow molecules in a “barrel” shape. Their structure is formed from glycoluryl (a urea derivative) and formaldehyde linked into a cyclic framework. The cavity of cucurbit[n]urils is hydrophobic and the entrances are hydrophilic, allowing them to “capture” and retain guest molecules. They are chemically stable, resistant to acids and high temperatures, and able to select guest molecules based on their size, shape and chemical nature. The presented review focuses on the properties of cucurbit[n]urils, their biological activity, in vitro and in vivo toxicity, their potential use in medicine as antidotes, for disease diagnosis, and targeted drug delivery. General information about cucurbit[n]urils as a basis for creating biomaterials for medical purposes and targeted drug delivery agents is considered. Generalized experimental data on the toxicity of cucurbit[n]urils both in vitro and in vivo are overviewed.
Keywords
Full Text:
PDFReferences
Lagona J, Mukhopadhyay P, Chakrabarti S, Isaacs L. The cucurbit[n]uril family. Angew Chem Int Ed. 2005;44(31):4844-70.
Assaf KI, Nau WM. Cucurbiturils: From synthesis to high-affinity binding and catalysis. Chem Soc Rev. 2015;44(2):394-418. doi:10.1002/anie.200460675
Kim K, Selvapalam N, Young S, Young HK, et al. Functionalized cucurbiturils and their applications. Chem Soc Rev. 2007;36(2):267-79. doi:10.1039/b603088m
Das D, Assaf KI, Nau WM. Applications of cucurbiturils in medicinal chemistry and chemical biology. Front Chem. 2019;7(September):1-23. doi:10.3389/fchem.2019.0061
Liu YH, Zhang YM, Yu HJ, Liu Y. Cucurbituril-Based Biomacromolecular Assemblies. Angew Chem Int Ed. 2021;60(8):3870-80. doi:10.1002/anie.202009797
Wagner A, Ly KH, Heidary N, Szabó I, Földes T, et al. Host-guest chemistry meets electrocatalysis: cucurbit[6]uril on a au surface as a hybrid system in CO2 reduction. ACS Catal. 2020;10(1):751-61. doi:10.1021/acscatal.9b04221
Assaf KI, Nau WM. Cucurbiturils: From synthesis to high-affinity binding and catalysis. Chem Soc Rev. 2015;44(2):394-418. doi:10.1039/C4CS00273C
Buczkowski A, Dominikowska J, Urbaniak P, Schroeder G, et al. Doubly or triply protonated? Complexes of cucurbit[n]urils (n = 6–8) with a tripodal ligand tris(2-aminoethyl)amine (TREN). J Mol Liq. 2021;336:116347. doi:10.1016/j.molliq.2021.116347
Zhu L, Zhu M, Zhao Y. Controlled movement of cucurbiturils in host–guest systems. ChemPlusChem. 2017;82(1):30-41. doi:10.1002/cplu.201600309
Webber MJ, Appel EA, Meijer EW, Langer R. Supramolecular biomaterials. Nat Mater. 2015;15(1):13-26. doi:10.1038/nmat4474
Song X, Cao M, Chen R, Wang H, Li H. Enhanced selectivity and stability towards CO2 reduction of sub-5 nm AuNPs derived from supramolecular assembly. Chem Commun (Camb). 2021;57(20):2491-4. doi:10.1039/d0cc08353d
Liu F, Chowdhury S, Rosas R, Monnier V, et al. Triple stack of a viologen derivative in a CB[10] Pair. Org Lett. 2021;23(14):5283-7. doi:10.1021/acs.orglett.1c00773
Lucas D, Minami T, Iannuzzi G, Cao L, Wittenberg JB, et al. Templated synthesis of glycoluril hexamer and monofunctionalized cucurbit[6]uril derivatives. J Am Chem Soc. 2011;133(44):17966-76. doi:10.1021/ja207198x
Bodoor K, El Barghouthi MI, Assaf KI, Jawabrah B, et al. A molecular dynamics study of the complexation of tryptophan, phenylalanine and tyrosine amino acids with cucurbit[7]uril. J Incl Phenom Macrocycl Chem. 2021;99(3-4):243-53. doi:10.1007/s10847-021-01211-3
Berta D, Szabó I, Scherman OA, Rosta E. Toward Understanding CB[7]-Based Supramolecular Diels-Alder Catalysis. Front Chem. 2020;8:1-10. doi:10.3389/fchem.2020.587084
Senthilnathan D, Solomon RV, Kiruthika S, Venuvanalingam P, et al. Are cucurbiturils better drug carriers for bent metallocenes? Insights from theory. J Biol Inorg Chem. 2018;23(3):413-23. doi:10.1007/s00775-018-1547-7
Singharoy D, Mati SS, Ghosh S, Bhattacharya SC, et al. CB[7] as a drug vehicle and controlled release of drug through non ionic surfactant: Spectroscopic technique. Colloids Surf B Biointerfaces. 2017;160:84-91. doi:10.1016/j.colsurfb.2017.08.067
Oun R, Plumb JA, Wheate NJ, et al. A cisplatin slow-release hydrogel drug delivery system based on a formulation of the macrocycle cucurbit[7]uril, gelatin and polyvinyl alcohol. J Inorg Biochem. 2014;134:100-5. doi:10.1016/j.jinorgbio.2014.01.015
Cheng G, Luo J, Liu Y, Chen X, et al. Cucurbituril-Oriented Nanoplatforms in Biomedical Applications. ACS Appl Bio Mater. 2020;3(12):8211-40. doi:10.1021/acsabm.0c01061
Andrae B, Bauer D, Gaß P, Koller M, et al. Influence of cyclic and acyclic cucurbiturils on the degradation pathways of the chemical warfare agent VX. Org Biomol Chem. 2020;18(27):5218-27. doi:10.1039/d0ob01167c
Yin H, Zhang X, Wei J, Lu S, et al. Recent advances in supramolecular antidotes. Theranostics. 2021;11(3):1513-26. doi:10.7150/thno.53459
Pedrini A, et al. The Role of Chain Length in Cucurbit[8]uril Complexation of Methyl Alkyl Viologens. Eur J Org Chem. 2021;2021(10):1547-52. doi:10.1002/ejoc.202100014
Kolesnichenko IV, Anslyn EV. Practical applications of supramolecular chemistry. Chem Soc Rev. 2017;46(9):2385-90. doi:10.1039/C7CS00078B
Xie X, et al. The Adsorption of Reactive Blue 19 Dye onto Cucurbit[8]uril and Cucurbit[6]uril: An experimental and theoretical study. J Phys Chem B. 2016;120(17):4131-42. doi:10.1021/acs.jpcb.6b03565
Li X, et al. Adsorption of reactive yellow X-RG and reactive brilliant red X-3B onto cucurbit[8]uril and cucurbit[6]uril: Effect factors, adsorption behavior and mechanism study. J Colloid Interface Sci. 2017;498:31-46. doi:10.1016/j.jcis.2017.04.044
Luo H, et al. Adsorption behavior and mechanism of acidic blue 25 dye onto cucurbit[8]uril: A spectral and DFT study. Spectrochim Acta A Mol Biomol Spectrosc. 2018;193:125-32. doi:10.1016/j.saa.2017.12.006
Zhu L, et al. A Highly selective and strong anti-interference host-guest complex as fluorescent probe for detection of amantadine by indicator displacement assay. Molecules. 2018;23(4):E769. doi:10.3390/molecules23040947
Yang MX, et al. pH-stimulus response dye-cucurbituril sensor for amino acids in aqueous solution. Spectrochim Acta A Mol Biomol Spectrosc. 2020;230:118076. doi:10.1016/j.saa.2020.118076
Corda E, et al. Cucurbit[n]urils (n = 6–8) used as host molecules on supramolecular complexes formed with two different drugs: Emodin and indomethacin. Colloids Surf A Physicochem Eng Asp. 2018;557:66-75. doi:10.1016/j.colsurfa.2018.03.053
Wu X, Zhang YM, Liu Y. Nanosupramolecular assembly of amphiphilic guest mediated by cucurbituril for doxorubicin delivery. RSC Adv. 2016;6(102):99729-34. doi:10.1039/C6RA21900D
Lytkina DN, Gutsalova AA, Fedorishin DA, Korotchenko NM, Akhmedzhanov RR, Kozik VV, Kurzina IA. Synthesis and properties of zinc-modified hydroxyapatite. J Funct Biomater. 2020;11(1):10. doi:10.3390/jfb11010010
Wheate NJ, et al. Cucurbit[n]uril binding of platinum anticancer complexes. Dalton Trans. 2006;(3):451-8. doi:10.1039/b513197a
Sasmal S, Sinha MK, Keinan E. Facile purification of rare cucurbiturils by affinity chromatography. Org Lett. 2004;6(8):1225-8. doi:10.1021/ol0499755
Deshayes S, Gref R, et al. Synthetic and bioinspired cage nanoparticles for drug delivery. Nanomedicine (Lond). 2014;9(10):1545-64. doi:10.2217/nnm.14.67
Saha P, Bhunia A, Saikia A. Synthesis of 2,3,5,6-tetrasubstituted tetrahydropyrans via (3,5)-oxonium-ene reaction. Org Biomol Chem. 2012;10:2470-81. doi:10.1039/c2ob06832j
Ghosh I, Nau WM. The strategic use of supramolecular pKa shifts to enhance the bioavailability of drugs. Adv Drug Deliv Rev. 2012;64(9):764-83. doi:10.1016/j.addr.2012.01.015
Yin H, et al. Challenges and opportunities of functionalized cucurbiturils for biomedical applications. JACS Au. 2023;3(9):2356-77. doi:10.1021/jacsau.3c00273
Ustrnul L, et al. Binding between cyclohexanohemicucurbit[n]urils and polar organic guests. Front Chem. 2021;9:1-13. doi:10.3389/fchem.2021.701028
Kim T, et al. Supramolecular Two-Dimensional Systems and Their Biological Applications. Adv Mater. 2020;32(51):e2004529. doi:10.1002/adma.202002405
Webber M, et al. Supramolecular PEGylation of biopharmaceuticals. Proc Natl Acad Sci U S A. 2016;113(50):14189-94. doi:10.1073/pnas.1616639113
Chen H, et al. Hexanoate-Cucurbit[7]uril: Highly Soluble with Controlled Release Ability. Chem. 2020;26(43):9445-8. doi:10.1002/chem.202001959
Ganapati S, Isaacs L. Acyclic Cucurbit[n]uril-type receptors: preparation, molecular recognition properties and biological applications. Isr J Chem. 2018;58(3-4):250-63. doi:10.1002/ijch.201700098
Miskolczy Z, Biczók L. Kinetics and Thermodynamics of Berberine Inclusion in Cucurbit[7]uril. J Phys Chem B. 2014;118(9):2499-505. doi:10.1021/jp500603g
Bhaumik SK, Biswas R, Banerjee S. Cucurbituril based luminescent materials in aqueous media and solid state. Chem Asian J. 2021;16(16):2195-210. doi:10.1002/asia.202100594
Li Y, et al. Molecular basis of cooperativity in pH-triggered supramolecular self-assembly. Nat Commun. 2016;7:13214. doi:10.1038/ncomms13214
Gaeta C, Wang DX. Editorial: New Macrocycles and Their Supramolecular Perspectives. Front Chem. 2020;8:128. doi:10.3389/fchem.2020.00128
Zhou J, et al. Supramolecular biofunctional materials. Biomaterials. 2017;129:1-27. doi:10.1016/j.biomaterials.2017.03.014
Steed JW, Atwood JL, Gale PA. Definition and emergence of supramolecular chemistry. 2nd ed. Chichester: John Wiley & Sons, Ltd; 2012. p. 1-4. doi:10.1002/9780470661345.ch1
Walker S, et al. The Potential of Cucurbit[n]urils in Drug Delivery. Isr J Chem. 2011;51(5-6):616-24. doi:10.1002/ijch.201100033
Bojesomo RS, et al. Benzimidazole–Piperazine–Coumarin/Cucurbit[7]uril Supramolecular Photoinduced Electron Transfer Fluorochromes for Detection of Carnosol by Stimuli-Responsive Dye Displacement and pKa Tuning. ACS Omega. 2022;7(7):5769-81. doi:10.1021/acsomega.1c06287
Apurba K, et al. Supramolecular encapsulation of benzimidazole-derived drugs by cucurbit[7]uril. Can J Chem. 2011;89(2):139-47. doi:10.1139/V10-079
Zhao Y, Truhlar DG. Size-Selective Supramolecular Chemistry in a Hydrocarbon Nanoring. J Am Chem Soc. 2007;129(27):8440-2. doi:10.1021/ja071884q
Chernikova EY, Berdnikova DV. Cucurbiturils in nucleic acids research. Chem Commun (Camb). 2020;56(98):15360-76. doi:10.1039/D0CC06583H
Gale PA, Steed JW, editors. Supramolecular Chemistry: From Molecules to Nanomaterials. Hoboken, NJ: Wiley; 2012. doi:10.1002/9780470661345.smc066
Koc A, Khan R, Tuncel D. “Clicked” Porphyrin-Cucurbituril Conjugate: A New Multifunctional Supramolecular Assembly Based on Triglycosylated Porphyrin and Monopropargyloxycucurbit[7]uril. Chem. 2018;24(58):15550-5. doi:10.1002/chem.201804024
Aktanova A, et al. Assessment of the biocompatibility of cucurbiturils in blood cells. Nanomaterials (Basel). 2021;11(6):1423. doi:10.3390/nano11061356
Szoka L, Isidorov V, Nazaruk J, Stocki M, et al. Cytotoxicity of Triterpene Seco-Acids from Betula pubescens Buds. Molecules. 2019;24(22):4060. doi:10.3390/molecules24224060
Fink S, et al. Evaluation of cell and hemocompatibility of Cucurbiturils. Eur J Pharm Sci. 2020;146:105271. doi:10.1016/j.ejps.2020.105271
Hettiarachchi G, et al. Toxicology and drug delivery by cucurbit[n]uril type molecular containers. PLoS One. 2010;5(5):e10514. doi:10.1371/journal.pone.0010514
Burkhanbayeva T, et al. Development of new composite materials by modifying the surface of porous hydroxyapatite using cucurbit[n]urils. Materials (Basel). 2024;17(9):2041. doi:10.3390/ma17092041
Vikhrov SP. Biomedical Materials Science. Moscow: Goryachaya Liniya-Telekom; 2006. Russian.
Chelu M, Musuc AM. Advanced biomedical applications of multifunctional natural and synthetic biomaterials. Processes. 2023;11(9):2602. doi:10.3390/pr11092696
Vadalà G, et al. Bioceramics and Biocomposites in Spine Surgery. Handbook of Bioceramics and Biocomposites. Cham: Springer International Publishing; 2016. p. 967-87. doi:10.1007/978-3-319-12460-5_44
Shpinyak SP. Experimental study of antimicrobial activity of hydroxyappatite and metal nanoparticles in vitro. Mod Probl Sci Educ. 2015;(6):75-84. Russian.
Marchenko E, et al. Functionalization of the surface of porous nickel–titanium alloy with macrocyclic compounds. Materials (Basel). 2023;16(1):65. doi:10.3390/ma16010066
Oun R, et al. The ex vivo neurotoxic, mytoxic and cardiotoxic activity of cucurbituril-based macrocyclic drug delivery vehicles. Toxicol Res (Camb). 2014;3(6):447-55. doi:10.1039/C4TX00082J
Lei W, et al. Greatly enhanced binding of a cationic porphyrin towards bovine serum albumin by cucurbit[8]uril. Phys Chem Chem Phys. 2010;12(40):13255-60. doi:10.1039/C001013H
Urbach AR, Ramalingam V. Molecular recognition of amino acids, peptides, and proteins by cucurbit[n]uril receptors. Isr J Chem. 2011;51(5-6):664-78. doi:10.1002/ijch.201100035
Uzunova V, et al. Toxicity of cucurbit[7]uril and cucurbit[8]uril: An exploratory in vitro and in vivo study. Org Biomol Chem. 2010;8(9):2037-42. doi:10.1039/B925555A
Gangemi CMA, et al. Supramolecular complexes for nanomedicine. Bioorg Med Chem Lett. 2018;28(20):3290-301. doi:10.1016/j.bmcl.2018.09.015
Neira I, et al. Cucurbiturils as Effectors on the Self-Assembly of Pd(II) and Pt(II) Metallacycles. J Org Chem. 2021;86(21):14608-16. doi:10.1021/acs.joc.1c01460
Wang L, et al. Host-guest supramolecular nanosystems for cancer diagnostics and therapeutics. Adv Mater. 2013;25(28):3888-98. doi:10.1002/adma.201301202
Zhang X, et al. A systematic evaluation of the biocompatibility of cucurbit[7]uril in mice. Sci Rep. 2018;8(1):8819. doi:10.1038/s41598-018-27206-6
Suriya Prabha A, et al. Chapter 7 - Recent advances in the study of toxicity of polymer-based nanomaterials. Nanotoxicity: Prevention and Antibacterial Applications of Nanomaterials. Elsevier; 2020. p. 143-65. doi:10.1016/B978-0-12-819943-5.00007-5
Canton M, et al. Reactive Oxygen Species in Macrophages: Sources and Targets. Front Immunol. 2021;12:734229. doi:10.3389/fimmu.2021.734229
DOI: https://doi.org/10.15826/chimtech.9216
Copyright (c) 2025 Dmitry A. Fedorishin, Sedigheh Mousanezhad, Shohreh Mashayekhan, Yelena G. Shapovalova, Irina A. Kurzina a, Abdigali A. Bakibaev

This work is licensed under a Creative Commons Attribution 4.0 International License.
Chimica Techno Acta, 2014–2025
eISSN 2411-1414
Copyright Notice





