Posted by Microencapsulation of drugs with cyclodextrins (CDs) is a commonly applied strategy to solubilize lipophilic drugs in aqueous environment and/or to enhance drug absorption/penetration. However, the formation of highly stable ligand-CD complexes can result in the entrapment of guest molecules in CD cavity, leading to the disruption of ligand-protein interaction, poor membrane penetration, and/or faster excretion from the body. This latter principle explains the medical application of sugammadex to rapidly terminate rocuronium-induced skeletal muscle relaxation [1] or the utilization of hydroxypropyl-beta-CD to decrease the accumulation of intracellular unesterified cholesterol in Niemann-Pick type C disease [2]. As we shortly summarized in our recent report, it is reasonable to hypothesize that approximately 10^4 L/mol or higher binding constants (K) of ligand-CD complexes may give a good starting point to examine the protective action of a CD against xenobiotics-induced toxicity [3]. Antidotal impacts of CDs have been examined in some studies, employing typically in vitro or in vivo models. Therefore, only very limited information is available in regard to the comparison of in vitro vs. in vivo results. Now, I will shortly summarize the major observations and conclusions based on our recent studies.
1st study [4]: Under physiological conditions, native beta-CD formed less stable complexes (K = 6.5 × 10^3 L/mol) with mycotoxin zearalenone compared to its chemically-modified derivatives succinyl-methyl-beta-CD (K = 4.7 × 10^4 L/mol), methyl-beta-CD (K = 2.0 × 10^4 L/mol), and sulfobutyl-beta-CD (K = 1.4 × 10^4 L/mol). In agreement with these data, native beta-CD barely affected while its above-listed derivatives strongly alleviated the zearalenone-induced cytotoxicity in HeLa cells. In zebrafish embryos, even beta-CD showed strong protective effects vs. the toxic impacts of zearalenone, and chemically-modified CDs listed were more effective than beta-CD. Thus, in this study, complex stability, in vitro experiments, and in vivo studies showed excellent correlations.
2nd study [5]: We explored that sugammadex forms highly stable complexes with mycotoxin alternariol (K = 4.8 × 10^4 L/mol) compared to any other CDs tested previously, including native beta-CD (K = 3.2 × 10^2 L/mol) and sulfobutyl-beta-CD (K = 4.8 × 10^3 L/mol). In accordance with this observation, sugammadex showed strong protective action against alternariol-induced cytotoxicity in HeLa cells, while sulfobutyl-beta-CD and beta-CD caused minor and no protective effects, respectively. Each CD listed proved to be protective in zebrafish experiments: Surprisingly, native beta-CD was more effective in this model than sulfobutyl-beta-CD and sugammadex.
3rd study [3]: A recent report described the strong interactions of the antipsychotic drug chlorpromazine with certain CDs, suggesting 2 × 10^4 L/mol and 6 × 10^9 L/mol as the binding constants of the 1:1 complex of chlorpromazine with sulfobutyl-beta-CD and the 1:2 complex of chlorpromazine with sugammadex, respectively [6]. In our study, both sulfobutyl-beta-CD and sugammadex strongly relieved the chlorpromazine-induced cytotoxicity in SH-SY5Y cells. Sulfobutyl-beta-CD proved to be also protective in NMRI mice, while sugammadex did not affect (lower dose) or even increased (higher dose) the chlorpromazine-induced 24 h mortality.
Major conclusions: (1) Binding constants showed good correlation with the results of in vitro cell experiments: If the binding constant of the ligand-CD complex is higher, then the protective effect of the CD is typically stronger. (2) Sometimes the results of in vitro and in vivo experiments show good correlations (e.g., in the 1st study), while other examples (e.g., 2nd and 3rd studies) demonstrated that cell experiments provided poor predictions for the impacts in animal studies. (3) High binding constants of ligand-CD complexes and strong protective actions of CDs in cell experiments can give a good starting point to develop new CD-based antidotes; however, certain, still unknown, parameters/interactions can overwrite the expectations in animal experiments.
References:
[1] Keating, G.M., Sugammadex: A Review of Neuromuscular Blockade Reversal. Drugs 76 (2016) 1041–1052. https://doi.org/10.1007/s40265-016-0604-1
[2] Davidson, J.; Molitor, E.; Moores, S.; Gale, S.E.; Subramanian, K.; Jiang, X.; Sidhu, R.; Kell, P.; Zhang, J.; Fujiwara, H.; Davidson, C.; Helquist, P.; Melancon, B.J.; Grigalunas, M.; Liu, G.; Salahi, F.; Wiest, O.; Xu, X.; Porter, F.D.; Pipalia, N.H.; Cruz, D.L.; Holson, E.B.; Schaffer, J.E.; Walkley, S.U.; Maxfield, F.R.; Ory, D.S., 2-Hydroxypropyl-b-cyclodextrin is the active component in a triple combination formulation for treatment of Niemann-Pick C1 disease. Biochim. Biophys. Acta 1864 (2019) 1545–1561. https://doi.org/10.1016/j.bbalip.2019.04.011
[3] Fliszár-Nyúl, E.; Csepregi, R.; Benkovics, G.; Szente, L.; Poór, M., Testing the Protective Effects of Sulfobutylether-Beta-Cyclodextrin (SBECD) and Sugammadex against Chlorpromazine-Induced Acute Toxicity in SH-SY5Y Cell Line and in NMRI Mice. Pharmaceutics 14 (2022) 1888. https://doi.org/10.3390/pharmaceutics14091888
[4] Faisal, Z.; Garai, E.; Csepregi, R.; Bakos, K.; Fliszár-Nyúl, E.; Szente, L.; Balázs, A.; Cserháti, M.; Kőszegi, T.; Urbányi, B.; Csenki, Z.; Poór, M. Protective effects of beta-cyclodextrins vs. zearalenone-induced toxicity in HeLa cells and Tg(vtg1:mCherry) zebrafish embryos. Chemosphere 2020, 240, 124948. https://doi.org/10.1016/j.chemosphere.2019.124948
[5] Fliszár-Nyúl, E.; Bock, I.; Csepregi, R.; Szente, L.; Szabó, I.; Csenki, Z.; Poór, M. Testing the protective effects of cyclodextrins vs. alternariol-induced acute toxicity in HeLa cells and in zebrafish embryos. Environ. Toxicol. Pharmacol. 2022, 95, 103965. https://doi.org/10.1016/j.etap.2022.103965
[6] Wang, Z.; Landy, D.; Sizun, C.; Cézard, C.; Solgadi, A.; Przybylski, C.; de Chaisemartin, L.; Herfindal, L.; Barratt, G.; Legrand, F.-X., Cyclodextrin complexation studies as the first step for repurposing of chlorpromazine. Int. J. Pharmaceut. 584 (2020) 119391. https://doi.org/10.1016/j.ijpharm.2020.119391