The Potential of Cucurbit[<i>n</i>]urils in Drug Delivery

Walker, Shonagh; Oun, Rabbab; McInnes, Fiona; Wheate, Nial J.

doi:10.1002/ijch.201100033

Cited by 256 publications

(277 citation statements)

References 69 publications

(75 reference statements)

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“…1,2 Various approaches have been investigated to improve solubility of drugs, including cocrystal, 3,4 salts, 5 prodrugs, 6 solid dispersion, 7 macrocyclic hosts (e.g., cyclodextrins, cucurbiturils), 8,9 etc. Triamterene, 2,4,7-triamino-6-phenylpteridine (Scheme 1) is a mild potassium-sparing diuretic used either alone or in combination with potassium-wasting diuretics such as hydrochlorothiazide.…”

Section: ■ Introductionmentioning

confidence: 99%

The Delivery of Triamterene by Cucurbit[7]uril: Synthesis, Structures and Pharmacokinetics Study

Chen

Jiang

et al. 2013

Mol. Pharmaceutics

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In recent years, cucurbit [7]uril (CB [7]) has attracted great attention in drug delivery. Though the effect of CB [7] in enhancing the solubility of water insoluble drugs has been validated, the underlying mechanism remains poorly understood, particularly at a molecular level. This study is designed to evaluate a CB [7]-based pharmaceutical formulation to improve solubility and bioavailability of triamterene (a mild potassium-sparing diuretic). Two polymorphs of triamterene@CB [7] were obtained, and their crystal structures were determined by single crystal X-ray diffraction. The CB [7] molecule forms a stable host−guest complex with triamterene (K a = 1.69 ± 0.34 × 10 4 M −1 ) in aqueous solution (pH = 1.0). The results of dissolution study demonstrate that the apparent solubility value of triamterene@CB [7] complex in 0.1 M HCl is 1.6 times as large as that of triamterene, while free triamterene was released from triamterene@CB [7] complex in phosphate buffer of pH 6.8. Pharmacokinetic studies in rats reveal that the AUC 0−∞ value of triamterene@CB [7] complex increases 2.8-fold compared with that of free triamterene, and t 1/2 is prolonged from 1.42 to 2.61 h (P < 0.05) after oral administration. The increased solubility and oral bioavailability are attributed to the formation of a hydrophilic capsule composed of two CB [7] molecules, in which two insoluble triamterene molecules are encapsulated. These results demonstrate that triamterene@CB [7] complex is a stable and effective pharmaceutical formulation. KEYWORDS: cucurbit [7]uril, triamterene, crystal structure, solubility, pharmacokinetics ■ INTRODUCTIONPoor aqueous solubility is a major bottleneck in drug discovery and drug development: more than 40% of drug candidates are poorly water-soluble, and poor aqueous solubility is the main factor to restrict the bioavailability of drugs.1,2 Various approaches have been investigated to improve solubility of drugs, including cocrystal, 3,4 salts, 5 prodrugs, 6 solid dispersion, 7 macrocyclic hosts (e.g., cyclodextrins, cucurbiturils), 8,9 etc. Triamterene, 2,4,7-triamino-6-phenylpteridine (Scheme 1) is a mild potassium-sparing diuretic used either alone or in combination with potassium-wasting diuretics such as hydrochlorothiazide.10,11 It displays low oral bioavailability, and there exists wide intersubject variation because of its poor aqueous solubility (45 mg/L). 12,13 Though triamterene contains three primary amine groups, various methods to obtain soluble salts failed, probably due to its weak basicity. 12 To date, only a few formulations have been proposed to improve the solubility of triamterene, including cyclodextrins 14,15 and solid dispersions. 16,17 However, parenteral administration of β-cyclodextrin results in renal toxicity, 18 and solid dispersions are often physically unstable upon storage at elevated temperature and humidity, 19 and neither of the two triamterene formulations has been applied for clinical therapy. Therefore, the development of new pharmaceutical formulation of triam...

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Section: ■ Introductionmentioning

confidence: 99%

The Delivery of Triamterene by Cucurbit[7]uril: Synthesis, Structures and Pharmacokinetics Study

Chen

Jiang

et al. 2013

Mol. Pharmaceutics

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“…CB also favour the binding of protonated forms of drugs, known as pK a shifts, that may be relevant in tumours where the pH is usually slightly acidic. 30,32 [Saleh 2013, Walker 2011 The modelling results of this study suggest that a TPZ@CB [7] complex may be quite stable, and that release of the TPZ from the complex is also feasible. A TPZ@CB [7] could offer an alternative drug delivery vehicle approach to the conventional structure activity approach to improving drug transport and efficacy.…”

Section: Dft Modelling Of Tpz@cb[7]mentioning

confidence: 79%

“…Recently there has been much interest in using cucurbit[n]urils (CB) as molecular delivery containers that enhance drug delivery to the intended target by protecting the drug from attack and degradation by biological agents. [30][31][32] [Saleh 2013, Nau 2011, Walker 2011] Many drugs have been found to be encapsulated within the cavity of CB, particularly cucurbit [7]urils, CB [7], and it may that TPZ or some its analogues may also form inclusion complexes with CB [7]. If this were so, then the formation of TPZ@CB [7] inclusion complexes may be beneficial in delivering increased quantities of TPZ compared to free TPZ to tumours and so increasing anti-cancer efficacy within the tumour.…”

Section: [Agarwal 2015]mentioning

confidence: 99%

The extravascular penetration of tirapazamine into tumours: a predictive model of the transport and efficacy of hypoxia specific cytotoxic analogues and the potential use of cucurbiturils to facilitate delivery

Fong¹

2017

IJCBDD

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To cite this version:Clifford Fong. The extravascular penetration of tirapazamine into tumours: a predictive model of the transport and efficacy of hypoxia specific cytotoxic analogues and the potential use of cucurbiturils to facilitate delivery. [Research Report] Eigenenergy. 2017, pp.2017 -2017 International Journal of Computational Biology and Drug Design: In press 2017 The extravascular penetration of tirapazamine into tumours: a predictive model of the transport and efficacy of hypoxia specific cytotoxic analogues and the potential use of cucurbiturils to facilitate delivery.Clifford W. Fong Eigenenergy, Adelaide, South Australia. AbstractA multiparameter model of the diffusion, antiproliferative assays IC 50 and aerobic and hypoxic clonogenic assays for a wide range of neutral and radical anion forms of tirapazamine (TPZ) analogues has found that: (a) extravascular diffusion is governed by the desolvation, lipophilicity, dipole moment and molecular volume, similar to passive and facilitated permeation through the blood brain barrier and other cellular membranes, (b) hypoxic assay properties of the TPZ analogues show dependencies on the electron affinity, as well as lipophilicity and dipole moment and desolvation, similar to other biological processes involving permeation of cellular membranes, including nuclear membranes, (c) aerobic properties are dependent on the almost exclusively on the electron affinity, consistent with electron transfer involving free radicals being dominant with little or no drug permeation of membranes, and most likely occurring in the extracellular matrix. Application of the model to the DNA binding equilibrium constants of TPZ analogues with acridine or acridine-like moieties show that ligand water desolvation and lipophilicity are the dominant processes governing the DNA intercalation of TPZ analogues. This conclusion is consistent with DFT modelling of the complexes formed by TPZ analogues with neutral and N-protonated acridine moieties which intercalate with the guanine DNA nucleobases.A quantum mechanical study has shown that TPZ can form stable complexes with cucurbit [7]uril as a precursor to proof of principle of improved TPZ delivery to tumours.Keywords: Tirapazamine analogues, intra-tumoural diffusion, anti-cancer, hypoxia, cytotoxicity, DNA binding, cucurbiturils, quantum mechanics Abbreviations Tirapazamine TPZ, free energy of water desolvation ΔG desolv,CDS , lipophilicity free energy ΔG lipo,CDS , cavity dispersion solvent structure of the first solvation shell CDS, multicellular layers MCL, extracellular matrix ECM, diffusion through support membrane D s , diffusion through multicellular layer D MCL , cucurbit[n]urils CB, cucurbit [7]urils, CB [7], highest occupied molecular orbital HOMO, lowest unoccupied molecular orbital LUMO, density functional molecular orbital theory DFT, adiabatic electron affinity AEA, cisplatin CisPt, ratio aerobic property:hypoxic property HCR, aerobic aer, hypoxic hyp, DNA binding equilibrium constant K DNA, multiple correlation coeffici...

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“…[45][46] CBn hosts have considerable potential in the delivery, stabilization, solubilization and controlled release of drugs. [47][48] We have demonstrated that berberine (B + ), a pharmaceutically important isoquinoline alkaloid, is an excellent guest for the investigation of the complex formation dynamics with CB7. 44 Activation enthalpy of 32 and 69 kJ mol −1 were found for the association and dissociation implying that the tight carbonyl-laced portal of the host constituted a steric barrier.…”

Section: Introductionmentioning

confidence: 99%

Sequential inclusion of two berberine cations in cucurbit[8]uril cavity: kinetic and thermodynamic studies

Miskolczy

Biczók

2014

Phys. Chem. Chem. Phys.

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A combination of absorption and fluorescence spectroscopic studies with isothermal calorimetric titrations and stopped-flow measurements is a powerful way to reveal the thermodynamics and kinetics of inclusion complex formation with cucurbit[8]uril (CB8). The unique photophysical characteristics of berberine (B + ), a pharmaceutically important natural alkaloid, was exploited to distinguish the consecutive encapsulation processes, and to examine the confinement in CB8 cavity. The highly environment sensitive fluorescence lifetime of B + permitted of the selective detection of various cucurbituril complexes, and indicated to what extent the embedded guest is available for interaction with water. Highly stable 1:1 and 2:1 B + CB8 complexes were produced due to the release of the high energy water molecules from the CB8 interior, and the second binding step proved to be almost 3 times more exothermic. The favorable entropy change appreciably contributed to the driving force of 1:1 encapsulation. Contrarily, the embedment of the second B + in CB8 led to substantial entropy diminution. The kinetics of encapsulation was followed in real time by recording the fluorescence intensity change after rapid mixing of B + and CB8. No evidence was found for intermediates. The rate constants of (64 ± 9)×10 6 , and (5.0 ± 0.5)×10 6 M 1 s 1 were found for 1:1 and 2:1 associations, whereas 3.8 ± 0.6, and 0.6 ± 0.1 s 1were obtained for the rate constants of the reverse processes at 283 K, respectively.3

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The Potential of Cucurbit[n]urils in Drug Delivery

Cited by 256 publications

References 69 publications

The Delivery of Triamterene by Cucurbit[7]uril: Synthesis, Structures and Pharmacokinetics Study

The Delivery of Triamterene by Cucurbit[7]uril: Synthesis, Structures and Pharmacokinetics Study

The extravascular penetration of tirapazamine into tumours: a predictive model of the transport and efficacy of hypoxia specific cytotoxic analogues and the potential use of cucurbiturils to facilitate delivery

Sequential inclusion of two berberine cations in cucurbit[8]uril cavity: kinetic and thermodynamic studies

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