A chemical preformulation study of a host–guest complex of cucurbit[7]uril and a multinuclear platinum agent for enhanced anticancer drug delivery

Kennedy, Alan R.; Florence, Alastair J.; McInnes, Fiona; Wheate, Nial J.

doi:10.1039/b907917c

Cited by 62 publications

(28 citation statements)

References 38 publications

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“…1, le) in particular has drawn considerable interest because of both its good watersolubility and its capacity to encapsulate organic molecules of a wide range of sizes. It has been demonstrated by numerous research groups including ours that CB [7] can effectively encapsulate a variety of drugs and bioactive molecules, including atenolol (a beta-blocker), 12 pyrazinamide (a tuberculosis drug), 13 platinum-based anti-cancer drugs such as cisplatin and others, [14][15][16] prilocaine and various other local anaesthetic, 17 as well as ranitidine and coumarin. 18,19 In addition, we have also actively investigated the complexation behaviors of steroidal NMBAs 20 and local anesthetic agents 17 by CB [7] and reviewed the use of CB[n]-type hosts for the reversal of steroidal NMBAs.…”

Section: Introductionmentioning

confidence: 99%

In vivo reversal of general anesthesia by cucurbit[7]uril with zebrafish models

Chen

Chan

et al. 2015

RSC Adv.

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A general anesthetic is a drug that brings about a reversible loss of consciousness, during a surgical or therapeutic procedure to render the patient free of pain and anxiety. However, the effect of anesthetics may linger far beyond the necessary time required and induce adverse effects. In addition, many surgical patients need to recover to a conscious state that allows them to make important decisions soon after their surgery. Unfortunately, there are currently no clinically-available anti-dotes to reverse the effects of anesthetics. In this study, we demonstrate the in vitro supramolecular host-guest complexations between macrocyclic cucurbit [7]uril (CB [7]) and a commonly used general anesthetic in fish, tricaine mesylate (TM), and we report for the first time the in vivo reversal effect of CB [7] to general anesthesia induced by TM with zebrafish models. These findings might lead to a new approach that may allow patients to regain lucidity much faster than their natural recovery from general anesthesia, and may also be used to reverse potentially life-threatening toxic effects encountered by some patients in response to general anesthesia.

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Section: Introductionmentioning

confidence: 99%

In vivo reversal of general anesthesia by cucurbit[7]uril with zebrafish models

Chen

Chan

et al. 2015

RSC Adv.

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“…6,7 They have a hydrophobic cavity, accessible through two hydrophilic oxygen lined portals, and are capable of storing and releasing small molecules. 8,9 Encapsulation of a drug molecule by cucurbituril can provide a range of benefits including: chemical [10][11][12] and thermal stability, [13][14][15] improved drug solubility, 16,17 controlled drug release, 18,19 and potential taste masking of some drugs.…”

Section: Introductionmentioning

confidence: 99%

Cucurbit[7]uril encapsulated cisplatin overcomes cisplatin resistance via a pharmacokinetic effect

et al. 2012

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The cucurbit [n]uril (CB[n]) family of macrocycles has been shown to have potential in drug delivery where they are able to provide physical and chemical stability to drugs, improve drug solubility, control drug release and mask the taste of drugs. Cisplatin is a small molecule platinum-based anticancer drug that has severe dose-limiting side-effects. Cisplatin forms a host-guest complex with cucurbit [7]uril (cisplatin@CB[7]) with the platinum atom and both chlorido ligands located inside the macrocycle, with binding stabilised by four hydrogen bonds (2.15-2.44 Å ). Whilst CB [7] has no effect on the in vitro cytotoxicity of cisplatin in the human ovarian carcinoma cell line A2780 and its cisplatin-resistant sub-lines A2780/cp70 and MCP1, there is a significant effect on in vivo cytotoxicity using human tumour xenografts. Cisplatin@CB [7] is just as effective on A2780 tumours compared with free cisplatin, and in the cisplatin-resistant A2780/cp70 tumours cisplatin@CB [7] markedly slows tumour growth. The ability of cisplatin@CB [7] to overcome resistance in vivo appears to be a pharmacokinetic effect. Whilst the peak plasma level and tissue distribution are the same for cisplatin@CB [7] and free cisplatin, the total concentration of circulating cisplatin@CB [7] over a period of 24 hours is significantly higher than for free cisplatin when administered at the equivalent dose. The results provide the first example of overcoming drug resistance via a purely pharmacokinetic effect rather than drug design or better tumour targeting, and demonstrate that in vitro assays are no longer as important in screening advanced systems of drug delivery.

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“…[5][6][7] Except for the extremely unlikely event that the drug itself would be photochromic, this greatly complicates the design of such systems, because both the drug and one isomeric form of the photoactive guest would need to show a high affinity to the macrocycle (''competitive approach''). Since numerous drug complexes of different macrocycles have already been characterised and are in fact partially being used, [8][9][10][11][12][13] a ''stimulus approach'' would be complementary, in which the photoactive component does not need to compete for the macrocycle, but rather causes an effect on the macrocycle-drug equilibrium through a relay mechanism or chemical output. In the working principle established herein, this is a photoinduced pH jump.…”

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confidence: 99%