Cucurbituril-based nanoparticles: a new efficient vehicle for targeted intracellular delivery of hydrophobic drugs

Park, Kyeng Min; Suh, Kyungwon; Jung, Hyuntae; Lee, Don-Wook; Ahn, Youngjoo; Kim, Jeeyeon; Baek, Kangkyun; Kim, Kimoon

doi:10.1039/b815009e

Cited by 117 publications

(121 citation statements)

References 28 publications

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“…Recently, cucurbit [n]urils (CB [n], Scheme 1) have attracted much attention due to their wide applications in chemistry, 20 material, 21 biology, 22,23 and medicine science, 24,25 following the discovery of CB [n] homologues (CB [5], CB [6], CB [7], CB [8], CB [5]@CB [10], CB [10] and CB [14]). 26−30 Cucurbituril (Scheme 1) contains a hydrophobic cavity with two uniform hydrophilic portals composed of carbonyl functional groups.…”

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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“…[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.…”

mentioning

confidence: 99%

A photoinduced pH jump applied to drug release from cucurbit[7]uril

et al. 2011

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“…As mentioned in the discussion of CB [7], Day [40][41][42] as well as Kim [43] have studied complexation between CB [7] and platinum-based anti-cancer drugs. Kim and co-workers have recently explored the use of nanoparticles based on functionalized CB [6] as drug delivery vehicles [44,45]. Also, depending on the situation, they may also improve the solubility of a drug [46], reduce its undesired toxicity [47], improve its stability or activate the drug [48].…”

Section: Hostmentioning

confidence: 99%