Encapsulation of Drug Molecules by Cucurbiturils: Effects on their Chemical Properties in Aqueous Solution

The effects of the encapsulation of drugs and other molecules of biomedical interest by cucurbit[n]uril (n=5–8, 10) host molecules on the chemical properties of the drugs in aqueous solution are reviewed. The cucurbituril complexation of drug molecules has been shown to generally increase the guests’ pK_a values through preferential inclusion of the protonated species, modulate other equilibria involving the guest, improve the solubility in aqueous solution, reduce the toxicity and other side effects, as well as enhance the stability and targeted delivery of the drug molecule. These benefits have led to an increasing interest in the applications of cucurbit[n]urils in novel drug formulations.     

The association constant of macrocyclic ether–cation interactions in 1,4-dioxane/water mixtures. III. Effect of temperature on the binding

The association constant, K_a of Na⁺ with [12]crown-4, [15]crown-5 and [18]crown-6 crown ethers were determined in a binary mixture, 1,4-dioxane/water (50/50) using a Na⁺ ion selective electrode at different temperatures. K_a values were determined with the relationship, 1/K_a [L_o]^n+m–1 = (1–nP′)ⁿ(1–mP′)^m/P′, for various stoichiometries, (n:m), where P′ is the mole fraction of the complexed cation. The exothermic association constants and the thermodynamic data for cation–macrocycle complexes explained in terms of Eigen–Winkler binding mechanism are given. The binding power found for Na⁺, however, was the highest with [18] crown-6.     

Deep Inside Cucurbiturils: Physical Properties and Volumes of their Inner Cavity Determine the Hydrophobic Driving Force for Host–Guest Complexation

Cucurbit[n]urils (CBn) bind guest molecules through a combination of electrostatic interactions with the carbonyl rims and hydrophobic interactions with the inner cavity. Investigations with solvatochromic probes in CB7 reveal that the polarity of the cavity resembles that of alcohols (e.g., n-octanol), while its polarizability (P=0.12) and apparent refractive index (n_D=1.10±0.12) are extremely low, close to the gas phase. The calculated molecular quadrupole moments of CBs are extremely large (Θ_zz=−120 to −340 Buckingham). A survey of reported binding constants of neutral guests and hydrophobic residues that form 1 : 1 inclusion complexes with CB6, reveals a preferential inclusion of C3–C5 residues in its cavity. The largest guests which show non-negligible binding contain 7 heavy atoms (excluding hydrogen). For CB7, the strongest binding is observed for guests with adamantyl (10 heavy atoms) and ferrocenyl groups (11 heavy atoms), while the largest guests known to be complexed are carborane and the adduct of two pyridine derivatives (12 heavy atoms). The evaluation of different volumes shows that the most meaningful cavity, namely that responsible for binding of hydrophobic residues, is confined by the planes through the oxygen carbonyls. The volume of this inner cavity follows the formula V/ų=68+62(n−5)+12.5(n−5)², affording representative cavity volumes of 68 ų for CB5, 142 ų for CB6, 242 ų for CB7, and 367 ų for CB8. The volume of the 2 bond dipole regions is comparably smaller, amounting, for example, to 2×35 ų for CB6. The analysis of packing coefficients for representative sets of known guests with clearly defined hydrophobic binding motifs reveals average values of 47 % for CB5, 58 % for CB6, 52 % for CB7, and 53 % for CB8, which are well in line with the preferred packing (“55 % solution”, see S. Mecozzi, J. Rebek, Chem. Eur. J. 1998 , 4, 1016–1022) in related supramolecular host–guest assemblies. The driving force for binding of hydrophobic guests and residues by CBs is interpreted in terms of the unimportance of dispersion interactions (owing to the low polarizability of their cavity) and the dominance of classical and nonclassical hydrophobic effects related to the removal of very-high-energy water molecules (2 for CB5, 4 for CB6, 8 for CB7, and 12 for CB8) from the cavity.     

Aggregation behavior of poly(methacrylic acid) with cucurbit[7]uril and the effect of ammonia ions on aggregation

The interaction between poly(methacrylic acid) (PMAA) and cucurbit[7]uril (CB[7]) in aqueous solution were investigated by dynamic light scattering (DLS), fluorescence techniques, UV-spectrophotometer, and resonance light scattering (RLS). The experimental results show that the aggregates were formed between CB[7] and H⁺ of PMAA by the hydrogen bonding interaction that increases with increasing the concentration of CB[7], which leads to the formation of the larger aggregates. Interestingly, PMAA has temperature sensitivity with the addition of CB[7] by UV-spectrophotometer and DLS. The pH of the solution of PMAA appears a inflection point with increasing the concentration of CB[7] comparing with the increase of the electrical conductivity all the time with the addition of CB[7]. In addition, in order to investigate the effect of cation on the size of the aggregates and avoid the effect of other anions at the same time, the dilute ammonia was added into the solution of PMAA. The experimental data show that the size of the aggregates increases with adding CB[7] because CB[7] could combine with both NH₄⁺ by the electrostatic and iondipole interactions and H⁺ by the hydrogen bonding interaction, and a possible model is proposed to explain the host-guest interactions between PMAA and CB[7].     

Molecular Containers Bind Drugs of Abuse in Vitro and Reverse the Hyperlocomotive Effect of Methamphetamine in Rats

We measured the affinity of five molecular container compounds (calabadions 1 and 2 , CB[7], sulfocalix[4]arene, and HP‐β‐CD) toward seven drugs of abuse in homogenous aqueous solution at physiological pH by various methods (¹H NMR, UV/Vis, isothermal titration calorimetry [ITC]) and found binding constants (K_a values) spanning from <10² to >10⁸ m ^?1. We also report X‐ray crystal structures of CB[7] ? methamphetamine and 1? methamphetamine. We found that 2 , but not CB[7], was able to ameliorate the hyperlocomotive activity of rats treated with methamphetamine. The bioavailability of the calabadions and their convergent building block synthesis suggest potential for further structural optimization as reversal agents for intoxication with nonopioid drugs of abuse for which no treatments are currently available.     

Catalytic potential of a poly(AAc‐co‐HPMA‐cl MBAm)‐matrix‐immobilized lipase from a thermotolerant Pseudomonas aeruginosa MTCC‐4713

A purified alkaline thermo‐tolerant lipase from Pseudomonas aeruginosa MTCC‐4713 was immobilized on a series of five noble weakly hydrophilic poly(AAc‐co‐HPMA‐cl MBAm) hydrogels. The hydrogel synthesized by copolymerizing acrylic acid and 2‐hydroxy propyl methacrylate in a ratio of 5 : 1 (HG_5:1 matrix) showed maximum binding efficiency for lipase (95.3%, specific activity 1.96 IU mg^?1 of protein). The HG_5:1 immobilized lipase was evaluated for its hydrolytic potential towards p‐NPP by studying the effect of various physical parameters and salt‐ions. The immobilized lipase was highly stable and retained ～92% of its original hydrolytic activity after fifth cycle of reuse for hydrolysis of p‐nitrophenyl palmitate at pH 7.5 and temperature 55°C. However, when the effect of pH and temperature was studied on free and bound lipase, the HG_5:1 immobilized lipase exhibited a shift in optima for pH and temperature from pH 7.5 and 55°C to 8.5 and 65°C in free and immobilized lipase, respectively. At 1 mM concentration, Fe³⁺, Hg²⁺, NH₄⁺, and Al³⁺ ions promoted and Co²⁺ ions inhibited the hydrolytic activities of free as well as immobilized lipase. However, exposure of either free or immobilized lipase to any of these ions at 5 mM concentration strongly increased the hydrolysis of p‐NPP (by ～3–4 times) in comparison to the biocatalysts not exposed to any of the salt ions. The study concluded that HG_5:1 matrix efficiently immobilized lipase of P. aeruginosa MTCC‐4713, improved the stability of the immobilized biocatalyst towards a higher pH and temperature than the free enzyme and interacted with Fe³⁺, Hg²⁺, NH₄⁺, and Al³⁺ ions to promote rapid hydrolysis of the substrate (p‐NPP). © 2006 Wiley Periodicals, Inc. J Appl Polym Sci 100: 4252–4259, 2006     

Synthesis, characterization and properties of side-chain pseudopolyrotaxanes consisting of cucurbituril[6] and poly-N-(4-vinylbenzyl)-1,4-diaminobutane dihydrochloride

Pseudopolyrotaxanes 3 is synthesized from cucurbituril[6] (CB[6]) and polymer 2 (poly-N¹-(4-vinylbenzyl)-1,4-diaminobutane dihydrochloride) in water by simple stirring at room temperature. The monomer 1, polymer 2 and pseudopolyrotaxanes 3 are characterized by ¹H NMR, ¹³C NMR, FT-IR and elemental analysis. In 3, the CB[6] beads are localized on tetramethylene units in side chains of 2, and combine N⁺ by noncovalent bonds. The degree of threading (number of CB[6] beads per repeat unit) can be controlled from 0 to 1.0 by controlling the amount of CB[6] added. The properties of polymer 2 and pseudopolyrotaxanes 3 are researched by TGA, X-ray powder diffraction (XRD), environment scanning electron microscope (ESEM) and potentiometric titrations. The pseudopolyrotaxanes have higher thermal stability and chain regularity than the parent polymer which are attributed to the bulkiness and the rigidity of the CB[6] threaded. The decomposition temperature and chain regularity of the pseudopolyrotaxanes increase with increasing amount of CB[6] threaded. The effects of salts (NaCl, NaBr or NaI) to pseudopolyrotaxanes are studied by the transmittance with UV-vis, and the results show that NaI is the satisfied precipitant to the pseudopolyrotaxanes. The surface morphologies of pseudopolyrotaxanes 3 observed by ESEM shows a series of spherical particle with different diameter. The results of potentiometric titrations show that the pseudopolyrotaxanes 3 have larger pK_av and smaller n than polymer 2.     

Stimuli-Responsive Cucurbit[n]uril-Mediated Host-Guest Complexes on Surfaces

Supramolecular functional surfaces are at the heart of many materials and medical applications. Increasing interest can be seen for devising new supramolecular functionalization strategies of surfaces. In this review we place particular emphasis on the use of cucurbit[n]uril-mediated host-guest complexation as surface functionalization strategy. The state of the art of cucurbit[n]uril-mediated host-guest complexes on surfaces is reviewed. Cucurbit[n]urils (CB[n]) are able to form strong host-guest complexes with affinities that span several orders of magnitudes up to the regime of the biotin-streptavidin pair and that can be modulated by applying remote stimuli provided suitably sensitive guests were selected. Strategies to fabricate stimuli-responsive surfaces creates versatile supramolecular systems and several applications of these types of surfaces are outlined.     

Micelle ionization degree of anionic gemini surfactant having <Emphasis Type="Italic">N,N</Emphasis>-dialkylamide and carboxylate groups

The critical micelle concentration (cmc) behavior in aqueous NaCl solutions of the anionic gemini surfactant N,N′-ethylenebis(sodium N-dodecanoyl-β-alanate), (CH₂)₂[N-(COC₁₁H₂₃)CH₂CH₂(CO₂Na)]₂ (212), having N,N-dialkylamide and carboxylate groups in a molecule was investigated to measure the value of micelle ionization degree (α). For comparison, the behavior of sodium N-dodecanoyl-N-methyl-β-alanate (SDMA), a monomer corresponding to 212, also was investigated. The α value obtained from the Corrins-Harkins plot for 212 is 0.97 when [Na⁺]≤0.025 M and the value for SDMA is 0.51 when [Na[⁺]≤0.1 M. That the α for 212 is larger than that for SDMA reflects the higher pK _a1 value for 212 than the pK _a value of SDMA. For 212, when [Na⁺]≤0.025 M the amount of Na⁺ released during micellization is so large that the Na⁺ concentration above the cmc is almost equal to that below the cmc, and therefore 212 nearly behaves as a nonionic surfactant.     

Anthracene-Walled Acyclic CB[n] Receptors: in vitro and in vivo Binding Properties toward Drugs of Abuse

We report studies of the interaction of six acyclic CB[n]-type receptors toward a panel of drugs of abuse by a combination of isothermal titration calorimetry and ¹H NMR spectroscopy. Anthracene walled acyclic CB[n] host ( M3 ) displays highest binding affinity toward methamphetamine (K_d=15 nM) and fentanyl (K_d=4 nM). Host M3 is well tolerated by Hep G2 and HEK 293 cells up to 100 μM according to MTS metabolic and adenylate kinase release assays. An in vivo maximum tolerated dose study with Swiss Webster mice showed no adverse effects at the highest dose studied (44.7 mg kg⁻¹). Host M3 is not mutagenic based on the Ames fluctuation test and does not inhibit the hERG ion channel. In vivo efficacy studies showed that pretreatment of mice with M3 significantly reduces the hyperlocomotion after treatment with methamphetamine, but M3 does not function similarly when administered 30 seconds after methamphetamine.     

Gas Phase Cucurbit[n]uril Chemistry

The chemistry of cucurbit[n]urils is commanding increasing interest because of potential applications of these molecules in supramolecular structures; in drug encapsulation, protection, and delivery; and in sensitive new analytical assays. It is widely recognized that the binding properties of cucurbit[n]urils are sensitively dependent on solvents and counterions. Hence, gas phase studies, where neither solvent nor counterion species are present, are vital to gain fundamental understanding of cucuribituril complexes and to facilitate future applications. We use Fourier transform ion cyclotron resonance mass spectrometry (FTICR-MS) and ion mobility techniques to investigate the gas phase chemistry of cucurbit[n]urils and related species, addressing problems such as how trapping molecules inside the cucurbit[n]uril cavity affects the binding of cations on the rims, the mechanism of exchange of bound/trapped species, and the origin of the large pK_a shifts that occur for trapped guests. This paper is a review of our work.     

INTRAPARTICLE MASS TRANSFER IN THERMALLY REGENERABLE ION EXCHANGER

An intraparticle mass transfer model was developed for a thermally regenerable ion exchanger which is coagulated by weak acidic and basic microspheres. It was assumed that salt diffuses (hrough macropore and microspheres in the radial direction of a resin particle. Uptake curves were measured not only in [R_aCOOH + R_bN] + NaCl ) [R_aCOONa + R_bNHCl] system but also in [R_aCOO²²Na⁺ + R_aN] + Na⁺ )[R_aCOONa⁺ + R_bN] + ²²Na⁺ and [R_aCOOH + R_aN] + HCl ) [R_aCOOH + R_bNHCl] systems. Macropore diffusivity D_p.Na, tortuosity factor τ_p and diffusivity through weak acidic microspheres D_a,Na were obtained from the isotopic ion exchange. The uptake curves of HC1 gave diffusivity through weak basic microspheres.D_b,Hcl The experimental uptake and desorption curves of NaCl agreed fairly well with the theoretical values. Diffusions through both macropore and microspheres were significant. The diffusivity through microspheres D_b,Nacl NaCI are smaller than D_a,Na. and can be estimated by D_bHcl approximately.     

Photochemical-induced polymerization kinetics of styrene and methyl methacrylate by initiation of binary system composed of polyethylene oxide with aniline end group and benzophenone

The kinetics of photochemical polymerization of styrene (St) and methyl methacrylate (MMA) using a binary initiation system composed of poly(ethylene oxide) with an aniline end group (PEO_a) and benzophenone (BP) was investigated by a modified dilatometer. The effect of the concentration of the monomer, BP and PEO_a, and of the molecular weight of PEO_a on the polymerization rate (R_p) and conversion of monomers is discussed in detail. The formulas of R_p ∝︁ [PEO_a]^0.38 [St]^0.33 [BP]^0.56 and R_p ∝︁ [PEO_a]^0.36 [MMA]^0.30 [BP]^0.54 using benzene as a solvent are derived when the molecular weight of PEO is 11,000 (PEO_a — 11,000). Compared with the small aminophenol (AP), there existed a critical PEO_a concentration to affect the R_p and conversion of the monomers and the critical concentration is strongly dependent on the polarity of the solvents and molecular weight of PEO_a. It is confirmed that in the same conditions the solution polymerization behavior of St and MMA initiated by the imino radical of PEO would not be affected by the properties of the second block although PMMA is miscible and PS is immiscible with PEO_a in the bulk. © 1997 John Wiley & Sons, Inc. J Appl Polym Sci 65: 2095–2103, 1997     

Guest-responsive,Non-proteolytic Harvest of a Cell-sheet using Controllable Host-guest Chemistry

A new non-proteolytic method to harvest a cell-sheet was demonstrated using controllable host-guest interactions which can be dissociated by treating a strong guest on demand. Fibroblast cells (NIH3T3) were grown to confluence on a 1,6-diammoniumhexane conjugated hyaluronic acid (DAH-HA) polymer which was anchored to a cucurbit[7]uril (CB[7]) surface using the host-guest interaction between DAH and CB[7]. Treating with a strong guest allowed the cultured cells to be detached from the surface as a free standing sheet. This approach demonstrated the great potential of controllable host-guest chemistry as a novel tool for non-proteolytic harvesting of cell-sheets useful for regenerative therapy.     

Cathodic reduction of acids in dimethylformamide on platinum

A linear correlation was shown to exist between the acidity and the cyclic voltammetric half-potential of the reduction of acids in DMF for carboxylic and N-acids in the pK_a range of 6-16. Chlorophenols are reduced at slightly lower potentials giving a separate parallel line. Applying the obtained equation and employing the same method to literature data in DMSO, the pK_a values for conjugate aids of DMF and DMSO can be calculated, showing DMSO·H⁺ to be more acidic (pK_a = 2.9) than DMF·H⁺ (pK_a = 5.7). The analysis of cyclovoltammetric data demonstrated that a CE mechanism operates in the reduction of strong acids, including the conjugate acid of DMF. Weaker acids are reduced by direct discharge or a mixed mechanism.     

An unprecedented bonding mode for potassium within a PCP-pincer palladium hydride–K-Selectride complex

The reaction of (PCP)^i-PrPdCl and the commonly-used reductant K-Selectride^® solution [K(sec-Bu₃BH) in THF] does not yield a simple (PCP)^i-PrPdH species, but rather an adduct of the Pd–H that contains bound K(sec-Bu₃BH). This adduct has been characterized by X-ray crystallography and shown to be a centrosymmetric dimer in the solid state. The most unique feature of the structure is that the tri-coordinate K⁺ ion bonds only to the terminal palladium hydride and the two bridging boron hydrides. Despite being prepared in THF, no other donor ligands are bound to K⁺. This [H₃K]⁺ bonding mode for K⁺ ions has not been previously reported.     

Experimental pKa Value Determination of All Ionizable Groups of a Hyperstable Protein

Electrostatic interactions significantly contribute to the stability and function of proteins. The stabilizing or destabilizing effect of local charge is reflected in the perturbation of the pK_a value of an ionizable group from the intrinsic pK_a value. Herein, the charge network of a hyperstable dimeric protein (ribbon–helix–helix (rhh) protein from plasmid pRN1 from Sulfolobus islandicus) is studied through experimental determination of the pK_a values of all ionizable groups. Transitions were monitored by multiple NMR signals per ionizable group between pH 0 and 12.5, prior to a global analysis, which accounted for the effects of neighboring residues. It is found that for several residues involved in salt bridges (four Asp and one Lys) the pK_a values are shifted in favor of the charged state. Furthermore, the pK_a values of residues C40 and Y47, both located in the hydrophobic dimer interface, are shifted beyond 13.7. The necessary energy for such a shift is about two-thirds of the total stability of the protein, which confirms the importance of the hydrophobic core to the overall stability of the rhh protein.     

The synthesis and complexation study of some novel 3-methoxyphenyl chromenone crown ethers using conductometry

7,8-Dihydroxy-3-(3,4-dimethoxyphenyl)-2H-chromenones, 7,8-dihydroxy-3-(3,5-dimethoxyphenyl)-2H-chromenones and 7,8-dihydroxy-3-(3,4,5-trimethoxyphenyl)-2H-chromenones, o-dihydroxy-3-methoxyphenylcoumarins, were prepared from 2,3,4-trihydroxybenzaldehyde and corresponding methoxyphenylacetic acid in NaOAc/Ac₂O, respectively. 3-Methoxyphenyl-7,8-dihydroxy-2H-chromenone reacted with the polyethylene glycol ditosylate or dichloride in CH₃CN/alkali carbonate to afford [12]crown-4, [15]crown-5 and [18]crown-6-chromonones.The chromatographically purified novel chromenone crown ethers were identified with IR, ¹H NMR, ¹³C NMR and low and high resolution mass spectroscopy and elemental analysis.Stability constants for the 1:1 complexes of Na⁺ and K⁺ with different substituted methoxyphenyl derivatives of coumarino[12]crown-4, coumarino[15]crown-5 and coumarino[18]crown-6 (5a–5i) have been determined by conductometry at 25 °C in a binary solvent, dioxane/water. For all the coumarino crown ether derivatives, the stability constant decreases for K⁺ ion compared to Na⁺ ion.The selectivity sequence of these crown ethers in dioxane/water has showed an irregular order with respect to their cavity size.     

Concave π-prismand hydrocarbon [2.2.2]cyclophanes and their crystalline Ag-triflate complexes

New small concave hydrocarbon cyclophanes were prepared via the well-known HD-2SO₂-method. The cyclophanes obtained are isomers of the very well-known [2.2.2]p,p,p-cyclophane, C₂₄H₂₄, a π-prismand efficiently complexing Ag⁺-ion. X-ray crystal structure determinations showed the bis-sulfide 7 (1,10-dithia[3.3.2]m,p,p-cyclophane) to be helically chiral and that the conformation of the parent hydrocarbon cyclophane 13 ([2.2.2]m,p,p-cyclophane) does not change dramatically upon complexation with the Ag⁺-ion. The 16- and 17-membered [2.2.2]m,m,p- and [2.2.2]m,p,p-cyclophane ( 15 and 16 ) also act as π-prismands and form surprisingly similar crystalline 1:1 Ag-triflate complexes (π-prismates) as the well-known 18-membered p,p,p-isomer proved by the X-ray structure analysis.     

Effects of the orientation of smectite particles and ionic strength on diffusion and activation enthalpies of I and Cs ions in compacted smectite

The apparent diffusion coefficients (D_a) for I⁻ and Cs⁺ ions in compacted Na-smectite which is a major constituent clay mineral of bentonite were studied as a function of smectite's dry density (0.9–1.4 Mg/m³), ionic strength ([NaCl] = 0.01, 0.51 M), temperature (22–60 °C) and diffusion direction to the orientated direction of smectite particles. The Na-smectite was prepared by ion-exchanging with Na⁺ ions a Na-bentonite, Kunipia-F®, of which smectite content is over 99 wt.%. The D_a-values for both ions showed a tendency to be higher in the parallel direction than in the perpendicular direction to the orientated direction of smectite particles at a low-ionic strength of [NaCl] = 0.01 M. The D_a-values for I⁻ ions showed different trends depending on diffusion direction and dry density at a high-ionic strength of [NaCl] = 0.51 M. Namely, although the D_a-values for I⁻ ions showed a tendency to be higher in the parallel direction than in the perpendicular direction to the orientated direction of smectite particles at a high-dry density of 1.4 Mg/m³, these showed a reciprocal tendency at dry densities of 0.9–1.0 Mg/m³. The D_a-values for Cs⁺ ions uniformly increased with an increase of ionic strength in both diffusion directions. Considering electrostatic effect from smectite surface and the change in tortuosity on dry density, ionic strength and diffusion direction to the orientated direction of smectite particles, I⁻ ions are considered to mainly diffuse in interstitial pores. While, Cs⁺ ions can diffuse in both interlayer and interstitial pores, and the D_a-values are considered to have elevated by competing with Na⁺ ions. The activation enthalpies (ΔE_a) for I⁻ ions, slightly higher (ΔE_a = 19.8−20.0 kJ/mol) than that of the diffusion coefficient in free water (D^o) for I⁻ ions (ΔE_a = 17.36 kJ/mol) at a low-ionic strength of [NaCl] = 0.01 M, decreased with an increase of ionic strength, became of similar level to that of the D^o at a high-ionic strength of [NaCl] = 0.51 M, increased with an increase of dry density. On the contrary, the ΔE_a-values for Cs⁺ ions, clearly higher (ΔE_a = 25.6−28.4 kJ/mol) than that of the D^o for Cs⁺ ions (ΔE_a = 16.47 kJ/mol) even in low-dry density over the ionic strength, increased with an increase of dry density. The ΔE_a-values for Cs⁺ ions are considered to be due to the decrease in the activity of porewater in addition to the effect of ion exchange enthalpy between Cs⁺ and Na⁺ ions in smectite.