Supramolecular biomaterials for bio-imaging and imaging-guided therapy.

Benefiting from their unique advantages, including reversibly switchable structures, good biocompatibility, facile functionalization, and sensitive response to biological stimuli, supramolecular biomaterials have been widely applied in biomedicine. In this review, the representative achievements and trends in the design of supramolecular biomaterials (mainly those derived from biomacromolecules) with specific macromolecules including peptides, deoxyribonucleic acid, and polysaccharides, as well as their applications in bio-imaging and imaging-guided therapy are summarized. This review will serve as an important summary and "go for" reference for explorations of the applications of supramolecular biomaterials in bio-imaging and image-guided therapy, and will promote the development of supramolecular chemistry as an emerging interdisciplinary research area.

Encapsulation of Vitamin B(1) and Its Phosphate Derivatives by Cucurbit[7]uril: Tunability of the Binding Site and Affinity by the Presence of Phosphate Groups.

Vitamin B1 (1) and its phosphate derivatives, thiamine monophosphate (2) and thiamine pyrophosphate (3), are shown to form stable 1:1 host-guest complexes with cucurbit[7]uril (CB[7]) in aqueous solution. The binding sites of CB[7] on these guests shift from the ethylthiazolium region of 1 to the pyrimidine moiety of 2 and 3 due to the presence of phosphate groups, leading to variations of binding affinities as well as C(2)-H/D exchange rate constants and C(2)-H pKa values with these guest molecules.

Inhibition of C(2)-H Activity on Alkylated Imidazolium Monocations and Dications upon Inclusion by Cucurbit[7]uril.

The inclusions of 1-methyl-3-alkylimidazolium cations (ICn+, n = 4, 6, and 8) and 3,3'-bis(3-(1-methylimidazolium))-1,n-alkane (DICn2+, n = 4, 6, and 8) in the macrocyclic cucurbit[7]uril result in a decrease (up to 25-fold) of the C(2)-H/D exchange rate constants and an increase in the C(2)-H pKa values (ΔpKa = 0.34 to 1.45). The alkyl chain lengths were found to play an important role in the extent of C(2)-H activity inhibition, upon complexation with cucurbit[7]uril.

Selective sensitization of Eu(III) and Tb(III) emission with triarylboron-functionalized dipicolinic acids.

Three triarylboron- (Mes2BAr-) functionalized dipicolinic acids, namely, 4-(4-(dimesitylboranyl)-2,3,5,6-tetramethylphenyl)pyridine-2,6-dicarboxylic acid (H2L1), 4-(4-(4-dimesitylboranyl)-2,3,5,6-tetramethylphenyl)-1H-1,2,3-triazol-1-yl)pyridine-2,6-dicarboxylic acid (H2L2), and 4-(4-(4-dimesitylboranyl) phenyl)-1H-1,2,3-triazol-1-yl)pyridine-2,6-dicarboxylic acid (H2L3), have been designed and synthesized. Lanthanide(III) complexes with the general formula of [NBu4]3[LnL3] (Ln = Eu or Tb; L = L1, L2, or L3) were obtained. The new triarylboron-functionalized ligands were found to be effective in the selective sensitization of the emissions of Eu(III) and Tb(III) ions with a high quantum efficiency (e.g., 0.54 for [NBu4]3[TbL13] in the solid state) upon excitation at ∼330 nm. An intraligand charge-transfer (ILCT) transition from the mesityl or aryl group to the boron or boron-aryl unit was found to play a key role in the activation of the Eu(III) and Tb(III) emissions, based on TD-DFT computational data and luminescence titration experiments performed using fluoride and cyanide ions.

Cucurbit[8]uril-based supramolecular hydrogels for biomedical applications.

As a member of the cucurbit[n]uril family (where n denotes the number of glycoluril units), cucurbit[8]uril (CB[8]) possesses a large cavity volume and is able to accommodate two guests simultaneously. Therefore, CB[8] has been adapted as a dynamic noncovalent crosslinker to form various supramolecular hydrogels. These CB[8]-based hydrogels have been investigated for various biomedical applications due to their good biocompatibility and dynamic properties afforded by host-guest interactions. In this review, we summarize the hydrogels that have been dynamically fabricated via supramolecular crosslinking of polymers by CB[8] reported during the past decade, and discuss their design principles, innovative applications in biomedical science and their future prospects.

Host-guest complexations of local anaesthetics by cucurbit[7]uril in aqueous solution.

The cucurbit[7]uril (CB[7]) host molecule forms very stable host-guest complexes with the local anaesthetics procaine (K(CB[7]) = (3.5 +/- 0.7) x 10(4) dm(3) mol(-1)), tetracaine (K(CB[7]) = (1.5 +/- 0.4) x 10(4) dm(3) mol(-1)), procainamide (K(CB[7]) = (7.8 +/- 1.6) x 10(4) dm(3) mol(-1)), dibucaine (K(CB[7]) = (1.8 +/- 0.4) x 10(5) dm(3) mol(-1)) and prilocaine (K(CB[7]) = (2.6 +/- 0.6) x 10(4) dm(3) mol(-1)) in aqueous solution (pD = 4.75). The stability constants are 2-3 orders of magnitude greater than the values reported for binding by the comparably sized beta-cyclodextrin host molecule. The inclusion by CB[7] raises the first pK(a) values of the anaesthetics by 0.5-1.9 pK units, as the protonated forms are bound more strongly in acidic solution. The complexation-induced chemical shift changes in the guest proton resonances provide an indication of the site(s) of binding and the effects of protonation on the location of the binding sites.

Cucurbit[7]uril host-guest complexes of cholines and phosphonium cholines in aqueous solution.

The neutral host cucurbit[7]uril forms very stable complexes with a series of cationic cholines (R(3)NCH(2)CH(2)OR'(+)) and their phosphonium analogues (R(3)PCH(2)CH(2)OR'(+)) (R(3) = Me(3), Et(3), or Me(2)Bz, or R(3)N = quinuclidinium, and R' = H, COCH(3), CO(CH(2))(2)CH(3), or PO(3)H), and (+/-)-carnitine, in aqueous solution. The complexation behaviour has been investigated using (1)H and (31)P NMR spectroscopies, and ESI mass spectrometry. The complexation-induced chemical shift changes of the guests clearly indicate the effects of replacing the N(CH(3))(3)(+) end group by P(CH(3))(3)(+), and changing the nature of R on the position of the guest with respect to the CB[7] cavity and its polar portal-lining carbonyl groups. This study demonstrates that molecular recognition of cholines in aqueous solution is achievable with a neutral host without the need for aromatic walls for cation-pi interactions.

Host-guest complexes and pseudorotaxanes of cucurbit[7]uril with acetylcholinesterase inhibitors.

Pseudorotaxanes may be assembled in aqueous solution using dicationic acetylcholinesterase inhibitors, such as succinylcholine, BW284c51, and alpha,omega-bis(trialkylammonium)alkane dications (or their phosphonium analogues), as bolaform axles and cucurbit[7]uril (CB[7]) as the wheel. With the exceptions of the shorter [(CH(3))(3)N(CH(2))(n)N(CH(3))(3)](2+) (n = 6, 8) dications, the addition of a second CB[7] results in the translocation of the first CB[7], such that the hydrophobic -NR(3)(+) and -PR(3)(+) end groups (R = Me or Et) are located in the cavities of the wheels, while the central portion of the axles extend through the CB[7] portals into the bulk solvent. In the case of the [Quin(CH(2))(10)Quin](2+) (Quin = quinuclidinium) dication, the CB[7] host(s) resides only on the quinuclidinium end group(s). The 1:1 host-guest stability constants range from 8 x 10(6) to 3 x 10(10) M(-1) and are dependent on both the nature of the end group as well as the length and hydrophobicity of the central linker. The magnitude of the stability constants for the 2:1 complexes closely follow the trend observed previously for CB[7] binding with the NR(4)(+) and PR(4)(+) cations.

Cucurbit[7]uril host-guest and pseudorotaxane complexes with alpha,omega-bis(pyridinium)alkane dications.

The host molecule cucurbit[7]uril forms very stable host-guest complexes (1:1 and 2:1) and [2]pseudorotaxanes with alpha,omega-bis(pyridinium)alkane dications in aqueous solution. With the dications containing pyridinium, 2- and 3-picolinium, and 4-dimethylaminopyridinium end groups and a hexyl chain, [2]pseudorotaxanes are formed with one equivalent of CB[7] positioned over the central chain. A second equivalent of CB[7] encapsulating one of the end groups results in the translocation of the first CB[7] to the other end group. For the dications with these end groups, the 2:1 host-guest complexes exhibit stability constants which are considerably smaller than the 1:1 values as the result of steric and electronic repulsions between the two CB[7] hosts.

Encapsulation of charge-diffuse peralkylated onium cations in the cavity of cucurbit[7]uril.

Cucurbit[7]uril binds, with considerable size selectivity, NR(4)(+), PR(4)(+), and SR(3)(+) cations (R=Me, Et, (n)Pr, (n)Bu), with the smaller guests inside its cavity, rather than at the carbonyl-lined portals.

Cucurbit[7]uril: an emerging candidate for pharmaceutical excipients.

Cucurbit[7]uril (CB[7]), belonging to the cucurbit[n]uril family (CB[n], n = 5-8, 10, or 13-15), may form host-guest complexes with a variety of small molecules of biomedical interest. The physical and chemical properties of the complexed drugs are often improved as a result of this complexation, suggesting the potential application of CB[7] as a pharmaceutical excipient. This review has summarized the most recent research progress reported between 2011 and early 2017 regarding the biocompatibility of CB[7] and the influence of CB[7] on the stability, solubility, biouptake, and biological activities (including therapeutic efficacies and toxicities) of guest drug molecules. Through this systemic summary and analysis, we intend to stimulate further research efforts in this area and promote the use of CB[7] as an emerging pharmaceutical excipient to improve various properties of drug molecules (or active pharmaceutical ingredients).

Supramolecular Nanostructures Based on Cyclodextrin and Poly(ethylene oxide): Syntheses, Structural Characterizations and Applications for Drug Delivery.

Cyclodextrins (CDs) have been extensively studied as drug delivery carriers through host⁻guest interactions. CD-based poly(pseudo)rotaxanes, which are composed of one or more CD rings threading on the polymer chain with or without bulky groups (or stoppers), have attracted great interest in the development of supramolecular biomaterials. Poly(ethylene oxide) (PEO) is a water-soluble, biocompatible polymer. Depending on the molecular weight, PEO can be used as a plasticizer or as a toughening agent. Moreover, the hydrogels of PEO are also extensively studied because of their outstanding characteristics in biological drug delivery systems. These biomaterials based on CD and PEO for controlled drug delivery have received increasing attention in recent years. In this review, we summarize the recent progress in supramolecular architectures, focusing on poly(pseudo)rotaxanes, vesicles and supramolecular hydrogels based on CDs and PEO for drug delivery. Particular focus will be devoted to the structures and properties of supramolecular copolymers based on these materials as well as their use for the design and synthesis of supramolecular hydrogels. Moreover, the various applications of drug delivery techniques such as drug absorption, controlled release and drug targeting based CD/PEO supramolecular complexes, are also discussed.

Supramolecular Inhibition of Neurodegeneration by a Synthetic Receptor.

Cucurbit[7]uril (CB[7]) was found in vitro to sequester the neurotoxins MPTP (N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) and MPP(+) (N-methyl-4-phenylpyridine). The CB[7]/neurotoxin host-guest complexes were studied in detail with (1)H NMR, electrospray ionization mass spectrometry, UV-visible spectroscopic titration, and molecular modeling by density functional theory. The results supported the macrocyclic encapsulation of MPTP and MPP(+), respectively, by CB[7] in aqueous solutions with relatively strong affinities and 1:1 host-guest binding stoichiometries in both cases. More importantly, the progression of MPTP/MPP(+) induced neurodegeneration (often referred to as a Parkinson's disease model) was observed to be strongly inhibited in vivo by the synthetic CB[7] receptor, as shown in zebrafish models. These results show that a supramolecular approach could lead to a new preventive and/or therapeutic strategy for counteracting the deleterious effects of some neurotoxins leading to neurodegeneration.

Cucurbit[7]uril host-guest complexes with small polar organic guests in aqueous solution.

The host-guest stability constants for the inclusion of a series of small neutral polar organic guests in cucurbit[7]uril (CB[7]) have been determined in aqueous solution by (1)H NMR titrations. The dependence of the stability constant on the nature of the guests indicates that hydrophobic and dipole-quadrupole interactions are responsible for the binding. The complexation-induced chemical shift changes in the guest proton resonances, coupled with energy-minimization calculations, suggest that the guests are located such that their dipole moment is aligned perpendicular with the quadrupole moment of the CB[7] host. The stability constants for acetone and acetophenone decrease in the presence of Na(+) or K(+) cations as a result of cation capping of the CB[7] portals.