Electrochemical Quantitation of Supramolecular Excipient@Drug Complexation: A General Assay Strategy Based on Competitive Host Binding with Surface-Immobilized Redox Guest

The macrocyclic cucurbit[7]­uril (CB[7]) host has exhibited great application potential as a pharmaceutical excipient due to its versatile abilities to modulate the chemical/physical properties of drug molecules (guests) and to control their in vivo delivery and release (upon complexation). The formation of stable CB[7]@drug complexes is the prerequisite for these promising applications; we report herein a general assay strategy to quantitate the complexation based on competitive binding with surface-immobilized redox guests in conjunction with conventional electrochemical techniques (e.g., cyclic voltammetry). Particularly, by incubating a mixture of CB[7] and a drug molecule with ferrocene (Fc)-terminated self-assembled monolayers (SAMs) on gold, the competitive host@guest binding between the CB[7]@drug complex formed in solution and the CB[7]@Fc complex formed on surface can be quantified with direct cyclic voltammetry measurements. On the basis of the known concentrations of CB[7]/drug and electrochemically determined surface densities of free/complexed Fc groups, the formation constant of CB[7]@drug complex can be determined. With several drug molecules as examples, we have demonstrated the capability of this method for quantitative studies of the formation of supramolecular excipient@drug complexes that are of interest in pharmaceutical and biomedical sciences. More importantly, this work promises a general assay strategy that allows electrochemical quantitation of a wide range of electro-inactive analytes based on the competitive supramolecular host@guest binding at redox-tagged molecular interfaces

Binding Modes of Cucurbit[6]uril and Cucurbit[7]uril with a Tetracationic Bis(viologen) Guest

Binding behaviors of two cucurbit[n]urils (CB[n]) hosts with the [CH3bpy(CH2)6bpyCH3]4+ (bpy = 4,4‘-bipyridinium) guest were investigated by 1H NMR and MALDI-TOF-MS experiments. While the CB[6] and CB[7] form [2]pseudorotaxanes with the host located over the hexamethylene chain of the guest, only the CB[7] forms a [3]pseudorotaxane with both host molecules residing over the bipyridinium groups. The initial CB[7] host vacates the inclusion of the hexamethylene chain as a result of the electrostatic and steric repulsions that would arise in simultaneous binding of adjacent aliphatic and aromatic portions of the guest

Cucurbit[7]uril Mediates the Stereoselective [4+4] Photodimerization of 2-Aminopyridine Hydrochloride in Aqueous Solution

The 2:1 guest−host complex of 2-aminopyridine hydrochloride with cucurbit[7]uril (CB[7]) undergoes a stereoselective [4+4] photodimerization reaction in aqueous solution to yield exclusively the anti-trans isomer of 4,8-diamino-3,7-diazatricyclo[4.2.2.22,5]dodeca-3,7,9,11-tetraene, and in the absence of CB[7], the photochemical reaction produces the anti-trans and syn-trans photodimers in a 4:1 ratio. In addition, encapsulation of the photodimer product in the CB[7] cavity stabilizes it with respect to the otherwise observed rearomatization to the 2-aminopyridine monomer at room temperature

Stabilization of the (<i>E</i>)-1-Ferrocenyl-2-(1-methyl-4-pyridinium)ethylene Cation by Inclusion in Cucurbit[7]uril

The (E)-1-ferrocenyl-2-(1-methyl-4-pyridinium)ethylene cation, (E)-FcMPE+, forms a very stable guest−host complex (KCB7 = (1.3 ± 0.5) × 1012 M-1) in aqueous solution with cucurbit[7]uril (CB[7]). The 1H NMR, ES-MS, and UV−visible spectra are consistent with 1:1 {(E)-FcMPE·CB[7]}+ species formation, in which the CB[7] encapsulates the ferrocenylethylene portion of the guest. The reduction potential of the (E)-FcMPE2+/+ couple increases slightly (+0.03 V) in the presence of CB[7], while the rate constant for the oxidation of (E)-FcMPE+ by Co(dipic)2- (dipic2- = 2,6-pyridinedicarboxylate) decreases significantly. UV−visible spectra of (E)-FcMPE+ in the absence and in the presence of CB[7] during photoirradiation demonstrate that the photoisomerization to (Z)-FcMPE+ is fully inhibited and photostabilization of (E)-FcMPE+ is dramatically enhanced upon inclusion in CB[7]

A study of binding interactions between terpyridine derivatives and cucurbit[10]uril

<p>The binding interactions of a series of 2,2′:6′,2″-terpyridine (TPY) derivatives and their metal complexes with cucurbit[10]uril (CB[10]) were investigated by ¹H NMR, UV/Vis, emission spectroscopy, and ESI mass spectrometry. ¹H NMR titrations revealed CB[10] could encapsulate methylated TPY (MTPY), and the binding ratio between guest MTPY and host was 1:1 and 2:1 via ESI-MS characterization. For the transition metal complexes composed of Fe(II) or Ru(II) or Rh(III) and TPY derivatives, the octahedral TPY−metal−TPY core can be included in the cavity of CB[10]. Three binding modes (1:1, 1:2 and 1:3) have been detected for the binding of the metal−MPTY complexes with CB[10] by ESI-MS.</p

“Zombie” Macrophages for Targeted Drug Delivery to Treat Acute Pneumonia

A cell-based drug delivery system has emerged as a promising drug delivery platform. Due to their innate inflammatory tropism, natural and engineered macrophages have exhibited targeted accumulation in inflammatory tissues, which has allowed targeted delivery of medicine for the treatment of a variety of inflammatory diseases. Nevertheless, live macrophages may take up the medicine and metabolize it during preparation, storage, and in vivo delivery, sometimes causing unsatisfactory therapeutic efficacy. In addition, live macrophage-based drug delivery systems are usually freshly prepared and injected, due to the poor stability that does not allow storage. “Off-the-shelf” products would be indeed conducive to the timely therapy of acute diseases. Herein, a cryo-shocked macrophage-based drug delivery system was developed via supramolecular conjugation of cyclodextrin (CD)-modified “zombie” macrophages and adamantane (ADA)-functionalized nanomedicine. “Zombie” macrophages exhibited a much better storage stability over time than their counterpart live macrophage drug carriers and maintained cell morphology, membrane integrity, and biological functions. In an acute pneumonia mouse model, “zombie” macrophages carried quercetin-loaded nanomedicine, hand-in-hand, to the inflammatory lung tissues and effectively alleviated the inflammation in mice

Facile Preparation of Cucurbit[6]uril-Based Polymer Nanocapsules for Targeted Photodynamic Therapy

Covalently self-assembled polymer nanocapsules (NCs) based on cucurbit[6]­uril have been previously prepared and their applications in payload delivery and bioimaging have been demonstrated, showing significant potentials. However, the preparation of these NCs often requires laborious and tedious multistep reactions, including a low-yield conversion of perhydroxycucurbit[6]­uril to perallyloxycucurbit[6]­uril, subsequent photopolymerization of perallyloxycucurbit[6]­uril with dithiol linkers, and two additional steps of treatment to remove disulfide loops and create cationic sulfoniums. Herein, we report a novel, facile approach leading to cucurbit[6]­uril-based polymer NCs via direct alkylation of perhydroxycucurbit[6]­uril with a ditopic linker, thereby saving significant time and efforts, which may lead to significant expansion in investigations of these unique materials in various applications, particularly biomedical sciences. As a proof of concept, we have further demonstrated that a photosensitive therapeutic payload, such as chlorin e6, may get encapsulated inside the NCs for improved, targeted photodynamic therapy against cancer cells

“Click” Cucurbit[7]uril Hosts on Self-Assembled Monolayers: Quantitative Supramolecular Complexation with Ferrocene Guests

The ultrahigh stability of the ferrocene@cucurbit[7]­uril (Fc@CB[7]) host–guest inclusion complex enables its promising application as a novel immobilization/conjugation motif for constructing biosensors and molecular devices. However, its supramolecular complexation on surface has been rarely studied, which is partially due to the limited success of current CB[7] immobilization strategies (suffering from either poor stability or inconvenient and time-consuming procedures). In this work, we have successfully tethered alkyne-functionalized CB­[7] (-O-CB[7]) on azide-terminated self-assembled monolayers (SAMs) on gold via the copper­(I)-catalyzed azide–alkyne cycloaddition reaction with high efficiency. With this new approach, highly stable and uniform CB[7]-functionalized SAMs were obtained, which enabled us to gain insights into the recognition properties of CB[7] toward various Fc derivatives on the surface. In particular, the derived complexation thermodynamic (e.g., for FcMeOH, Kf = (1.6 ± 0.3) × 107 M–1) and kinetic (ka = (2.6 ± 0.4) × 103 M–1 s–1, kd = (5.1 ± 0.3) × 10–5 s–1) data indicate the strong interfacial host–guest binding of surface-bound CB[7] toward both cationic and neutral ferrocene derivatives. Remarkably, a comparable binding stability was observed for the anionic ferrocene derivative with an increased distance between the ferrocene core and negatively charged substituent, which is significant for immobilizing/conjugating negatively charged biological macromolecules (e.g., DNA probes)

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

Mitochondria-Targeting Multifunctional Fluorescent Probe toward Polarity, Viscosity, and ONOO^– and Cell Imaging

Abnormal changes occurring in the mitochondrial microenvironment are important markers indicating mitochondrial and cell dysfunction. Herein, we designed and synthesized a multifunctional fluorescent probe DPB that responds to polarity, viscosity, and peroxynitrite (ONOO–). DPB is composed of an electron donor (diethylamine group) and electron acceptor (coumarin, pyridine cations, and phenylboronic acid esters), in which the pyridine group with a positive charge is responsible for targeting to mitochondria. D-π–A structure with strong intramolecular charge transfer (ICT) and twisted intramolecular charge transfer (TICT) properties give rise to respond to polarity and viscosity. The introduction of cyanogroup and phenylboronic acid esters increases the electrophilicity of the probe, which is prone to oxidation triggered by ONOO–. The integrated architecture satisfies the multiple response requirements. As the polarity increases, the fluorescence intensity of probe DPB at 470 nm is quenched by 97%. At 658 nm, the fluorescence intensity of DPB increases with viscosity and decreases with the concentration of ONOO–. Furthermore, the probe is not only successfully used to monitor mitochondrial polarity, viscosity, and endogenous/exogenous ONOO– level fluctuations but also to distinguish cancer cells from normal cells by multiple parameters. Therefore, as-prepared probe provides a reliable tool for better understanding of the mitochondrial microenvironment and also a potential approach for the diagnosis of disease