The research team, led by Wenjuan Ma and Rongfang Lin of Fujian Medical University with co-first authors Jingjing Lin, Yiwei Liu, and Jiayuan Lai, set out to test an idea that goes beyond conventional formulation science. Pharmaceutical excipients are usually treated as passive helpers that improve dissolution or stability. But a growing body of evidence suggests that macrocyclic host molecules such as cyclodextrins and cucurbiturils can do more than dissolve their cargo: they can alter the cargo’s conformation, cellular uptake, and even its biological activity. CB[7], a rigid barrel-shaped molecule with a hydrophobic cavity and carbonyl-lined portals at both ends, is a particularly intriguing candidate because it binds neutral and positively charged guests with high affinity and has previously been shown to modify the behavior of platinum-based anticancer drugs.

To establish that ticagrelor and CB[7] actually form a complex, the researchers deployed a battery of complementary techniques. Job’s method of continuous variation, a classic supramolecular chemistry analysis, produced a maximum at a mole fraction of 0.5, supporting a 1:1 host-to-guest stoichiometry. Ultraviolet–visible titration data, fitted to a 1:1 binding model, yielded an apparent association constant of (3.90 ± 0.12) × 10⁴ M⁻¹ in 10 percent methanol and 0.1 M hydrochloric acid, with an excellent coefficient of determination of 0.9952. Proton nuclear magnetic resonance spectroscopy added further support: when CB[7] was added stepwise to ticagrelor, signals in both the aromatic and aliphatic regions shifted upfield by between 0.05 and 0.71 parts per million, a hallmark of guest molecules being shielded inside a host cavity.

Computational modelling provided a structural picture of the assembly. The team used GFN-xTB molecular dynamics at 500 K to generate two thousand candidate conformations, then refined the lowest-energy structure with density functional theory at the B3LYP-D3/6-31G(d,p) level. The calculated gas-phase association free energy came out at −53.3 kcal/mol, indicating favorable binding within the computational model. In the predicted geometry, part of the ticagrelor molecule sits inside the CB[7] cavity while several functional groups protrude near the carbonyl-lined portals, a positioning compatible with portal-associated noncovalent interactions. The authors are careful to note that the gas-phase calculation cannot be compared directly with the solution-phase binding constant, and that the specific orientation of the drug inside the cage has not been experimentally pinned down.

The practical payoff showed up most clearly in phase-solubility experiments. In 0.1 M hydrochloric acid, mimicking the acidic environment of the stomach, CB[7] enhanced the apparent solubility of ticagrelor by approximately 79-fold, with an apparent stability constant of (9.81 ± 0.73) × 10³ M⁻¹. In phosphate-buffered saline at pH 7.4, the enhancement was a more modest 7.5-fold, with a stability constant of (6.44 ± 0.41) × 10² M⁻¹. The authors caution that the two media differ in both pH and ionic composition, so the difference cannot be attributed solely to changes in drug ionization. Solid-state analysis told a complementary story: X-ray powder diffraction revealed that the characteristic crystalline peaks of free ticagrelor nearly vanished in the formulated powder, replaced by broadened peaks and a diffuse halo consistent with a predominantly amorphous solid state, a form that generally dissolves faster than crystals.

What elevates the study beyond a standard solubility exercise is its exploration of immunology. Ticagrelor is known to have anti-inflammatory effects independent of platelet inhibition, including attenuation of procoagulant extracellular-vesicle release and inflammasome-associated signaling. The researchers therefore examined how the formulation affected RAW264.7 macrophages, the workhorse immune cells of the mouse laboratory, after stimulating them with lipopolysaccharide to induce an inflammatory state. Macrophages exist on a functional spectrum: pro-inflammatory M1-like cells, marked by iNOS and CD80, drive tissue-damaging inflammation, while M2-like cells, marked by CD206, participate in repair and resolution. Excessive M1 skewing is a feature of many chronic inflammatory diseases.

The results were striking. Free ticagrelor reduced the proportion of iNOS-positive, CD206-negative M1-like cells in a dose-dependent manner, but the Tica@CB[7] formulation pushed the shift further, decreasing M1-like cells and increasing M2-like cells relative to the free drug. Immunofluorescence staining showed reduced iNOS and increased CD206 protein, and quantitative PCR revealed stronger downregulation of the pro-inflammatory genes Nos2 and Il1b alongside increased expression of Hmox1, a gene associated with antioxidant and resolution responses. Interestingly, the effect peaked at the nominal 1:1 drug-to-host ratio; raising the CB[7] concentration from 20 to 80 micromolar while holding ticagrelor constant produced no additional benefit. The authors note an important caveat: based on the measured binding constant, only about 34 percent of the drug would be complexed at the tested concentrations, and no physical-mixture control was evaluated, so the enhanced response cannot be attributed exclusively to the preformed complex.

A more complicated finding emerged when the team probed oxidative stress and cell death. Under inflammatory conditions, the formulation was associated with higher reactive-oxygen-species fluorescence, greater lipid peroxidation measured with the C11-BODIPY 581/591 probe, and increased proportions of Annexin V-positive dying cells compared with free ticagrelor. These responses were non-monotonic with CB[7] concentration, peaking at the equimolar composition. The study does not establish the mechanism of cell death or a causal link between oxidative stress and the macrophage phenotype shift, and the authors flag this as unresolved. Separately, the formulation promoted cholesterol efflux from macrophages, a process tied to anti-inflammatory polarization, with the largest efflux responses at higher CB[7] concentrations of 40 and 60 micromolar, a pattern distinct from the polarization data and suggesting that different components of the mixture drive different effects.

The in vivo experiments translated the laboratory findings into whole-animal pharmacology. When mice received the formulation by oral gavage at an equivalent ticagrelor dose of 100 milligrams per kilogram, the area under the plasma concentration–time curve over 18 hours rose 1.9-fold compared with free drug, from 3074.65 to 5812.76 nanogram-hours per milliliter, and the maximum plasma concentration increased 3.2-fold, from 376.50 to 1218.99 nanograms per milliliter. Peak concentrations arrived slightly earlier, at 2.40 versus 3.20 hours, while the elimination half-life and mean residence time were shorter. In a parallel seven-day dosing experiment followed by an inflammatory challenge with lipopolysaccharide, flow cytometry of circulating immune cells showed that mice given the formulation had a lower proportion of CD86-positive cells within the CD11b-positive, Ly6C-positive monocyte population, particularly at 12 and 24 hours after challenge, indicating a dampened inflammatory profile in the bloodstream.

The study stops well short of clinical translation, and its authors are appropriately measured about the limits of their data. The binding constant was measured under acidic conditions that do not match the cell-culture environment, the fraction of complexed drug during biological experiments is unknown, and cyclodextrin-based ticagrelor formulations reported by other groups cannot be compared quantitatively because of differing experimental conditions. Nevertheless, the work makes a compelling case that cucurbit[7]uril is not merely a solubilizing wrapper but an active formulation component capable of reshaping both the pharmacokinetics and the immunological behavior of a drug. If the approach holds up in further preclinical testing, molecular caging could become a general strategy for rescuing poorly soluble immunomodulatory compounds, a class of molecules that keeps growing as inflammation is implicated in ever more diseases.

Subject of Research: Cucurbit[7]uril host–guest complexation of the antiplatelet drug ticagrelor to enhance oral bioavailability and modulate macrophage inflammatory responses

Article Title: Cucurbit[7]uril complexation of ticagrelor: host–guest characterization, enhanced oral bioavailability, and immunomodulatory effects

Article References: Lin, J., Liu, Y., Lai, J., Xu, J., Lin, Y., Zhong, C., Lin, R., & Ma, W. (2026). Cucurbit[7]uril complexation of ticagrelor: host–guest characterization, enhanced oral bioavailability, and immunomodulatory effects. Results in Chemistry, 31, Article 103935. https://doi.org/10.1016/j.rechem.2026.103935

Image Credits: AI Generated

DOI: 10.1016/j.rechem.2026.103935

Keywords: cucurbit[7]uril, ticagrelor, host–guest chemistry, supramolecular chemistry, oral bioavailability, drug solubility, macrophage polarization, P2Y12 receptor, pharmacokinetics, immunomodulation, inclusion complex, drug delivery

Ticagrelor is a mainstay of modern cardiology. It works by reversibly blocking the platelet P2Y12 receptor, which prevents adenosine diphosphate from activating platelets and triggering the clotting cascade. Physicians prescribe it, often alongside aspirin, to patients with acute coronary syndrome or ST-segment elevation myocardial infarction to ward off further thrombotic events. Because the drug’s therapeutic effect depends on careful dosing and because patients differ widely in how they metabolize it, analytical methods that can measure ticagrelor quickly and accurately are clinically valuable. Until now, that job has mostly fallen to chromatography-based techniques such as high-performance liquid chromatography, liquid chromatography coupled with mass spectrometry, reverse-phase HPLC, and various spectrophotometric and bio-analytical approaches. These methods are accurate but typically require expensive instrumentation, trained operators, lengthy sample preparation, and centralized laboratory facilities.

Electrochemical sensing offers an appealing alternative. By translating molecular interactions at an electrode surface into an electrical current, such sensors can be fast, cheap, portable, and sensitive. The catch is that a bare electrode rarely provides enough signal for trace-level detection of a drug in a complex biological matrix. The standard remedy is to coat the electrode with a nanomaterial or nanocomposite that boosts conductivity, surface area, and catalytic activity. The Iranian-led team behind the new study chose an unusual pairing: carbon black, an abundant and highly conductive industrial carbon, and a silver-based metal-organic framework, a crystalline coordination network built from silver ions and the organic linker 1,3,5-benzenetricarboxylic acid.

Each component brings distinct strengths. Carbon black offers excellent porosity, high surface area, strong electrical conductivity, and a wide potential window, making it an ideal conductive backbone. Metal-organic frameworks, meanwhile, are prized for their enormous surface areas, tunable structures, and high porosity, all of which improve the interface between electrode and electrolyte. In this system, the silver framework performs three critical jobs: it supplies metal-based catalytic activity, it acts as an intrinsic electrochemical signal source through its own silver-related redox chemistry, and its tunable porosity facilitates molecular diffusion while enlarging the effective surface area available for recognition events. The researchers synthesized the framework by dissolving the organic linker and silver nitrate separately in methanol, combining the solutions, and heating the mixture at 120 degrees Celsius overnight, a straightforward and economical preparation.

Microscopy and spectroscopy confirmed that the marriage worked. Field-emission scanning electron microscopy showed carbon black forming a spherical film-like coating, while the silver framework appeared as sheet-like crystals with sharp, regular morphologies. In the composite, the two components merged into a porous, spongy, interconnected architecture with no phase separation, exactly the kind of structure that maximizes both conductivity and accessible surface area. Energy-dispersive X-ray analysis and elemental mapping verified that carbon, oxygen, nitrogen, and silver were uniformly distributed throughout the material. Fourier-transform infrared spectroscopy revealed characteristic bands from the aromatic linker and carboxylate groups, and X-ray diffraction showed that the framework’s crystalline structure survived composite formation intact, with no detectable separate crystalline silver oxide or metallic silver impurity phases.

Electrochemical tests then revealed why the composite outperforms its ingredients. Using cyclic voltammetry and electrochemical impedance spectroscopy with a ferricyanide redox probe, the team found that adding carbon black to a glassy carbon electrode increased current and lowered charge-transfer resistance from 687 ohms for the bare electrode to 344 ohms. The silver framework alone, hampered by its intrinsically low conductivity, actually raised resistance to 2016 ohms. But the combined composite slashed resistance to just 221 ohms, clear evidence of synergy. Calculations based on the Randles-Sevcik equation showed the composite electrode’s electrochemically active surface area reached 0.045 square centimeters, more than double the 0.021 square centimeters of the bare electrode.

Perhaps the most intriguing finding concerns how the sensor actually detects ticagrelor. Neither the bare electrode nor the carbon-black-modified electrode produced a distinct response to the drug. Instead, the signal originates from the silver-containing framework itself: the drug, with its sulfur-, nitrogen-, and oxygen-containing functional groups, accumulates on the electrode through affinity interactions with accessible silver sites and hydrogen bonding with the organic linker, thereby blocking the electroactive silver sites and suppressing the silver-related current. The result is an indirect, signal-off mechanism in which the drug’s presence is measured by how much it dampens the baseline signal. Carbon black amplifies this effect dramatically. The drug-induced current change was approximately 519 microamperes at the composite electrode versus 196 microamperes at the framework alone, a roughly 2.6-fold enhancement, because the conductive carbon network improves electron transfer between the electroactive silver sites and the underlying electrode while also dispersing the framework particles more effectively.

After optimizing the composite ratio, buffer pH, and salt concentration, the sensor delivered striking analytical performance. Differential pulse voltammetry yielded a linear response across an extraordinarily wide concentration range spanning 0.01 to 2500 nanomolar, with a correlation coefficient of 0.9983 and a calculated detection limit of 0.0033 nanomolar. For comparison, previously reported ticagrelor sensors based on carbon paste electrodes modified with multiwalled carbon nanotubes and titanium nanoparticles, zeolite-modified carbon paste, or solid gold electrodes achieved detection limits in the hundreds of nanomolar to micromolar range. The authors caution that such cross-study comparisons should be interpreted carefully, since electrode architectures, sample preparation, and detection-limit calculations differ, but the numbers nonetheless underline the platform’s analytical promise. Microscopy before and after testing also confirmed the composite’s structural stability under operating conditions.

The sensor proved robust in the ways that matter for real-world use. It tolerated high concentrations of structurally related drugs and common biological interferents, including ticlopidine, clopidogrel, warfarin, ascorbic acid, dopamine, uric acid, and glucose. Five identical electrodes produced responses with a relative standard deviation of just 2.5 percent, and five repeated measurements on a single electrode gave 3.1 percent. After fifteen days of storage at room temperature, the electrode retained 93 percent of its initial response, and fifty consecutive voltammetric cycles preserved 95.32 percent of the original signal. Most importantly, when the team spiked human serum samples with 50, 100, and 200 nanomolar ticagrelor after protein precipitation, the sensor recovered between 99.5 and 101.2 percent of the added drug with relative standard deviations below 2.8 percent, demonstrating that the platform can function in a genuine biological matrix rather than only in pristine buffer solutions.

The broader significance of the work lies in its demonstration that cheap, readily available materials can be engineered into sensors rivaling far costlier analytical instruments. Carbon black costs pennies, the silver framework is synthesized in a single overnight reaction, and the entire electrode modification involves ultrasonicating the two powders in a drop of solvent and drying five microliters onto a glassy carbon electrode. A sensor built this way could, in principle, support point-of-care or bedside monitoring of ticagrelor, helping clinicians tailor antiplatelet therapy to individual patients and detect abnormal drug levels before they translate into bleeding or clotting complications. The signal-off design, in which the analyte suppresses a built-in silver redox signal, also offers a template that other researchers could adapt to different drug molecules capable of binding silver sites. While further validation in larger clinical studies would be needed before any diagnostic deployment, the study adds a compelling entry to the growing toolkit of metal-organic framework sensors and shows how the right nanoscale partnership can turn an ordinary electrode into an extraordinarily perceptive one.

Subject of Research: Electrochemical detection of the antithrombotic drug ticagrelor using a silver metal-organic framework and carbon black nanocomposite-modified electrode

Article Title: Electrochemical sensor based on Ag-metal organic framework/carbon black nanocomposite for the selective detection of Ticagrelor

Article References: Roushani, M., Karazan, Z. M., & Makki, I. S. (2026). Electrochemical sensor based on Ag-metal organic framework/carbon black nanocomposite for the selective detection of Ticagrelor. Results in Chemistry, 31, Article 103939. https://doi.org/10.1016/j.rechem.2026.103939

Image Credits: AI Generated

DOI: 10.1016/j.rechem.2026.103939

Keywords: ticagrelor, electrochemical sensor, metal-organic framework, carbon black, nanocomposite, glassy carbon electrode, antithrombotic drug, differential pulse voltammetry, human serum, detection limit, silver framework, P2Y12 receptor