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Investigation on Pure and Cr, Fe, Ni and Si-doped Fullerene Nanostructures for Enhanced Warfarin Delivery: A DFT Study

This DFT study demonstrates that doping C20 fullerene with transition metals, particularly chromium (Cr), significantly enhances its potential as a carrier for warfarin drug delivery by improving adsorption energy, facilitating charge transfer, and optimizing electronic and thermodynamic properties.

Original authors: Sima Esmailpour, Sadegh Afshari, Sayyed Ahmad Nabavi-Amri, Mahvash Yarahmadi

Published 2026-10-09

📖 5 min read🧠 Deep dive

CC BY 4.0

Original authors: Sima Esmailpour, Sadegh Afshari, Sayyed Ahmad Nabavi-Amri, Mahvash Yarahmadi

Original paper licensed under CC BY 4.0 (https://creativecommons.org/licenses/by/4.0/). ✨ This is an AI-generated explanation of the paper below. It is not written or endorsed by the authors. For technical accuracy, refer to the original paper. Read full disclaimer

Medicine often walks a tightrope between healing and harming. Take warfarin, a common blood thinner used to prevent dangerous clots. It is a life-saving tool, but it demands extreme precision. If the dose is too low, a patient risks a stroke; if it is too high, they risk severe bleeding. Because the window for a safe dose is so narrow, doctors must constantly monitor patients and adjust their medication. This challenge has driven scientists to look for better ways to deliver the drug, hoping to find a carrier that can hold the medicine securely, release it only when needed, and keep the dose steady in the bloodstream. In recent years, the field of nanotechnology has offered a new set of tools for this task, using tiny carbon structures that are only a few billionths of a meter wide. Among these, fullerenes are hollow, cage-like molecules made entirely of carbon atoms. They are known for their strength and stability, and researchers have long wondered if they could be modified to act as tiny delivery trucks for drugs like warfarin.

To answer this question, a team of researchers at Damghan University and Lorestan University in Iran turned to the power of computer simulation. Instead of mixing chemicals in a lab, they built digital models of these carbon cages and tested how they would interact with warfarin molecules. Their goal was to see if they could improve the carbon cages by swapping out a single carbon atom for a different metal atom, a process known as doping. They tested four specific metals: chromium, iron, nickel, and silicon. By running complex calculations based on the laws of quantum mechanics, they could observe how the atoms would arrange themselves, how strongly they would hold onto the drug, and how the electrical properties of the cage would change once the drug was attached. This approach allowed them to screen many possibilities quickly and safely before any physical experiments were attempted.

The researchers first built a perfect, hollow carbon cage made of twenty atoms. They then created four new versions by replacing one carbon atom in the cage with one of the four metals. When they placed a warfarin molecule near these structures, they found that the metal-doped cages behaved very differently from the pure carbon one. The pure carbon cage and the silicon-doped version held the drug very weakly, like a loose handshake that would break apart almost instantly. However, the cages doped with chromium, iron, or nickel grabbed the warfarin much more firmly. The chromium-doped cage proved to be the most effective, holding the drug with a strength that suggested a strong chemical bond rather than a weak physical one. This strong grip is crucial because it means the carrier can transport the drug without it falling off prematurely, yet the bond is not so permanent that the drug cannot be released later.

Beyond just holding the drug, the team examined the stability and the timing of the delivery. They calculated how much energy was released when the drug attached to the cage, finding that the process was spontaneous and energetically favorable for the metal-doped versions. They also looked at how long it would take for the drug to detach from the carrier, a factor known as recovery time. For the chromium, iron, and nickel cages, the time required for the drug to release was measured in seconds, which is a practical timeframe for a delivery system. In contrast, the pure carbon and silicon cages released the drug in fractions of a second, making them useless for controlled delivery. The simulations also revealed that when the drug attached to the metal-doped cages, electrons moved from the drug to the cage, changing the electrical nature of the structure. This shift suggests that the interaction is not just a simple sticking together, but a deeper chemical engagement that alters the properties of both the drug and the carrier.

The study also looked at the shape and surface of these tiny structures to understand exactly how they connect. The metal atoms in the doped cages caused the carbon cage to deform slightly, creating a specific spot where the drug could attach. The warfarin molecule latched onto this metal spot through an oxygen atom in its structure. The researchers used various advanced visualization tools to map the invisible forces at play. They saw that the interaction involved a mix of electrostatic attraction and partial chemical bonding, depending on which metal was used. For the chromium cage, the bond was primarily electrostatic, while the iron and nickel cages formed bonds with some partial covalent character, meaning the atoms shared electrons to a degree. These details confirmed that the metal atoms were the key to making the carbon cage a viable carrier.

Finally, the team simulated how these drug-carrier pairs would behave under light, which is important for detecting the drug in the body. They found that when the warfarin attached to the metal-doped cages, the way the molecules absorbed light changed significantly. The chromium-doped complex showed the strongest absorption, suggesting that this specific combination would be easy to track and monitor. The researchers concluded that while the pure carbon cage is not suitable for this job, the metal-doped versions, especially the one with chromium, show great promise. The simulations suggest that these nanostructures could serve as stable, efficient carriers for warfarin, potentially allowing for better control over the drug's release in the body. While these results are currently limited to computer models, they provide a clear roadmap for future experiments, pointing toward a specific type of nano-carrier that could one day help doctors manage this difficult medication more effectively.

Technical Summary: Investigation on Pure and Cr, Fe, Ni, and Si-doped Fullerene Nanostructures for Enhanced Warfarin Delivery

Problem Statement
The administration of the anticoagulant drug Warfarin (WAR) presents significant clinical challenges due to its narrow therapeutic index. Sub-optimal concentrations can lead to thromboembolic events (blood clots and stroke), while excessive concentrations pose a risk of dangerous bleeding. Consequently, developing innovative drug delivery systems capable of maintaining precise drug concentrations and controlled release is critical. While nanomaterials like fullerenes have shown promise as drug carriers, their interaction with Warfarin, particularly when modified to enhance reactivity, requires further theoretical investigation to identify optimal nanocarriers.

Methodology
This study employs Density Functional Theory (DFT) calculations to investigate the potential of pure $C_{20}$ fullerenes and metallofullerenes ( $MC_{19}$ , where M = Cr, Fe, Ni, Si) as nanocarriers for Warfarin. The research was conducted in the gas phase using the B3LYP hybrid functional with the 6-31G(d) basis set, implemented via the GAMESS software package.

The methodology involved:

Structural Optimization: Optimizing the geometries of pure $C_{20}$ and metal-doped $MC_{19}$ structures, followed by the optimization of the Warfarin molecule and the resulting drug-carrier complexes.
Thermodynamic Analysis: Calculating adsorption energies ( $E_{ads}$ ), enthalpy changes ( $\Delta H$ ), Gibbs free energy changes ( $\Delta G$ ), and entropy changes ( $\Delta S$ ) to assess stability and spontaneity. Recovery times were also estimated to evaluate the feasibility of drug release.
Electronic Property Analysis: Examining Frontier Molecular Orbitals (HOMO/LUMO), energy gaps ( $E_{gap}$ ), work functions ( $\Phi$ ), and Density of States (DOS) to understand electronic interactions and conductivity changes.
Advanced Interaction Analysis: Utilizing Molecular Electrostatic Potential (MEP), Quantum Theory of Atoms in Molecules (QTAIM), Reduced Density Gradient (RDG), Independent Gradient Model based on Hirshfeld partitioning (IGMH), Electron Localization Function (ELF), and Localized Orbital Locator (LOL) to characterize the nature and strength of non-covalent interactions.
Excited State Properties: Performing Time-Dependent DFT (TD-DFT) calculations to simulate UV-Vis spectra and determine excitation energies.

Key Results

Adsorption and Stability: All complexes exhibited negative adsorption energies, indicating stable interactions. However, the strength varied significantly. Pure $C_{20}$ and Si-doped $SiC_{19}$ showed weak physical adsorption ( $E_{ads} \approx -2.2$ kcal/mol) with non-spontaneous thermodynamic parameters ( $\Delta G > 0$ ). In contrast, Cr, Fe, and Ni-doped structures demonstrated strong chemical adsorption. The Cr-doped structure ( $CrC_{19}$ ) exhibited the highest adsorption energy at -38.285 kcal/mol.
Thermodynamics and Recovery: The interactions for $CrC_{19}$ , $FeC_{19}$ , and $NiC_{19}$ were found to be exothermic and spontaneous ( $\Delta G < 0$ ). Recovery time calculations indicated that while pure and Si-doped structures had femtosecond-scale recovery times (unsuitable for sensing/carrier applications), the Cr, Fe, and Ni-doped structures had recovery times in the range of seconds (e.g., ~565,947 s for Cr, ~136 s for Fe, ~14.7 s for Ni), suggesting they are viable candidates for drug delivery.
Electronic Properties: Doping the fullerene cage significantly altered the electronic structure. Upon adsorption of Warfarin, the energy gap ( $E_{gap}$ ) decreased, indicating increased reactivity and semiconducting behavior. Charge transfer analysis confirmed that electrons transfer from the Warfarin molecule (donor) to the nanostructures (acceptor). The work function values decreased upon drug interaction, attributed to the formation of surface dipole moments.
Nature of Interaction:
- MEP and Charge Transfer: MEP maps identified the metal atoms in $MC_{19}$ and the carbonyl oxygen of Warfarin as active sites. Charge transfer was confirmed from the drug to the nanostructure.
- QTAIM and NCI: QTAIM analysis revealed that the interaction in the $CrC_{19}$ complex is primarily electrostatic (weak electrostatic interaction), whereas the $FeC_{19}$ and $NiC_{19}$ complexes exhibit partial covalent character (dative bonds). IGMH and RDG analyses visualized these interactions, showing strong attractive regions (blue isosurfaces) between the metal atoms and the Warfarin oxygen.
- ELF/LOL: These analyses confirmed higher electron localization and interaction strength for the $CrC_{19}$ complex compared to Fe and Ni variants.
Excited State Properties: UV-Vis simulations showed a significant redshift and increased absorption intensity for the complexes compared to free Warfarin. The $CrC_{19}$ complex displayed the lowest excitation energy and highest absorption value, suggesting its potential for real-time monitoring.

Significance and Claims
The authors conclude that metal-doped fullerenes, particularly those doped with Chromium ( $CrC_{19}$ ), Iron ( $FeC_{19}$ ), and Nickel ( $NiC_{19}$ ), are superior to pure $C_{20}$ and Silicon-doped variants for Warfarin delivery. The study claims that $CrC_{19}$ is the most prominent candidate due to its high adsorption energy, favorable thermodynamic spontaneity, and appropriate recovery time.

The paper posits that these theoretical findings provide crucial insights for the development of experimental nanomaterial-based drug delivery systems. By stabilizing Warfarin dosage and enabling controlled release, these nanostructures could address the challenges of Warfarin's narrow therapeutic window. The authors state that their computational approach offers a roadmap for designing carriers that can prevent adverse effects associated with Warfarin therapy, with future work planned to replicate these findings experimentally.

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