Diamond & Related Materials 146 (2024) 111262 Contents lists available at ScienceDirect Diamond & Related Materials journal homepage: www.elsevier.com/locate/diamond Exploring the naproxen adsorption at the surface of iron-decorated C24 fullerene-like nanocages for providing drug delivery insights along with DFT calculations C.Y. Hsu a, M.J. Saadh b, A.I. Ayesh c, M.D. El-Muraikhi c, M. Mirzaei d, *, M. Da'i e, *, S. Ghotekar f, M.M. Salem-Bekhit g a Department of Pharmacy, Chia Nan University of Pharmacy and Science, Tainan, Taiwan Faculty of Pharmacy, Middle East University, Amman 11831, Jordan c Department of Physics and Materials Sciences, College of Arts and Sciences, Qatar University, P.O. Box 2713, Doha, Qatar d Department of Natural and Mathematical Sciences, Faculty of Engineering, Tarsus University, Tarsus, Turkiye e Faculty of Pharmacy, Universitas Muhammadiyah Surakarta, Surakarta, Indonesia f Centre for Herbal Pharmacology and Environmental Sustainability, Chettinad Hospital and Research Institute, Chettinad Academy of Research and Education, Kelambakkam 603103, Tamil Nadu, India g Department of Pharmaceutics, College of Pharmacy, King Saud University, PO Box 2457, Riyadh 11451, Saudi Arabia b A R T I C L E I N F O A B S T R A C T Keywords: Drug adsorption Drug delivery Drug detection Molecular characterization Nanostructure Due the importance of developing successful drug delivery platforms, the current research work done to assess the iron-decorated C24 fullerene-like nanocages for the adsorption of naproxen (NPX) drug along with density functional theory (DFT) calculations. NPX is among the important non-steroidal anti-inflammatory drugs (NSAIDs), in which its enhancement has been still under development. Accordingly, the focus of this work was on the customization of a carrier model for the NPX drug by investigating the electronic and structural features of interacting conjugated systems. To do this, three iron-decorated nanocages including FeC24, FeC23, and FeC22 models were prepared to assess the adsorption process to yield the NPX@FeC24, NPX@FeC23, and NPX@FeC22 conjugated systems. Different levels of electronic molecular orbital levels and adsorption strengths were achieved regarding the interaction of NPX and iron-decorated nanocages, in which the NPX@FeC22 model was at the highest level of strength and also electronic variations. Accordingly, suitable adsorption and detection of NPX drug were found by the assistance of iron-decorated nanocage models. Especially in the water solvent, the models of conjugations were found still stable by the advantage of iron-decorated conjugated systems. The results of this work could be proposed for further study of NPX drug delivery issues based on the iron-decorated fullerene-like nanocages. 1. Introduction The occurrence of inflammation symptoms in human body is very common because of several reasons such as daily lifestyles, diseases, infections, surgeries, etc. [1,2]. Although the conventional medications are currently available for working as anti-inflammatory agents, but their efficiency is not certain enough to completely overcome the occurred harmful issues [3,4]. Accordingly, enhancing the available anti-inflammatory drugs or developing new ones are crucial for recov­ ering the patients to their normal life [5,6]. Based on the results of earlier research efforts, advantages of non-steroidal anti-inflammatory drugs (NSAIDs) for dealing with the inflammation symptoms have been indicated especially by reducing the pain and fever to help the treatment of harmed tissues [7,8]. However, there are still serious risks of medi­ cation by NSAIDs, in which the occurrence of serious adverse effects such as the gastrointestinal bleeding, kidney diseases, and heart attacks has been reported up to now [9,10]. Hence, further efforts are required to deal with the unwanted impacts of NSAIDs for the patients in addition to the enhancement of their therapeutic efficiency [11,12]. Naproxen (Fig. 1) is among the NSAIDs category for medicating the inflammatory diseases such as rheumatoid arthritis, gout and fever in addition to the pain reduction [13,14]. However, serious adverse effects such as heart * Corresponding authors. E-mail addresses: mahmoudmirzaei@tarsus.edu.tr (M. Mirzaei), muhammad.dai@ums.ac.id (M. Da'i). https://doi.org/10.1016/j.diamond.2024.111262 Received 2 March 2024; Received in revised form 28 May 2024; Accepted 1 June 2024 Available online 2 June 2024 0925-9635/© 2024 Elsevier B.V. All rights are reserved, including those for text and data mining, AI training, and similar technologies. C.Y. Hsu et al. Diamond & Related Materials 146 (2024) 111262 new specifications for the nanostructures regarding the existence of an activated surface region for involving in more successful communica­ tions with other substances [35]. Especially in the case of iron decora­ tions, an advantage of iron compatibility with the biological systems has been already investigated very well [36–38]. Among the several avail­ able nanostructures, fullerenes have been found as single standing ar­ chitectures with the spherical shapes for working in the interaction and adsorption processes [39]. Besides the well-known (5,6)-rings C60 fullerene, several other architectures of fullerene-like nanocages have been investigated up to now, in which (4,6)-rings C24 fullerene-like nanocage was found as a possible configuration [40–42]. Accordingly, the application of this nanocage has been investigated for adsorbing the drug substances along with computational assessments [43–45]. Addi­ tionally, the atomic decoration of nanostructure was also done for providing more customized scaffolds for approaching the targeted pur­ poses [46]. Hereby, a representative model of C24 fullerene-like nano­ cage was employed within the current research work to adsorb the naproxen NSAIDs substance for providing drug delivery insights along with DFT calculations. For obtaining detailed information of interacting substances, DFT calculations could reveal insights into the details of conjugated system before and after the occurrence of interaction or adsorption processes [47].To this aim, various models of iron-decorated fullerene-like nanocages were explored and the possibility of in­ teractions between drug and nanocage substances were examined along with the formation of naproxen@nanocage conjugations (Fig. 3). Based on the results of earlier works, the formation of naprox­ en@nanostructure conjugation was found as a way of drug enhancement through the development of smart drug delivery processes [48–50]. Accordingly, the formation of naproxen@nanocage conjugations was assessed within this work for assigning the advantages of iron-decorated fullerene-like nanocages towards the adsorption of naproxen drug. As mentioned earlier, tailoring the nanostructures to customize them for employing in the drug delivery process is a complex subject, in which the recognition of detailed information for the conjugated formations could help to provide more insights into the development of new carrier scaffolds [51–53]. The required features of naproxen and nanocage counterparts were evaluated within this work to discuss their electronic and structural specifications before and after the formation of naprox­ en@nanocage conjugations; all details were summarized in Figs. 1–4 and Tables 1–4. Fig. 1. The naproxen (NPX) model; the molecular heads were assigned for the formation of Config. I and Config. II conjugations. diseases, strokes, gastrointestinal bleeding, stomach pain, dizziness, headache, bruising, and allergic reactions have been observed for the patients after their medication by naproxen [15–18]. To this point, considerable efforts have been done to develop safe protocols for the naproxen medication in a safe level along with structural customizations and officiations, in which smart drug delivery platforms have been supposed as a useful method of enhancement [19–24]. In this case, exploring a suitable carrier for a specific drug is an essential step of developing successful drug delivery processes [25,26]. Besides, learning details of interactions between drug and carrier counterparts is very essential for approaching the purpose [27]. To this aim, a drug…carrier system was investigated within the current research work based on density functional theory (DFT) assessments of the naproxen (Fig. 1) adsorption at the surface of iron-decorated C24 fullerene-like nanocages (Fig. 2) along with the formation of naproxen@nanocage conjugations (Fig. 3). Since the innovation of nanotechnology, considerable efforts of re­ searchers have been focused on the characterization of nanostructures to customize them for the specific functions and applications [28,29]. Accordingly, several architectures of nanostructures have been devel­ oped to this time to fulfill the criteria of working in the specific fields from industry to biology [30–32]. Supplying a suitable surface for involving in interaction and adsorption processes with other substances was one important practical issue about the nanostructures [33]. Not only the pure composition, but also the doped or decorated nano­ structures could do a good jog for the providing the communicating surface [34]. Decorating with metal atoms such as iron, even brought 2. Materials and methods The naproxen drug substance (NPX; C14H14O3) and the pure and iron-decorated fullerene-like nanocages (Figs. 1 and 2) were the starting materials of this work. A representative model of C24 fullerene-like nanocage, which was already known as a possible mode of fullerenes [40–42], was employed as the basic model of this work and three irondecorated models were generated by inserting one iron atom to create FeC24, FeC23, and FeC22 models regarding the condition of atomic decoration. One iron atom was attached to the exterior surface of nanocage to make the FeC24 model. One iron atom was substituted instead of one carbon atom of nanocage to make FeC23 model. One iron atom was substituted instead of two carbon atoms of nanocage to make the FeC22 model [52]. Since the spin polarization of iron atom is an important issue as described by the earlier works of iron medicated systems [54,55], energies of structures in singlet (0, 1), triplet (0, 3), and quintet (0, 5) states were calculated for the models of this work (Table S1 of Supplementary file). Although the non-singlet models were found more stable in some cases, but the energy convergence was not obtained for all of them and the structures were not found trustable. In this regard, the structures of this work were all investigated in the zero global charge and singlet multiplicity to represent the trustable struc­ tures of nanocage models and their complexes in a unique electronic state. Subsequently, the interacting conjugations were found as NPX@C24, NPX@FeC24, NPX@FeC23, and NPX@FeC22 models as shown Fig. 2. The pure and iron-decorated fullerene-like nanocages; the bond dis­ tances were written in Å. 2 C.Y. Hsu et al. Diamond & Related Materials 146 (2024) 111262 Fig. 3. The naproxen@nanocage conjugations in two configurations; Config. I and Config. II, and their green dotted lines interactions as indicated by accompa­ nying numbers. Fig. 4. The HOMO-LUMO distribution patterns embedded DOS diagrams of naproxen@nanocage conjugated systems and the singular nanocages. in Fig. 3. The models were optimized to obtain the minimized energy geometries and their structural features were evaluated for the opti­ mized systems. Although the free optimization calculations were formed for the formation of conjugated systems, but Config. I and Config. II were found as two main interacting configurations for the formation of each conjugated system Based on the oxygen heads of NPX as shown in Fig. 1. 3 C.Y. Hsu et al. Diamond & Related Materials 146 (2024) 111262 Table 1 Electronic features based on HOMO-LUMO levels and their related quantities. Model HOMO eV C24 FeC24 FeC23 FeC22 [52] NPX@C24 − − − − − − − − − − − − NPX@FeC24 NPX@FeC23 NPX@C22 Config. Config. Config. Config. Config. Config. Config. Config. I II I II I II I II 7.91 7.08 7.29 6.80 7.40 7.41 6.62 6.56 6.67 6.46 6.86 6.62 LUMO eV − − − − − − − − − − − − Fermi eV 1.68 1.01 1.52 3.27 1.57 1.24 0.51 0.45 0.76 0.54 1.47 1.18 − − − − − − − − − − − − O1 |e| O2 |e| O3 |e| Fe |e| Q |e| NPX C24 FeC24 FeC23 FeC22 NPX@C24 − 0.537 n/a n/a n/a n/a − 0.536 − 0.534 − 0.633 − 0.530 − 0.607 − 0.531 − 0.540 − 0.532 − 0.624 n/a n/a n/a n/a − 0.624 − 0.587 − 0.622 − 0.683 − 0.623 − 0.648 − 0.623 − 0.523 − 0.724 n/a n/a n/a n/a − 0.0724 − 0.723 − 0.722 − 0.675 − 0.720 − 0.667 − 0.722 − 0.748 n/a n/a 0.883 0.837 0.820 n/a n/a 0.806 0.794 0.775 0.760 0.876 0.906 n/a n/a n/a n/a n/a 0.018 0.025 0.111 0.103 0.154 0.175 0.271 0.213 NPX@FeC24 NPX@FeC23 NPX@C22 Config. I Config. II Config. I Config. II Config. I Config. II Config. I Config. II WF eV CH eV EI eV 6.23 6.07 5.77 3.52 5.83 6.17 6.11 6.11 5.90 5.92 5.38 5.44 4.79 4.05 4.40 5.04 4.49 4.33 3.56 3.51 3.71 3.50 4.17 3.90 3.12 3.04 2.89 1.77 2.92 3.09 3.06 3.06 2.96 2.96 2.70 2.72 3.69 2.70 3.36 7.18 3.45 3.03 2.08 2.01 2.34 2.07 3.22 2.80 density of states (DOS) were also exhibited in Fig. 4 for the investigated models. Natural bond orbital (NBO) based charges were evaluated for the models besides. Additionally, the thermochemistry features were evaluated to show the impact of water solvent on the stability of con­ jugated systems based on the polarizable continuum model (PCM). All evaluated electronic and structural quantities were summarized in Tables 1–4. Indeed, the main idea of this work was focusing on the exploration of variations of models along with the conjugation forma­ tions and also assessing the possibility of formations of such conjugated systems. In this case, the challenges of similarity of computationally evaluated features and those of experimentally obtained ones could be treated in a better mode by clarifying the main idea of this work. Even in the case of used methods of calculations, there are challenges of reli­ ability and validity of employed theoretical methods for performing computations [56]. To this point, the DFT calculations of this work were done using the ωB97XD/6-31G* level of theory, in which the ωB97XD functional has been already found useful for exploring the interacting systems based on the dispersion correction effects [57–59] and the 6- Table 2 NBO atomic charges of oxygen and iron atoms and also transferred charges. Model 4.79 4.05 4.40 5.04 4.49 4.33 3.56 3.51 3.71 3.50 4.17 3.90 Gap eV The interactions were characterized by performing additional quantum theory of atoms in molecules (QTAIM) analyses to learn the numbers of interactions, their roles, and also the contributing atoms between the counterparts in each system. The total strength of interaction/adsorp­ tion was recognized by evaluating the structural energies in the term of adsorption energy (EAds). Vibrational frequencies were also examined for the models in both of singular and bimolecular conditions to examine the global minimization states; the evaluated spectra were included in a Supplementary file. By finalizing this step, the models were obtained for exploring their features regarding both of electronic and structural terms. The models were involved in the electronic characterizations by evaluating energy terms of the highest occupied molecular orbital (HOMO) and the lowest unoccupied molecular orbital (LUMO) and also their related parameters. In the case of electronic characterization, the features of models were compared before and after the occurrence of interaction/adsorption process and the results were evaluated accord­ ingly. Distribution patterns of HOMO and LUMO and diagrams of Table 4 Thermochemistry features of water solvent impacts. Model ΔGWater kcal/ mol NPX@C24 NPX@FeC24 NPX@FeC23 NPX@C22 Config. I Config. II Config. I Config. II Config. I Config. II Config. I Config. II ΔHWater kcal/ mol ΔSWater kcal/ mol.K − 7.81 − 8.71 − 7.62 − 8.38 0.65 1.11 − 21.29 − 22.66 − 22.37 − 23.45 − 2.67 − 3.63 − 14.81 − 15.41 − 15.53 − 16.91 − 2.41 − 5.01 − 11.24 − 13.65 − 11.10 − 14.29 − 1.46 − 2.16 Table 3 Structural features based on adsorption energies and interactions details. Model NPX@C24 NPX@FeC24 NPX@FeC23 NPX@C22 EAds kcal/mol Config. I − 4.53 Config. II − 2.55 Config. I Config. II Config. I Config. II Config. I − − − − − 36.16 39.75 29.19 32.31 41.16 Config. II − 41.42 Interaction Distance Å ρ au ∇2ρ au 1: 2: 1: 2: 1: 1: 1: 1: 1: 2: 1: 2: 3: 2.76 2.96 3.15 2.77 1.88 1.79 1.96 1.92 1.84 3.04 1.93 3.01 3.35 0.0143 0.0041 0.0067 0.0139 0.1053 0.1277 0.0856 0.0896 0.1054 0.0056 0.0849 0.0046 0.0026 0.0446 0.0134 0.0246 0.0436 0.6668 0.9032 0.4974 0.5604 0.7683 0.0158 0.5592 0.0408 0.0075 O1…C H…C O3…C O2…C O1…Fe O2…Fe O1…Fe O2…Fe O1…Fe H…C O3…Fe H…C H…C 4 H au − − − − − − 0.0009 0.0006 0.0004 0.0008 0.0101 0.0154 0.0154 0.0138 0.0112 0.0008 0.0128 0.0009 0.0005 C.Y. Hsu et al. Diamond & Related Materials 146 (2024) 111262 31G* basis set has been already found useful for exploring the involving atoms of this work [60]. The calculations were done using the Gaussian 09 program [61] and the data extractions and graphical representations were done using the ChemCraft [62], Multiwfn [63], and GaussSum [64] programs. Hereby, the required information for exploring the electronic and structural features of NPX@C24, NPX@FeC24, NPX@FeC23, and NPX@FeC22 conjugated systems were evaluated to assess a possible drug delivery platform of NPX drug using the repre­ sentative nanocages. For the case of such molecular issues, the results of earlier works showed benefits of employing computations to clarify details of complicated systems especially for the case of new substances identifications and developments [65,66]. comparison with the other two decorated models. The iron atom was doped at the exterior surface of nanocage to make the FeC24 model; however, that iron atom was doped inside the atomic structure of nanocage instead of one and two carbon atoms to make the FeC23 and FeC22 models. Accordingly, different electronic features were evaluated for the models regarding such structural decorations. Next, the results of DOS diagrams indicated different variations of molecular orbitals fea­ tures before the HOMO level and after the LUMO level with a significant change of energy gap (Gap) between two dominant levels of frontier molecular orbitals. It is known that the HOMO and LUMO energy levels stand for the electron transferring tendency of a molecular system for electron donating and accepting inside and outside the molecule. In this case, these levels are dominant for the frontier molecular orbitals and their information could be used for determining the model specifica­ tions. Comparing the obtained electronic features for the conjugated systems in Fig. 4 also reveal different electronic systems for the inter­ acting models based on the movement and localization of HOMO and LUMO levels. Comparing the electronic variations of conjugated models by those of the singular models could lead to approach a sensing func­ tion for the nanocages for adsorbing the NPX drug substance. Indeed, different Gap values could yield different conductance rates for the molecular systems regarding their sensing functions and activities. In the case of investigated models, such changes could be observed by the visual representations of HOMO and LUMO patterns and also illustrated DOS diagrams. Even the formation of each configuration could be determined by measuring the changes of such electronic features. Indeed, the conductance rate is related to the Gap variations and their changes could significantly change the features of models. For better describing these features, the quantitative values of HOMO and LUMO related features were summarized in Table 1. A quick look at the eval­ uated results could indicate meaningful variations of both of HOMO and LUMO levels in both of singular and conjugated states. Additionally, significant variations of models from the singular state to the conjugated state emphasized on the measurements of detection purposes. Accord­ ingly, the Fermi energy and Gap values detected changes of such elec­ tronic variations to show different environment in the investigated models. The values of HOMO and LUMO were directly calculated whereas Eqs. (1)–(5) were used to calculate the values of Fermi energy, Gap, work function (WF), chemical hardness (CH), and electrophilicity index (EI). 3. Results and discussion The term of “drug enhancement” is an important issue because of so many reasons such as drug inefficiencies and resistances, side effects, and many more things leading to the considerable efforts of researchers to work on the available drugs or innovating new ones. In this case, the results of earlier studies indicated that the conjugation of drugs with other substances such as nanostructures could yield a drug delivery platform under a controllable process and a smart mechanism. However, all details of such platforms are still unknown and further investigations are required to approach such a successful platform especially regarding the critical points of working in the living systems. Accordingly, customizing the nanostructures towards the specific drug substances is a crucial step for investigating new carriers to be employed for the drug delivery processes, in which learning details of drug adsorption at the surface of nanostructures could reveal insightful information about the formation of drug-carrier conjugated systems. By this importance, the current research work was initiated to explore the naproxen adsorption at the surface of representative iron-decorated C24 fullerene-like nanocages for providing drug delivery insights along with DFT calcu­ lations. As shown in Fig. 1, two oxygen heads of naproxen (NPX) were found very suitable to interact with the nanocages (Fig. 2) leading to the formation of two main Config. I and Config. II configurations for the naproxen@nanocage conjugations (Fig. 3). The structures were found during a free optimization process and the obtained conjugations were found as the final stabilized systems. The pure and iron-decorated fullerene-like nanocages were designed by employing a representative C24 model and its various models of iron-decorated architectures. As mentioned earlier, one iron atom was added to the exterior surface of C24 to make the FeC24 model, one iron atom was substituted instead of one carbon atom of C24 to make the FeC23 model, and one iron atom was substituted instead of two carbon atoms of C24 to make the FeC22 model. The geometries were fully optimized to find the stabilized structures in addition to the conformation by their vibrational frequency calculations; as available in a Supplementary file. At this step, the parental materials of study were prepared to be involved in interaction to each other to proceed the adsorption processes of conjugated system formations as shown in Fig. 3. Based on two oxygen heads of NPX, two configurations were found for the interaction of NPX with each nanocage as indicated by Config. I and Config. II in the model representations. Hereby, the stabilized models were found and their features were evaluated for approaching the goal of this work to assess the employed customization of investigated fullerene-like nanocages for adsorbing the NPX drug substance. Besides the structural representations of models in Figs. 1–3, their electronic features were exhibited in Fig. 4 showing the HOMO-LUMO distribution patterns and DOS diagrams for exploring the impacts of atomic decorations on the electronic system of models and formations of conjugations. As could be found by the patterns, the iron-decorated atom could show a significance of existence in the nanocage architec­ ture by localization of patterns around the decorated region. However, different levels of significance were found for all three decorated models, where the highest significance was found for the FeC22 model in Fermi = 1/2 (HOMO + LUMO) (1) Gap = (LUMO − HOMO) (2) WF ∼ − Fermi (3) CH = 1/2 (LUMO − HOMO) (4) / / EI = 1 4 (HOMO + LUMO)2 (LUMO − HOMO) (5) Among the iron-decorated models, the values of Gap in Table 1 were found to be 6.07, 5.77, and 3.52 eV for FeC24, FeC23, and FeC22 models all smaller than the pure C24 model with 6.23 eV. It is known that a smaller value of Gap could lead to a higher activity/reactivity of the molecular model; therefore, a higher activity/reactivity of irondecorated models could be found in comparison with the pure model. Besides the variations of electronic features for recognizing the models, the activities of molecular systems could be also assigned by such fea­ tures. In this case, the impacts of iron-decoration could be learned by monitoring the electronic features among the models. For the interac­ tion configurations, changes of electronic features were variable for the Config. I and Config. II. To confirm this claim, the values of Fermi were obvious to show the average values of HOMO and LUMO levels and their distances also. Accordingly, the values of WF, as an important factor of approaching sensing functions were changed regarding the changes of 5 C.Y. Hsu et al. Diamond & Related Materials 146 (2024) 111262 HOMO and LUMO levels, in which the results were found to detect the models in both of singular and conjugated states. As a consequence, the variations of electronic features were found for both of singular and conjugated states even with a significance of recognizing the formation of conjugations or distinguishing the conjugated models from each other. In complementary with these results, the values of CH could show an advantage of iron-decoration for approaching the nanocages with lower levels of hardness in comparison with the pure C24 model. Again, the magnitude of lowering the hardness was different for the nanocages based on the model of iron decoration, in which the FeC22 model was found with lowest level of hardness or the highest level of softness in the other words; as hardness and softness are in opposite with each other. On the other hand, the values of EI also approved the highlighted fea­ tures of FeC22 nanocage. The values of NBO atomic charges for the oxygen atoms of NPX and the iron atom of nanocages were listed in Table 2 besides the values of transferred charge (Q) from the NPX substance to the nanocage. Based on the results, different charges of oxygen atoms in the singular NPX and also different charges of iron atom in the singular nanocage were obvious. It was already mentioned that the nanocages were assigned as covalent complexes in this work and the iron atom was a part of this covalent architectures, because of it the zero global charge and the singlet multiplicity was used for the calculations. In this part of study, the charges of iron atoms could confirm the idea by the values of positive charges even below one showing their role as a member of covalent architecture. Additionally, different nanocages showed different charges for the iron atoms indicating the importance of customization way of nanocages for approaching the desirable results. Indeed, variations of charges and also their changes after the formation of conjugations could lead to the information about the investigated systems and their in­ teractions details. For example, participating only one oxygen of car­ boxylic group; O2 and O3, could be related to the variation of charges among the atomic sites. Accordingly, the models could be found variable by their charge features of dominant atoms; the oxygen atoms of NPX and the iron atom of nanocages. It seems that there was a competition between O2 and O3 to interact with the iron atom of nanocage for the formation of Config. II, in which only one oxygen was the winner; O2 for the formation of NPX@FeC24 and NPX@FeC23 and O3 for the formation of NPX@FeC22. It could be remembered that the EI of FeC22 was high­ lighted among the models, and the formation of both of Config. I and Config. II of NPX@FeC22 was by the assistance of formation of com­ plementary H…C interactions, which would be discussed later in this discussion. On the other hand, the direction of charge transferring from the NPX counterpart to the nanocage counterpart was found with a higher significance in the iron-doped models in comparison with the pure model showing the importance of iron-decoration for approaching more desirable adsorbent. To this aim, the models were recognizable and their features were available for approaching the purpose of elec­ tronic assessments of nanocage counterparts for adsorbing the NPX drug substance. As a highlighted remark, the iron-decoration increased the reactivity of nanocage for participating in stronger interactions with the NPX drug substance and they were recognizable in accordance with the measurement of such changes and variations. Based on the results of electronic variations, the models of pure and iron-doped nanocages were recognized to be assessed regarding their characteristic specifications. The structural features were also analyzed to approach details of adsorption processes regarding the involving in­ teractions. The optimized structures were shown in Figs. 1–3 including the interacting conjugated systems in Fig. 3. In addition to the optimi­ zation calculations for stabilizing the structures, the interactions were characterized by performing additional QTAIM analyses on the opti­ mized models. To find a general strength of interaction/adsorption process for the conjugated systems, Eq. (6) was used to evaluate the values of EAds and the results were summarized in Table 3 in addition to the QTAIM analyses results of each interaction. The features ρ, ∇2ρ, and H stand for electron density, Laplacian of electron density, and energy density, which are crucial to define the nature of interactions based on the QTAIM analyses. For the evolution of EAds, the basis set super­ position error (BSSE) was also implemented. EAds = ENPX@fullerene − ENPX − Efullerene + BSSE (6) With the exception of pure C24 nanocage, the strength of Config. II was found higher than that of Config. I in the iron-decorated models. Moreover, the iron-decorated models were found to make stronger in­ teractions because of the managing role of iron atom to contribute to stronger interactions with the oxygen heads of NPX. Indeed, the charges of iron atoms were also in a deterministic role of formation of such conjugations with different strengths. The formation of Config. I was due to the involvement of an ether type oxygen of NPX in interactions whereas the formation of Config. II was due to the involvement of a carboxylic type oxygen group. In the NPX@C24 model, one H…C interaction in additional to the O1…C interaction was found for the Config. I with the EAds − 4.53 kcal/mol whereas two O…C interactions (O3…C and O2…C) were found for the Config. II with the EAds − 2.55 kcal/mol. So, the formation of H…C interaction could be known as an important complementary interaction between the counterparts. Comparing the QTAIM features also approved the existence of a reasonable portion of electron sharing for the involving interactions with the final H values of 0.0009 and 0.0006 au for the O1…C and H…C of Config. I and 0.0004 and 0.0008 au of O3…C and O2…C of Config. II. In this case, the models were in the physical non-covalent mode of in­ teractions to each other. Comparing the EAds values for iron-decorated models indicated the highest strength for the NPX@FeC22 model whereas the NPX@FeC24 and NPX@FeC23 models were placed at the next levels. The iron-decoration way of nanocage was different in the complexes, in which the spherical shape was almost remained for the FeC22 model; while the shape was a little bit deformed for other FeC23 and FeC24 models. Indeed, that spherical shape was an advantage of FeC22 model for keeping the spherical architecture of fullerene models, in which the spherical shape helped the FeC22 model to contribute to stronger interactions with the NPX drug substance. For the NPX@FeC22 model, O1…Fe and H…C interactions were found for Config. I (EAds = − 41.16 kcal/mol) and O3…Fe and two H…C interactions were found for Config. II (EAds = − 41.42 kcal/mol). In this case, the existence of two complementary H…C interactions yielded a little bit stronger adsorption level for the formation of Config. II in comparison with that of Config. I. The obtained H values for O1…Fe (− 0.0112 au) and O3…Fe (− 0.128 au) indicated the meaningful contribution of O…C interactions for the formation of both of Config. I and Config. II, in which the negative sign could help to assess the interactions with higher electrostatic terms. For the NPX@FeC24 model, only one O…Fe interaction was found for the formation of each configuration, where O1…Fe was contributed to the formation of Config. I (EAds = − 36.16 kcal/mol) and O2…Fe was contributed to the formation of Config. II (EAds = − 39.75 kcal/mol). Similarly for the NPX@FeC23 model, only one O…Fe interaction was found for the formation of each configuration, where O1…Fe was contributed to the formation of Config. I (EAds = − 29.19 kcal/mol) and O2…Fe was contributed to the formation of Config. II (EAds = − 32.31 kcal/mol). In all cases of iron-decorated conjugated systems, the contribution of O…Fe interaction was dominant with a high portion of electrostatic feature for the formation of strong adsorption process. However, in the pure fullerene, such a highlighted feature was not found; hence, it could be claimed that the idea of iron-decoration was useful for obtaining strong adsorptions. It is worth to mention that the indicated bond distances of singular nanocages in Fig. 2 were only changed with a magnitude of ~0.02 Å from the singular state to the conjugated states. In the other words, the nanocage models kept their original structures with small changes from the singular state to the conjugation state. Comparing with a parallel work for the C–Fe distance of ~2 Å for the iron decorated C60 fullerene nanocage [67], the average results of this work were found ~1.9 Å, which could be known as a good agreement between the study of small and large nanocage systems. 6 C.Y. Hsu et al. Diamond & Related Materials 146 (2024) 111262 To investigate the impact of water solvent on the stability of conju­ gations, the PCM based calculations were performed to evaluate ther­ mochemistry features in the water solvent in comparison with the isolate gas phase as listed in Table 4. The quantities included the variations of sum of electronic and thermal free energies (ΔGWater), sum of electronic and thermal enthalpies (ΔHWater), and entropies (ΔSWater) as compared in the water solvent by the gas phase along with the symbolic Eq. (7). As could be found by the results, the models of conjugations were still stable in the water solvent with better features than the gas phase. In all cases, the results of Config. II were more highlighted than the results of Config. I in parallel with the already obtained higher level of stability of Config. II than Config. I. In this regard, the iron-doped models were found more stabilized in the water solvent especially by the negative values of ΔSWater; however, this value was positive for the conjugations of pure carbon models indicating a higher disordered in the water sol­ vent in comparison with the gas phase state. On the other hand, the irondoped conjugations showed higher ordered states in the water solvent in comparison with the gas phase state. As a consequence, the models were stabilized and the impacts of solvents indicated possibility of employing these systems in the water solvated systems. ΔXWater = XWater− solvent − XGas− phase X : G, H, or S. Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. Data availability Data will be made available on request. Acknowledgements The author (M.M. Salem-Bekhit) would like to extend his sincere appreciation to the Researchers Supporting Project Number (RSPD2024R986), King Saud University, Riyadh, Saudi Arabia. Appendix A. Supplementary data Supplementary data to this article can be found online at https://doi. org/10.1016/j.diamond.2024.111262. (7) References 4. Conclusions [1] A.L. Kiss, Inflammation in focus: the beginning and the end, Pathol. Oncol. Res. 27 (2022) 1610136. [2] X. Li, C. Li, W. Zhang, Y. Wang, P. Qian, H. Huang, Inflammation and aging: signaling pathways and intervention therapies, Signal Transduct. Target. Ther. 8 (2023) 239. [3] J. Ge, Z. Liu, Z. Zhong, L. Wang, X. Zhuo, J. Li, X. Jiang, X.Y. Ye, T. Xie, R. Bai, Natural terpenoids with anti-inflammatory activities: potential leads for antiinflammatory drug discovery, Bioorg. Chem. 124 (2022) 105817. [4] J.F. Oliveira-Costa, C.S. Meira, M.V. Neves, B.P. Dos Reis, M.B. Soares, Antiinflammatory activities of betulinic acid: a review, Front. 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Küçükgüzel, Anticancer and antimicrobial activities of naproxen and naproxen derivatives, Mini Rev. Med. Chem. 20 (2020) 1300. The drug adsorption by a nanostructure is indeed a complicated system, in which the focus of this work was on the assessment of irondecorated C24 fullerene-like nanocages for the NPX drug. The results indicated that the formation of NPX@nanocage conjugated systems was enhanced by employing iron-decorated fullerene-like nanocages. Although the iron-decorated models yielded strong adsorption process, a similarity to the original spherical shape of fullerene made the FeC22 model more suitable than the FeC24 and FeC23 models to work as an adsorbent of NPX drug substance. On the other hand, the iron atom played a managing role of adsorption by the formation of O…Fe in­ teractions in the NPX@nanocage conjugated systems. Based on the ox­ ygen heads of NPX, two interaction configurations were found for each conjugated system, in which the carboxylic group showed a priority of interaction strength with the iron atom in comparison with the ether group. As a consequence, the Config. II was stronger than the Config. I in the iron-decorated models. The electronic features of parental nanoc­ ages showed a significance of iron-decorated region based on the localization of molecular orbital distribution patterns and also changes of DOS diagrams. In this case, suitable interactions were also found for the NPX@FeC24, NPX@FeC23, and NPX@FeC22 conjugated systems. To this point, stabilities of the models and variations of the electronic fea­ tures leaded to the generation of strong and detectable conjugated sys­ tems. Additionally, the conjugated models were found stable in the water solvent especially for the iron-decorated conjugations. Hence, the idea of NPX adsorption at the surface of iron-decorated nanocages was supported by the results for providing drug delivery insights by intro­ ducing the suitable NPX@FeC24, NPX@FeC23, and NPX@FeC22 conju­ gated systems. CRediT authorship contribution statement C.Y. Hsu: Writing – original draft, Conceptualization. M.J. Saadh: Writing – original draft, Investigation. A.I. Ayesh: Writing – review & editing, Validation, Methodology. M.D. El-Muraikhi: Writing – review & editing, Formal analysis. M. Mirzaei: Writing – review & editing, Visualization, Supervision, Methodology. M. Da'i: Project administra­ tion, Conceptualization. S. Ghotekar: Methodology, Investigation. M. M. Salem-Bekhit: Writing – review & editing, Funding acquisition, Conceptualization. 7 C.Y. Hsu et al. Diamond & Related Materials 146 (2024) 111262 [46] M. Arshad, S. Arshad, M.K. Majeed, J. Frueh, C. Chang, I. Bilal, S.I. Niaz, M. S. Khan, M.A. Tariq, M. 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