Theoretical study of interaction between temozolomide anticancer drug and hydroxyethyl carboxymethyl cellulose nanocarriers for targeted drug delivery by DFT quantum mechanical calculation

In this article for the first time the quantum calculations of 3-methyl-4-oxoimidazo[5,1-d][1,2,3,5]tetrazine-8-carboxamide (Temozolomide) in HCM-Cellulose Substrate are evaluated using the B3LYP/6-31G level of theory. The non-bonded interaction effects of the molecule Temozolomide, HCM-Cellulose on the electronic properties, chemical shift tensors and natural charge have also been detected. Natural bond orbital analysis (NBO) suggests that Temozolomide as an electron donor and HCM-Cellulose acted as an electron acceptor in the Temozolomide/HCM-Cellulose complex. The electronic spectra of the Temozolomide drug and Temozolomide/HCM-Cellulose complex in were calculated by Time-Dependent Density Functional Theory (TD-DFT) for the investigation of the adsorption effect of the Temozolomide drug over HCM-Cellulose on maximum wavelength. As a result, the feasibility of using HCM-Cellulose to deliver Temozolomide to diseased cells has been established. Supplementary Information The online version contains supplementary material available at 10.1186/s13065-023-01029-7.


Introduction
The current treatment for cancer includes chemotherapy, radiation and surgery.The purpose of chemotherapy and radiotherapy is to destroy cancerous cells.The effectiveness of a treatment is directly related to its ability to destroy cancer cells so that healthy cells in the body are not affected.The limiting factor for cancer chemotherapy is the non-selective use of cancer cell drugs [1,2].Also, during chemotherapy, some cells become resistant to the treatment, and to solve this problem, they either increase the dose of the drug during the treatment, or several drugs are used at the same time.However, with these measures, the drug's toxicity also increases.Different drug administration systems have been developed to reduce these side effects.Recently, many researches in the field of chemotherapy have been investigated for the use of drug carriers and nanodrug delivery systems.The purpose of the development of these systems is the controlled release of the drug, maintaining the concentration of the drug in the therapeutic range for a suitable period of time and the specific transfer of the drug to the target tissue.These nanomedicine systems include liposomes, micelles, nanoparticles, and polymeric nanocarriers [3,4].Nowadays, Due to the many advantages of nanostructures, such as the ability to carry several drugs at the same time and reducing toxicity with the aim of delivering drugs to cancer cells, these structures have attracted the attention of many researchers.These new drug delivery systems will improve the performance of the drug [5][6][7].For many years, extensive research has been conducted in the field of using biodegradable polymers in drug delivery systems to target and control the rate of drug release.A biodegradable polymer drug release system can provide patient comfort and satisfaction by eliminating the side effects of drug use and reducing the number of times it is prescribed.Most of the drug delivery products based on biodegradable polymers are used in the form of injectable products, and the two categories of injectable drug delivery systems, particulate and formed in place, are more widely used.A drug delivery system based on a biodegradable polymer is designed in such a way that, in addition to obtaining a product with physical-mechanical properties appropriate to the tissue of the administration site in the body, the desired result of drug degradation and release is obtained [8][9][10][11][12][13][14].Cellulose is a natural linear polymer with chloropyranose unit, which has biodegradable, non-toxic, recyclable, hydrophilic and safe properties.Cellulose is used in various industries such as wood and pharmaceutical and health industries.One of the wide applications of cellulose and its derivatives is in pharmaceuticals and cosmetics.Microcrystalline cellulose is the most widely used in pharmaceuticals.Cellulose ether and cellulose ester are two important derivatives of cellulose in the pharmaceutical industry, which can be referred to as hydroxypropyl methyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, carboxymethyl cellulose, sodium carboxy Methyl Cellulose.Cellulose and its derivatives in the formulation of drugs, in the preparation of tablet and capsule coatings, targeted drug carriers, encapsulation of drug particles, drug release control has very wide applications.The unique properties of these materials, including high tensile strength, high hardness, and photonic properties, make them attractive for use in many fields, especially in medicine and drug delivery.The construction of biological scaffolds used in tissue engineering, anticancer drugs and dental ceramics are among the applications of cellulose nanomaterials due to their high biocompatibility and rapid degradability [15][16][17][18].
Considering the complications caused by the use of drugs, especially anticancer drugs, it seems necessary to target drug delivery using nanoparticles.In recent years, a lot of attention has been paid to the preparation of nanoparticles as drug carriers, because nanoparticles can be used as a drug due to their control and slow release, particle size smaller than cells, biocompatibility.Extensive research and development is underway in the world to identify the applications of bio-nanocarriers in drug delivery, but theoretical studies on the ability of surface-modified cellulose to absorb drugs are limited [19,20].Therefore, the main goal of this research is to theoretically study the interaction of the anticancer drug Temozolomide on the surface of HCM-Cellulose as a drug delivery system using the DFT quantum mechanical calculation method.In 2018, Seyedah Mehsa Mousavi Langari, Maryam Nikzad and colleagues reviewed the types of nanocellulose and its applications in medicine.Nanocellulose is a unique natural substance extracted from lignocellulosic materials, which in recent years has attracted the attention of many researchers for medical applications due to its remarkable physical, chemical and biological properties such as biocompatibility, biodegradability and low toxicity.The purpose of the present study is to review the types of nanocellulose and their applications in medicine, including drug delivery, tissue engineering, implants and implantation of alternative substances in the body and antibacterial substances.In general, three types of nanocellulose, namely cellulose nanofibers, cellulose nanocrystals and bacterial cellulose, have been introduced, whose presence in medical products improves mechanical and biological properties and reduces toxicity.The purpose of the present study is to review the types of nanocellulose and their applications in medicine, including drug delivery, tissue engineering, implants and implantation of alternative substances in the body and antibacterial substances.In general, three types of nanocellulose, namely cellulose nanofibers, cellulose nanocrystals and bacterial cellulose, have been introduced, whose presence in medical products improves mechanical and biological properties and reduces toxicity.In 2015, the design and synthesis of nanocellulose functionalized with vitamin A was investigated and its ability to absorb aflatoxin B1.Firstly, cellulose nanoparticles were synthesized by acid hydrolysis and then conjugated to vitamin A with the help of a cross-linking device.In order to study the structure, the method of imaging with transmission electron microscope and Fourier transform infrared spectrometry was used.The amount of aflatoxin absorption was evaluated under different conditions of temperature, time, pH and concentration [25].
In 2021 Raluca Nicu and et al., studied on the functional materials based on nanocellulose for pharmaceutical properties.Researchers have special attention Nanocelluloses (NCs), with their characteristics, biocompatibility and their physicochemical properties [26].In 2016, Mirdehghan and et al., investigated the interaction between conjugated nanocellulose with Aflatoxin drug.According to results, the decrease of pH led to increase of adsorption drug [27].
The present study aims to determine how Temozolomide absorbs HCM-Cellulose using DFT calculations at the B3LYP/6-31G* level of theory.Our work also included the study of, NBO analysis, electronic properties, NMR analysis and absorption spectrum of the compound Temozolomide, HCM-Cellulose and Temozolomide/HCM-Cellulose complex.

Theoretical calculations
The calculation of quantum theoretical properties of Temozolomide, HCM-Cellulose, and Temozolomide/ HCM-Cellulose complex was performed using Gaussian 09W program package [28] using the DFT method.The title compounds were first optimized, then frequency calculations were performed in gas phase to examine thermodynamic functions such as relative energies (E), free Gibbs energies (G), entropies (S), and enthalpies (H) [17,18].The NBO 5.G program was then used to calculate NBOs (natural bond orbitals) at the same level as a measure of inter-molecular delocalization or hyper-conjugation, which is a measure of second-order interactions.Temozolomide, HCM-Cellulose, and the Temozolomide/HCM-Cellulose complex were analyzed through NBO analysis to determine electronic properties like EHOMO, ELUMO, HOMO-LUMO energy gap (∆E gap), natural charges, molecular properties, dipole moment (μ), charge density, density of state (DOS).GaussView 09 software was used to visualize the optimized molecular structure, HOMO and LUMO surfaces [29].In addition, NMR parameters such as chemical shift anisotropic (CSA) and chemical shift isotropic (CSI) for title structures based on B3LYP/6-31G* level experiments were calculated [21].Temozolomide adsorption energy on HCM-Cellulose was computed according to the following formula: The energy of (E Temozolomide/HCM-Cellulose ) represents the total energy of the Temozolomide/HCM-Cellulose complex, including both the compound Temozolomide and the compound HCM-Cellulose.The energy of (E Temozo- lomide ) and (E Temozolomide /HCM-Cellulose ) represents the total energy of their respective compounds.

Optimized geometry
The optimized structures and frequency calculation of the Temozolomide, HCM-Cellulose and Temozolomide/ HCM-Cellulose complex and the interactions of the Temozolomide with the HCM-Cellulose were performed by the DFT method at B3LYP/6-31G* level of theory.In Fig. 1 the optimized structures of the compounds Temozolomide and the HCM-Cellulose are shown.We have considered four interactions between the Temozolomide with the HCM-Cellulose.The four optimized states (I-V) were calculated at the HF/STO-3G basic set (Fig. 2).
The calculated values of electronic energy (E) for the four states I-IV were calculated: − 2,318,950.95,− 2,318,959.385,− 2,318,957.524,− 2,318,954.605kcal/ mol, respectively.The state II has the lowest energy value, as indicated by Table 1.Table 1 shows the differences in the DFT-calculated energies of molecules for a number of calculated I-IV conformations.The II conformation turns to be the lowest by energy, and its energy were chosen as the reference energy.Relative DFT energies ΔE for a number of stable conformations Fig. 1 The optimized structures of the compounds Temozolomide and HCM-Cellulose using B3LYP/6-31G* level of theory of HCM-Cellulose optimized by HF/STO-3G" was calculated.As can be seen from the data of Table 1, the II conformation should exceed significantly the contents of the molecules in other conformations.
In addition, Table 2 presents the thermodynamic parameters optimized by the HF/STO-3G method for the four interactions between Temozolomide and HCM-Cellulose.These parameters include the thermal energies (T), the thermal enthalpies (H), and the thermal free energies (G).The negative electron energy, enthalpies, and Gibbs energies of I-IV make them stable vibrational states.Based on the results, state II has a lower energy value than all the other states, making it more stable.Following this, we considered the interaction between Temozolomide and Table 1 Shows the differences in the DFT-calculated energies (Relative energies) of molecules for a number of calculated I-IV conformations and the energy parameters for four interaction between the Temozolomide and HCM-Cellulose were optimized by HF/STO-3G method HCM-Cellulose at the state II and optimized using the B3LYP/6-31G* level of theory.Table 3 shows the thermochemical parameters for interaction of the compound Temozolomide with the HCM-Cellulose (state II) optimized using B3LYP/6-31G* method.A non-bonded interaction between Temozolomide and HCM-Cellulose results in lower Enthalpy and Gibbs energies.The energy values indicate that Temozolomide is less reactive and more stable with the presence of HCM-Cellulose.

Electronic properties and frontier analysis
Analysis of the frontier molecular orbitals (FMO) plays a major role in understanding electronic properties [22,30].This study examined the electronic properties of Temozolomide when it interacts with HCM-Cellulose using B3LYP at the level of 6-31G* (Table 4 the results of the calculations).According to Table 4, the chemical reaction between Temozolomide and HCM-Cellulose has an exothermic nature due to its negative adsorption energy (E ad = − 0.743 eV).
The FMO analysis of Temozolomide shows that the HOMO orbital spreads over the entire molecule, while the LUMO orbital focuses on the C=C, C=N, C=O, N=N, and NH groups, and also spreads over the entire molecule (Fig. 3).Hence, in Temozolomide, pi (p) bonds and nitrogen lone pairs are involved in transferring charge between the HOMO and LUMO.It can be seen in Fig. 4 that the LUMO orbitals focus on the carboxylic acid group while the HOMO orbitals focus on the HCM-Cellulose half structure.Upon adsorption of Temozolomide onto HCM-Cellulose, the LUMO/HOMO energy gap is 4.044 eV, which decrease from the original Temozolomide Eg value of 4.408 eV.Additionally, DOS plots depict changes in energy gaps.As seen in (Fig. 5) of the FMO analysis of the Temozolomide/HCM-Cellulose complex, the HOMO and LUMO orbitals mostly focus on the Temozolomide form as a whole.The (Table 4) provides a detailed description of ionization potential (I), electron affinity (A), global hardness (η), electronegativity (χ), electronic chemical potential (µ), electrophilicity (ω) and chemical softness (S) of Temozolomide, HCM-Cellulose and Temozolomide/HCM-Cellulose complex.Ionization potential (I) is directly related to HOMO's energy, while electron affinity (A) is directly related to LUMO's energy [23,24].
Based on the energy gap between HOMO and LUMO, the global hardness (η) can be determined.Molecules with a small energy gap are highly chemically reactive, have low kinetic stability, and are soft, while molecules with a large energy gap are hard.Based on global hardness values (η), Temozolomide, HCM-Cellulose and Temozolomide/HCM-Cellulose have 2.204 eV, 3.063 eV, and 2.022 eV respectively.
DFT method is a useful method to check the characteristics of chemical structures based on the reactivity index of molecules.The results of B3LYP/6-31G* calculations show that when the drug molecule is placed in the presence of the polymer, the energy gap value in the drug-polymer complex (Eg = 4.044 eV) compared   to the energy gap in the temozolamide drug molecule alone (Eg = 4.408 eV) has decreased.On the other hand, the reactivity of a molecule is related to its energy gap [23,24].Examining the energy gap of molecular orbitals (ELUMO-EHOMO) shows that a soft molecule has a small energy gap and a hard molecule has a large energy gap.Stabilizing orbital interactions increase by decreasing the energy level of the electron acceptor orbital and increasing the energy level of the electron donor orbital.In addition, electron delocalization is confirmed by changing the population of electron donor and acceptor orbitals.Also, in the functionalized temozolamidenanocellulose drug complex, compared to the drug alone, the hardness parameter, electronegativity and ionization energy have been reduced by reducing the Eg energy gap.
The results of the calculations show that the energy gap in the drug-nanocarrier mixture is slightly reduced compared to the drug alone.This can be explained by the polarity and hydrophilicity of the drug-nanocarrier complex compared to the drug alone.

NMR analysis
In this research, the parameters of chemical coverage (CS), in order to obtain structural information, dynamic behavior and intramolecular interactions for the optimal structures of the drug temozolamide and HCM-Cellulose and the drug-HCM-Cellulose complex have been calculated using the gauge-including atomic orbital (GIAO) method.Chemical shift isotropic and anisotropic shifts were calculated for selected atoms in the compound Temozolomide, HCM-Cellulose  5).

Molecular electrostatic potential (MEP) analysis
MEPs (molecular electrostatic potentials) reveal the electronic density of molecules and are used for electrophilic and nucleophilic attack and reaction sites [23].It was represented by different colors according to the electrostatic potential of the surfaces.Negative regions on MEP are colored red, indicating electrophilic reactivity, while positive regions are painted blue, indicating nucleophilic reactivity, and green, neutral reactivity.A theoretical calculation using the B3LYP/6-31G* level of energy was used to estimate the MEPs of the Temozolomide/HCM-Cellulose complex (Fig. 6) shows the molecular electrostatic potential (MEP) calculation for Temozolomide and Temozolomide/HCM-Cellulose.According to the MEP of Temozolomide, the positive charge density and the blue spectrum occur on the hydrogen atoms attached to Nitrogen and Nitrogens of tetrazine ring, while the negative charge density occupies the oxygen atom of the carboxamide groups.In the MEP of Temozolomide/ HCM-Cellulose complex, the positive charge density occur on the hydrogen atoms associated with oxygen or nitrogen and tetrazine ring has a blue color, while the negative charge density occupies all the oxygen atoms.Green color indicates zero and neutral potential areas in Temozolomide/HCM-Cellulose and Temozolomide.
The MEP (Molecular Electrostatic Potential) is plotted in Fig. 6 along with a colored bar indicating the maximum and minimum electrostatic potential presented.

NBO analysis
Molecular systems can be studied by NBO analysis by examining intra-and intermolecular bonds and interactions between them.A conjugative electron transfer  between donor and acceptor orbitals occurs when electrons delocalize from donor to acceptor orbitals.It is estimated that the stabilization energy involving the delocalization i → j will be as follows for each donor (i) and acceptor (j) [24]: 2) is a measure of how much electrons participate in the resonance between atoms in a molecule.When E(2) is high, electron donors are more likely to donate electrons to electron acceptors [33].NBO analysis of Temozolomide/HCM-Cellulose was conducted at the B3LYP/6-31G* level of theory as summarized in Table 6.Based on the NBO analysis, the oxygen lone pairs (LPs O1 and O9) of the HCM-Cellulose overlap to the anti-bonding orbital σ*(C54-H58) and π* N46-C53 of the Temozolomide in the Temozolomide/HCM-Cellulose complex.

Structural parameters
Structural parameters calculated using B3LYP/6-31G* theoretical level calculations for temozolamide drug compounds alone and in the presence of HCM-Cellulose can be seen in Table 7.The changes of structural parameters in the drug temozolamide and HCM-Cellulose alone with when these two compounds are in the presence of each other shows that the change of structural parameters in the areas involved in the interaction is significant.Based on the results of the calculations, there is a direct relationship between the changes in the structural parameters and the values of the resonance energies resulting from the calculated electronic destabilization.So that the higher the amount of resonance energy caused by electron transfers in a bond, the greater the change in the structural parameters of that bond.NBO analysis of interactions (bonding-antibonding) at the theoretical level of B3LYP/6-31G* shows that for the Temozolomide/HCM-Cellulose complex, the highest resonance energies caused by the electron destabilization from the drug temozolamide to the HCM-Cellulose takes place as LP(1) O43 → σ* O21-H40 and LP(2) O43 → σ* O21-H40 transition with stabilization energies E(2) of 12.26 kcal/ mol and 14.80 kcal/mol, respectively.Also, the highest resonance energies caused by electron transfers from the HCM-Cellulose to the drug temozolamide are σ O21-H40 → σ* O43-C55 and σ O21-H40 → π* O43-C55 transition with stabilization energies E(2) of 0.27 kcal/mol and 0.25 kcal/mol, respectively.In examining the changes in the structural parameters including bond lengths, bond angles and dihedral angles in the Temozolomide/HCM-Cellulose complex, it is observed that bond lengths and bond and dihedral angles related to the atoms involved in the reaction change, which can be one of the There are ways to justify the electronic interaction between temozolamide drug and HCM-Cellulose.Therefore, the difference in the structural parameters in the temozolamide drug-cellulose complex functionalized with reactive  raw materials (HCM-Cellulose and temozolamide drug) can be explained by increasing the resonance energies caused by electronic destabilization from the drug temozolamide to the HCM-Cellulose and also by HCM-Cellulose to temozolamide drug molecule.Therefore, changes in structural parameters can be one of the ways to justify the physical absorption reaction through electronic transfers between two systems involved in the reaction.

Electronic structure and excited states
A theoretical absorption spectrum of selected compounds in the gas phase was calculated using the TDB3LYP/6-31G* td = (nstates = 20,root = 1) method.
For the calculation, 20 excited states were considered.(Table 8)  8) shows that all other excited states of Temozolomide have very small intensities (f ≈ 0), which are nearly forbidden by orbital symmetry considerations.According to (Fig. 8), the calculated electronic absorption spectrum of Temozolomide appears in gas phase.
As summarized in (Table 9), the strongest absorption band in the Temozolomide/HCM-Cellulose complex absorption spectrum depends on the charge transfer into the S6 excited state and is defined by two configurations for one-electron excitations [(H-4-> LUMO) and (H-17 > LUMO)].Maximum wavelength at 307.64 nm is mainly due to the transition from HOMO-4 to LUMO (Fig. 9).HOMO-4 electron densities are mainly spread over the entire HCM-Cellulose structure.The electron density of HOMO-17 is distributed across the entire Temozolomide structure and the oxygen atoms of the HCM-Cellulose substrate located near the drug.In contrast, the LUMO orbital is spread over the entire Temozolomide structure, as shown in Fig. 9.In addition to the above excited states, S4 also exhibits three configurations of electronic excitations at 313.43 nm (f = 0.0676): Fig. 7 The MOs responsible for producing Temozolomide's absorption spectrum at max = 294.02nm(H-4 > LUMO), (H-17 > LUMO), and (HOMO-21 > LUMO).Based on orbital symmetry considerations, the other excited states of the title compound are nearly forbidden by their intensity (f ≈ 0).According to (Fig. 10), the Temozolomide/HCM-Cellulose complex exhibited a calculated electronic absorption spectrum in the gas phase (UV-Vis).It is reported that the maximum wavelength of the compound Temozolomide is 294.02 nm, while the maximum wavelength of the compound Temozolomide is increased to 307.64 nm after interacting with the HCM-Cellulose.As a result, Temozolomide adsorbs onto HCM-Cellulose and changes its value max.

Conclusion
In this work, the nonbonding interaction of Temozolomide anticancer drug    Fig. 9 The MOs responsible for producing of the Temozolomide/HCM-Cellulose's absorption spectrum at max = 307.64nm Fig. 10 UV-vis spectrum of the complex Temozolomide/ HCM-Cellulose

Fig. 2
Fig.2The four interaction of the Temozolomide with HCM-Cellulose optimized by HF/STO-3G

Fig. 6
Fig. 6 Generated molecular electrostatic potential (MEP) maps of temozolamide drug (a) and temozolamide-nanocellulose complex (b).The negative (red, orange, and yellow) regions are related to electrophilic reactivity, whereas positive (green and blue) regions accompany nucleophilic reactivity

C( 13
shows that the Temozolomide compound has a strong absorption peak at max = 294.02nm at oscillator strength f = 0.258.Maximum wavelengths formed at 294.02 nm are the result of electron charge transfer into excited state 4 and two electron excitation configurations [(H-1 > LUMO) and (H-2 > LUMO)].The shape molecular orbitals participants are shown in Fig. 7 at max = 294.02nm.As shown in Fig. 7, electron den- sity of HOMO-1 orbital spreads over the tetrazine ring and lone pairs of oxygen atoms and electron density of HOMO-2 orbital speared over lone pairs of oxygen and nitrogen atoms.The LUMO orbital electron density is located on the double bonds of Temozolomide drug.Thus, pi (*) bonds and lone pairs are responsible for this electronic transition between HOMO-1 and HOMO-2 to LUMO.A second example of an important excited state occurs at 193.47 nm (f = 0.1294) with two important electronic excitation configurations [(H-2-> L + 2) and (H-1-> L + 2)], (Table

Fig. 8
Fig. 8 UV spectrum of the compound Temozolomide

Table 2
The thermodynamic parameters for four interaction of the Temozolomide/HCM-Cellulose complex at HF/STO-3G level of theory calculated in kcal/mol

Table 4
The calculated electronic properties of Temozolomide, HCM-Cellulose and Temozolomide/HCM-Cellulose complex at B3LYP/6-31G* level of theory calculated

Table 5
Calculated NBO charges and NMR parameters (ppm) including CS I and CS A for the selected atoms in Temozolomide, HCM-Cellulose, and Temozolomide/HCM-Cellulose

Table 6
The donor-acceptor interactions and second-order perturbation energies (E(2), kcal/mol) related to charge transfer between Temozolomide and HCM-Cellulose

Table 7
Structural parameters calculated using B3LYP/6-31G* theoretical level calculations for temozolamide drug compounds alone and in the presence of HCM-Cellulose

Table 9
Electronic absorption spectrum of the Temozolomide/HCM-Cellulose complex