Predicting adsorption behavior of 6-mercaptopurine anticancer drug upon polyaxazoline nanocarrier: A theoretical study

doi:10.21203/rs.3.rs-2004707/v1

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Predicting adsorption behavior of 6-mercaptopurine anticancer drug upon polyaxazoline nanocarrier: A theoretical study

https://doi.org/10.21203/rs.3.rs-2004707/v1

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Predicting adsorption behavior of the 6-Mercaptopurine (MCP) anticancer drug upon the polyaxazoline nano-carrier was investigated using DFT and TD-DFT methods by B3LYP/6-31G* level in the gas phase and water solution. Based on the thermochemical parameters, the MCP/polymer complex in the solvent water is more stable rather than the gas phase. The adsorption energies of the MCP/polymer complex displayed that the adsorption process is exothermic. The UV/Vis absorption and IR spectra analysis were calculated to investigate the changes happening in the interaction of the MCP with polymer. FMO analysis indicated that the energy gap (Eg) of the polymer decreased after the adsorption process. Electronic properties and MEP analysis were also studied. Based on NBO analysis and charge difference (ΔN), the charge transfer in MCP/polymer occurs essentially from the polymer to the MCP drug, which is consistent with the results of NBO analysis. It is predicted that the POZ polymer can be used as a drug delivery system for MCP drug.

6-Mercaptopurine

polyaxazoline

adsorption

DFT

NBO

Nanocarriers are nanomaterials that including nanoparticles, dendrimers, and polymeric carriers. Nanocarriers with their wide surface and exclusive chemical and physical properties can deliver the drugs to the target cells [1]. The advantages of using nanocarriers are the prevention of the decay of the drug, higher concentrations in the target tissue, and reducing side effects [2]. Among biocompatible polymers that are used as nanocarriers in drug delivery are poly(ethylene glycol), hyaluronic acid, polysialic acid, hydroxyethyl starch, polyglutamic acid, polylactic and polyglutaric acid, N-(2-hydroxypropyl) methacrylamide, polyvinylpyrrolidone, and polydextrans [3]. Poly(ethylene glycol) (PEG) has been more successful in carrying protein molecules and small-sized drugs [3]. Polyoxazolines (POZ) are another type of biopolymers that are synthesized with high quality, diverse structures, and various functional groups by diverse techniques [4–6]. In addition to the important properties of PEG, POZs have new and exclusive characteristics in the drug delivery process such as stable structure, nonionic property, and high solubility in water and organic solvents; therefore POZ can be an appropriate supersede to PEG [3].

6-mercaptopurine (MCP), with the IUPAC name of 3,7-dihydropurine-6-thione, is an anticancer drug that is especially used in the treatment of leukemia [7]. Among the side effects of the MCP are bone marrow suppression, liver toxicity, vomiting, and loss of appetite [8]. MCP interacts with enzymes, to prevent DNA and RNA synthesis and inhibits proliferating of growing cells [9]. El-Mageed and co-workers have reported the adsorption behavior of mercaptopurine drug on the B₁₂N₁₂, AlB₁₁N₁₂, and GaB₁₁N₁₂ nanocages using the DFT method [10]. They have predicted that the MCP upon GaB₁₁N₁₂ is a more suitable drug delivery system rather than other nanocages. Based on the study of Yang and co-workers, the electronic and structural properties of the B₂₄N₂₄ nanocage is an appropriate nano-sensor for MCP drug [11]. Zaboli and co-workers have studied the boron nitride nanotube (BNNT) and carbon nanotube (CNT) as drug delivery for MCP drug by DFT calculations [12]. Their results displayed that the BNNT is a more suitable carrier rather than CNT for delivery of MCP. Adsorption of the MCP upon other nanocarriers has been studied such as Au₂₀ nanocluster [13], nanosheet [14], Fe-doped fullerene [15], silver/gold cluster [16], Si, Al and Ti doped C60 fullerenes [17].

We are reporting the adsorption behavior of MCP drug upon the POZ polymer by DFT and TD-DFT methods for investigating the applicability of POZ in drug delivery. The geometric and thermochemical parameters, FMO [18], MEP [19], NBO analysis [20], and charge difference (ΔN) [14] are performed. UV/Vis absorption analysis [21] and IR spectra MCP, POZ polymer, and MCP/polymer complex TRC/B₁₂N₁₂ were computed. It is hoped that the results of our work can give a more ideal perspective for the use of POZ polymer as a drug carrier system.

The interaction of the 6-Mercaptopurine (MCP) drug with polyaxazoline nanocarrier has been studied using the B3LYP/6-31G* level of theory. The thermodynamic parameters, FMO, and NBO were calculated by Gaussian 09 software [22] in the gas phase and water solution. The solvent effect has been carried out using the Polarized Continuum Model (PCM) [23]. The adsorption energies (E_ads) [24] of the MCP on Polymer nanonanocarrier were calculated by the Eq. (1):

E_ads = E_MCP/Polymer– [E_MCP + E_Polymer] (1)

where E_MCP/Polymer is the total energy of MCP adsorbed upon the nanocarrier. E_MCP and E_Polymer are the energies of the MCP and the isolated polymer, respectively. Quantum chemical molecular descriptors such as the chemical potential (µ), global hardness (η), and electrophilicity index (ω) [25] were calculated by the following equations:

$${\mu }=\frac{\left({\text{E}}_{\text{H}\text{O}\text{M}\text{O}}{+\text{E}}_{\text{L}\text{U}\text{M}\text{O}}\right) }{2}$$

$${\eta }=\frac{\left({\text{E}}_{\text{L}\text{U}\text{M}\text{O}}{-\text{E}}_{\text{H}\text{O}\text{M}\text{O}}\right) }{2}$$

$$\omega =\left(\frac{{{\mu }}^{2}}{2{\eta }}\right)$$

The charge difference (ΔN) was calculated to identify the donor and acceptor and the direction of the charge transfer in the MCP/polymer complex (Eq. 5):

$$\text{∆N= }\frac{\text{-}\text{(μA-μB)}}{\text{(ηA+ηB)}}$$

The images of optimized structures and orbitals were obtained by GaussView 05 software [26]. DOS graphs were visualized by the GaussSum 2.2 software [27]. The theoretical IR frequencies of the MCP, polymer, and related complexes were obtained in the water solution at 298.14 K and 1 atm. The UV-Vis absorption was computed TD-DFT method [28].

3.1. Optimized molecules and Thermodynamic Parameters

We have calculated 17 states for adsorption of the MCP upon polymer by the PM6 method. Then, the complex with the lowest value of energy was calculated using the DTF method. Figure 1 represents the optimized compounds of MCP, polymer, and MCP/polymer complexes. The bond lengths and bond angles of the MCP, isolated polymer, and MCP/polymer complexes were represented in Table 1. Based on data, the geometric parameter values in the gas phase and solvent water indicate that solvent has not much effect on the parameters. The C56 − O59 bond length in MCP/polymer complex is longer in comparison to the isolated polymer. The N105 − H114 bond length in the isolated polymer is 1.01 Å, whereas after the adsorption process of MCP upon polymer in the gas phase and solvent water increase to 1.03 Å and 1.04 Å, respectively. The values of N11-C56-O59 and H114-N105-C104 bond angles in the MCP/polymer complex are shorter than free polymer and free MCP. Actually, the change in the amount of the geometrical parameters demonstrate the interactions of the MCP drug with the polymer.

Table 1

The bond length (Å) and bond angles (^°) values of MCP, polymer, and MCP/polymer complex
Compound	Media	C56-O59	N105-H114	N11-C56-O59	H114-N105-C104
MCP drug	Gas	-	1.01	-	122.00
	Water	-	1.01	-	121.12
polymer	Gas	1.23	-	120.17	-
	Water	1.24	-	120.46	-
MCP/polymer	Gas	1.24	1.03	118.84	120.53
	Water	1.25	1.04	119.01	120.94

The thermochemical parameters were calculated for the MCP, polymer nanocarrier, and MCP/polymer and the results were represented in Table 2. The MCP/polymer complex in solvent water is more stable rather than the gas phase. Interaction of MCP with the polymer decreases the energy values and reactivity, while the stability of the MCP/polymer complex increases. The positive values of ΔG_ads show that the interaction of MCP with polymer is not spontaneous. The ΔH_ads values display that the adsorption process is exothermic in both phases.

Table 2

The values of thermodynamic parameters of the MCP, polymer, and MCP adsorbed upon the polymer
Property	E + G ¹	E + H¹	E + T ¹	ZPE ¹	S (cal/mol.K)	ΔG_ads	ΔH_ads
Gas
MCP	-810.070	-810.029	-810.030	-810.037	85.32	-	-
Polymer	-2070.596	-2070.442	-2070.443	-2070.496	322.76	-	-
MCP/Polymer	-2880.662	-2880.486	-2880.487	-2880.549	369.90	0.004	-0.015
Water
MCP	-810.094	-810.053	-810.054	-810.061	84.96	-	-
Polymer	-2070.624	-2070.474	-2070.475	-2070.527	315.26	-	-
MCP/Polymer	-2880.711	-2880.536	-2880.537	-2880.599	369.01	0.007	-0.009
¹ : Hartree

3.2. Electronic Properties

The electronic properties during the interaction of MCP with polymer were investigated and reported in Table 3. The dipole moment (D_M) value of the MCP/polymer complex is larger than isolated polymer due to the polar nature of the bond between the MCP and polymer. The change in D_M value confirms a charge transfer between the MCP and polymer. The D_M values of MCP/polymer in water solution are larger than the gas phase. The MCP/polymer in the gas phase has the larger adsorption energy (E_ads) value (-0.48) in comparison to the water solvent (-0.35). The images of HOMO and LUMO orbitals of the MCP, polymer, and MCP/polymer complexes are represented in Fig. 2. The HOMO and LUMO orbitals of the polymer are focused on the C-N bonds and O atoms. After the adsorption of the MCP upon the polymer, the HOMO and LUMO orbitals localized on the MCP section. The E_HOMO and E_LUMO values of the polymer and energy gap (E_g) of MCP, polymer, and MCP/polymer complex in the gas phase and water solution are computed and represented in Table 3. The E_g value of free polymer in the gas phase and water solution is 6.67 and 6.72 eV, respectively; while after the interaction with the MCP, the E_g values and conductivity are decreased for MCP/polymer complex in the gas phase (4.07 eV) and solvent water (4.11 eV). DOS graphs also confirm the adsorption of MCP upon the investigated polymer and it also shows the changes in E_g and electron density during the adsorption of the MCP upon polymer (Fig. 3).

MEP map is important in this sense because represents regions with negative and positive electrostatic potential as a colored range. The MEP map of the MCP/polymer complex is shown in Fig. 4(a). In MCP/polymer complex, the positive charge density (blue area) is focused on the middle part of the complex structure; whereas the negative charge density is located on the oxygen atoms of the carbonyl groups of the polymer and sulfur atom of the MCP drug; therefore, reactive centers are determined in MCP/polymer complex. Contour lines in Fig. 4(b) display the location of atoms involved in electron resonance in the adsorption of the MCP upon the studied polymer.

The ΔN was calculated to determine the donor and acceptor in the MCP/polymer complex and the direction of transfer between MCP and polymer. The value of ΔN > 0 represents the charge transfer from polymer to the drug and the value of ΔN < 0 shows the charge transfer from drug to the polymer. Based on the results, the ΔN value of the MCP/polymer in the gas phase and water solution is 0.074 and 1.195, respectively; therefore, the positive values of ΔN confirm the charge transfer from the polymer to the MCP drug.

Table 3

The electronic properties of the MCP, polymer, and the MCP/polymer complex
	Gas			Water
Property	MCP	Polymer	MCP/Polymer	MCP	Polymer	MCP/Polymer
D_M	5.82	2.64	6.14	9.36	2.89	10.78
E/a.u.	-810.135	-2071.399	-2881.552	-810.160	-2071.429	-2881.602
E_ads	-	-	-0.48	-	-	-0.35
E_HOMO	-5.51	-6.27	-5.15	-5.98	-6.27	-5.89
E_LUMO	-1.18	0.4	-1.4	-1.94	0.45	-1.78
E_g	4.33	6.67	4.07	4.04	6.72	4.11
I	5.51	6.27	5.15	5.98	6.27	5.89
A	1.18	-0.4	1.4	1.94	-0.45	1.78
η	2.16	3.33	1.87	2.02	3.36	2.05
µ	-3.34	-2.93	-3.27	-3.96	-2.91	-3.83
ω	2.58	1.28	2.85	3.88	1.26	3.57
ΔN	-	-	0.074	-	-	0.195

3.3. NBO analysis

NBO analysis was carried out to investigate the donor-acceptor transitions of the MCP/polymer complex in the gas phase and water solution. The structure with higher stabilization energy (E⁽²⁾) is the more stable system [29]. The NBO results of the MCP/polymer complex are presented in Table 4. The E⁽²⁾ values in the water solution are the larger than the gas phase. The charge transfer from the σ_N105−H114 bonding orbital of MCP to the σ*_C56−O59 antibonding orbital of the polymer was detected as the σ_N105−H114→σ*_C56−O59 transition in the gas phase and water solution with E⁽²⁾ 0.17 and 0.24 kcal/mol, respectively. Thus, in MCP/polymer complex, the MCP drug and polymer have the roles of electron donor and electron acceptor, respectively, and charge transfer occurs from the MCP to the polymer. The LP(2)_O59→σ*_N105−H114 transition is the most important intermolecular interaction of the MCP/polymer complex in the gas phase and water solution with E⁽²⁾ 15.62 and 24.33 kcal/mol, respectively. The lone pair of the O59 atom of the polymer is the electron donor and the σ*_N105−H114 orbital of the MCP drug is the electron acceptor. The charge transfer in MCP/polymer happens essentially from the polymer to the MCP drug due to high E⁽²⁾ (24.33 kcal/mol).

Table 4

The results of NBO analysis of the MCP/polymer complex
System	Gas	Water
LP(1)_O59→σ*_N105−H114	9.31	9.47
LP(2)_O59→σ*_N105−H114	15.62	24.33
σ_C56−O59→σ*_N105−H114	0.46	0.46
σ_N105−H114→σ*_C56−O59	0.17	0.24

3.4. UV-Vis spectra and IR frequency analysis

The UV-Vis absorption spectra of the MCP drug, polymer, and MCP/polymer complex were calculated using the TD-DFT method in the gas phase and water solution. The results are represented in Table 5. The λ_max of investigated structures is identified in the UV range (100–400 nm). The λ_max value of the free polymer in the gas phase and solvent water is detected at 202.96 and 199.78 nm, respectively. After the interaction of MCP with polymer, the λ_max of the MCP/polymer complex is increased to 306.22 nm (gas phase) and 310.90 nm (water) (redshift).

Table 5

Selected parameters of UV-Vis absorption of MCP, polymer, and MCP/polymer complex
System	Media	Excited state	λ_max (nm)	E_exc (eV)	f	State assignments
MCP	Gas	S₀→S₂₀	171.73	7.21	0.36	H-4→L + 1 (77%)
	Water	S₀→S₂	311.67	3.97	0.41	H-1→L (99%)
Polymer	Gas	S₀→S₉	202.96	6.11	0.10	H→L + 1 (51%)
	Water	S₀→S₇	199.78	6.20	0.24	H→L (73%)
MCP/Polymer	Gas	S₀→S₂	306.22	4.05	0.38	H-1→L (93%)
	Water	S₀→S₂	310.90	3.98	0.48	H-1→L (99%)
* H: HOMO; L: LUMO

The IR vibrational frequencies of the MCP, free polymer, and MCP/polymer complex were calculated using B3LYP functional and reported in Table 6. The isolated polymer in the gas phase and water solution has a vibration at 1728.99 and 1707.01 cm^− 1 respectively, belonging to the C = O bond (carbonyl group); while in MCP/polymer complex changes to 1682.86 cm^− 1 (gas phase) and 1645.91 cm^− 1 (water). Moreover, MCP in the gas phase and water solution has a vibration at 3612.89 and 3587.10 cm^− 1 that was related to the N-H bond, whereas after adsorption of MCP upon polymer is decreased to 3052.85 (gas phase) and 3027.26 cm^− 1 (water).

Table 6

The selected vibrational frequencies (cm^− 1) of MCP, polymer, and MCP/polymer complex
Compound	Media	C = O	N-H
MCP	Gas	-	3612.89
	Water	-	3587.10
Polymer	Gas	1728.99	-
	Water	1707.01	-
MCP/Polymer	Gas	1682.86	3052.85
	Water	1645.91	3027.26

The adsorption behavior of MCP on the investigated polymer was investigated by the DFT method. Based on the thermochemical parameters, the MCP/polymer complex in solvent water is more stable compared with the gas phase. The change of bond lengths and angles of the polymer and MCP indicates the adsorption of MCP upon the polymer. The values of E_ads and ΔH_ads represent the exothermic nature of the adsorption of MCP over polymer. It is found that after the interaction of polymer with the MCP, the E_g values and conductivity are decreased for the MCP/polymer complex in the gas phase and water solution. The positive values of ΔN confirm the charge transfer from polymer to the MCP drug, it is in agreement with the results obtained from NBO analysis. We hope that the results of our study can help the application in the drug delivery process.

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The authors declare no conflict of interest.

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Authors' contributions

Leila Rahmanifari: calculations, analysis, investigation

Fatemeh Azarakhshi: analysis, writing and reviewing

Elham Moniri: conceptualization, visualization, investigation

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Predicting adsorption behavior of 6-mercaptopurine anticancer drug upon polyaxazoline nanocarrier: A theoretical study

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Abstract

Figures

1. Introduction

2. Computational Methods

3. Results And Discussion

3.1. Optimized molecules and Thermodynamic Parameters

3.2. Electronic Properties

3.3. NBO analysis

3.4. UV-Vis spectra and IR frequency analysis

Conclusion

Declarations

References

Additional Declarations

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