**3. Boron clusters for biomedical applications**

In this section, we discuss the studies reported on boron clusters in two separate categories, biosensors and drug delivery systems.

#### **3.1 Biosensor applications**

Kaur and Kumar [109] proposed a B40-based biomarker for DNA sequencing from the results of DFT calculations using the Perdew-Burke-Ernzerhof (PBE) functional along with a double-zeta polarized basis set (DZP). These authors reported that all nucleobases are adsorbed on the surface of the B40 fullerene with the interaction energies of −18, −15, −16, and −23 kcal/mol for adenine, thymine, cytosine, and guanine, respectively. No complex between the nucleobases and B40 was visualized. The analysis of transmission spectra, density of states, and eigenstates of the HOMO and LUMO revealed that all molecular junctions show transmission dominated by the HOMO. The highest energy gap was found in the adenine molecular junction, and this molecule gives the least value of current in comparison to the other molecular junctions.

Thus, by analysis of differential conductance curves for all the nucleobase-B40 junctions, it is deduced that the values of conductance are different from each other for all the junctions considered. This implies that B40 can appropriately be used as a biomarker for DNA sequencing applications, in predicting the sequence of nucleobases in a DNA strand. As another direct application, B40 can thus be employed as a multipurpose sensor for detection of the DNA nucleobases.

Kaur and coworkers explored in 2022 [110] the interaction of uracil on B40 utilizing DFT (PBE/DZP) and nonequilibrium Green's function regime computations. The physisorption phenomenon of the uracil molecule on the B40 surface is found, with an interaction distance of 2.38 Å and an interaction energy of −19 kcal/mol. No orbital overlapping exists between uracil and B40 moiety according to an electron density analysis. The HOMO–LUMO energy gap of B40 decreases upon adsorption of uracil.

Although these authors suggested B40 as an effective biomarker to detect the presence of uracil molecule and thereby the mutations and cancerous tumors, the nature of the interaction is not well understood yet.

Rastgou et al. [111] examined the sensing ability of the quasi-planar B36 toward DNA nucleobases that might be used in a DNA sequencing device. The interaction energies for the most stable configuration of each complex were computed to be −57, −43, −38, and −10 kcal/mol for adenine-B36, guanine -B36, cytosine-B36, and thymine-B36, respectively. It was found from DFT calculations using the B97D/6-31G(d) method that the cytosine interacts more considerably with the edge of B36 than other nucleobases, resulting in a large decrease in the energy gap, by 96% with respect to the isolated cluster. Such a decrease in the energy gap was observed at 36, 20, and 15% for thymine, adenine, and guanine, respectively. As a result, a change in conductivity could allow cytosine, followed by thymine, adenine, and guanine to be detected.

In particular, acetone (CH3C〓OCH3) in the human breath exhaust is one of the commonly considered biomarkers for type-I as well as type-II diabetes. Yong and coworkers [112] studied in 2018 the potential capability of B40 and the doped M@B40 (M = Li and Ba) as acetone gas sensors using DFT calculations at the PBE/DZP level. The @ symbol stands hereafter for an encapsulation. The acetone molecule can easily adsorb on the B40, Li@B40, and Ba@B40 clusters with interaction energies of −16, −19, and − 8 kcal/mol, respectively. The recovery times were computed at 9.2 seconds for Li@B40 and 1.2 seconds for Ba@B40. Such a recovery time can be considered to be relatively long, as compared to a spectroscopic signal at the order of a microsecond, but it could be suitable for a sensor. The HOMO-LUMO gaps of M@B40 again decrease upon acetone adsorption. Accordingly, the change in eclectic conductance of Li@ B40 or Ba@B40 before and after the adsorption of acetone would be very distinctive, exhibiting the high sensitivity of M@B40 for sensing acetone. Thus, the B40 and M@ B40 were introduced as highly sensitive molecular sensors for acetone detection, but the recovery time is relatively long at the order of a second.

The quasi-planar B36 was further explored for prospective sensing of the metronidazole (ML, cf. **Figure 4**) drug, which is an antibiotic drug with widespread usage but can cause unwanted hazardous effects on the human body. DFT calculations at the B3LYP-D3/6-31G(d) level demonstrated that ML interacts more strongly with B36 by its edge with an adsorption energy as high as −22 and −21 kcal/mol in both gaseous and aqueous phases, respectively. The change in Gibbs energy of −19 kcal/mol implies spontaneous adsorption. The decrease of 64% in the energy gap upon complexation is considerable, resulting in a substantial increase in the conductivity of the structure. The recovery time of the sensor was further found to be as 1.5 s for the most stable adsorption complex at room temperature. Again, such a time is rather long, but these results could be used to develop a boron-based sensor to detect the ML drug [113] in more appropriate time.

## **3.2 Drug delivery application**

Solimannejad and coworkers investigated in 2018 [114] the possible complexes generated from the interaction between the amantadine drug (cf. **Figure 4**) and the bowl-like B30 using the DFT ωB97XD/6-31G (d, p) method in both gaseous and aqueous media. Amantadine drug has been used to treat the Parkinson's disease, influenza, or hepatitis for many years, even though in some cases it can cause some impairment of corneal endothelial function or corneal edema. The strongest interaction occurs between an edge boron atom of the B30 and an N atom of amantadine with binding

### *Boron Clusters in Biomedical Applications: A Theoretical Viewpoint DOI: http://dx.doi.org/10.5772/intechopen.106215*

energy −46 and −53 kcal/mol in both gaseous and aqueous phases, respectively. The energy gap of the complex is remarkably reduced in both phases, with respect to the separated B30. Thus B30 is quite sensitive to the presence of amantadine drug molecule, in such a way that it may be used in the sensor technology and possible drug delivery for amantadine for medicinal applications.

The interaction of fluorouracil (FU) with the quasi-planar B36 cluster was studied in 2017 [115] using the hybrid TPSSh functional with the 6–31 + G (d) basis set. The FU drug failed to generate any noticeable signal owing to the very weak interaction of this drug with the concave and convex surface of B36 ranging from −2 to −5 kcal/ mol. Meanwhile, the FU drug remarkably interacts at its O atom site on the edge of the B36 with interaction energy of −24 and −27 kcal/mol in the gaseous and aqueous media, respectively (cf. **Figure 5**). The FU drug can also be detected by the B36 cluster with a noticeable signal owing to a significant decrease of 47% in the energy gap with respect to the free cluster. The dipole moment of FU-B36 complex was also observed as high as 17 and 36 Debye in the gas and water media, respectively, which indicates a large increase of the solubility in a polar medium.

Kamalinahad et al. performed in 2020 [116] a study on the interactions between sulfonamide (cf. **Figure 4**) and the B36 nanocluster through M06-2X/6-31G (d, p) computations. As a functional group, sulfonamide exists in several classes of drugs. Sulfonamide remarkably tends to adsorb via its oxygen atoms at the edge of B36, alike FU drug, with interaction energy of −15 kcal/mol in both gaseous and aqueous

**Figure 5.**

*Configurations of the interaction in the FU-B36 complex. Values given are the interaction energies obtained by TPSSh/6-31G (d.p) computations.*

media. The results illustrate that the edge B atoms are more reactive than the inner atoms toward the sulfonamide molecule leading to some large changes in its electronic features. The dipole moment of the complex increases to 13 Debye with respect to 4 Debye for the bare B36 cluster in aqueous medium. The high polarity together with appreciable adsorption energy suggested that these systems could be a vehicle for drug delivery.

Zheng et al. in 2020 [117] reported DFT computations at the PBE0/6–31 + G (d) level on the pristine and amino acid-functionalized C4B32 fullerene as drug delivery agents for hydroxyurea (HU, cf. **Figure 4**) anticancer drug. These authors found that an alanine functionalization can significantly enhance the tendency of the carbondoped C4B32 cluster to the adsorption of HU. In this regard, the drug adsorption on the B atom of the clusters is more favorable than on the others. Indeed, the adsorption of HU drug on the cage part of the ala-C4B32 isomers is stronger than that adsorbed on the alanine within a range of −16 to −19 kcal/mol in gas phase. Also, more negative adsorption occurs in aqueous medium, ranging from −20 to −23 kcal/mol, whose solubility can modify their interactions with the HU drug. The interactions between the HU drug and the clusters in the acidic condition become weak, and thereby the drug can faster be released from the carrier.

Yunyu and Jameh-Bozorghi [118] reported a DFT study at the PBE0/6–31 + G (d) level on the endohedral fullerenes Li@C4B32 and Li@Si4B32 as materials for drug delivery applications of the 6-thioguanine (TG) anticancer drug. These authors suggested the pristine and Li-encapsulation C4B32 and Si4B32 clusters as suitable for drug delivery applications. Calculated interaction energies were found to be −42, −56, −38, and −43 kcal/mol for the TG/C4B32, TG/Li@C4B32, TG/Si4B32, and TG/Li@Si4B32 complexes, respectively. Such interaction energies are however quite large.

In fact, the strongest feature of the studied complexes bonding was found for TG/ Li@C4B32 with the maximum positive charge on B atoms, and the system with LUMOs orbitals distributed on B atoms that has been predicted as the most favorable site for the nucleophilic agents. Moreover, their computed ultraviolet–visible spectra reveal that the electronic spectra of the drug/cluster complexes exhibit a red shift toward higher wave lengths (lower transition energies). Furthermore, the interaction of TG with the clusters leads to narrower Eg values resulting again in an increase in conductivity. The effect of pH on the TG/Li@C4B32 pointed out that the interaction energy in the acidic environment tends to decrease from 56 to 30 kcal/mol. Hence, the interactions between the drug and Li@C4B32 become again weaker in an acidic medium.

The alkali metal encapsulated fullerenes M@C4B32 with M = Li, Na, and K were considered as drug carrier agents for nitrosourea (NU) anticancer drug (cf. **Figure 4**) on the basis of calculations carried out using the PBE0/6–31 + G (d) approach [119]. A comparison between the interaction energies reveals that a potassium encapsulation inside C4B32 can considerably enhance the tendency of cluster for adsorption of NU drug with an interaction energy of −37 kcal/mol. In this case, the interaction energy tends to increase to −41 kcal/mol in aqueous medium, and thereby the K@ C4B32 cluster can increase its solubility and modify its interaction with the NU drug. The *p*H-dependent mechanism for drug release was also explored in which the proton (H<sup>+</sup> ) species attached to the NU. Results showed that the interaction between the NU drug and the K@C4B32 in an acidic environment is weaker with an interaction energy of −20 kcal/mol. Hence, the NU drug could better be released from a carrier in the targeted cancer cell in an acidic environment.

Furthermore, Luo and Gu [120] explored the ability of C4B32 and Si4B32 together with the Li encapsulated clusters for cisplatin (cf. **Figure 4**), using the PBE0/6–31 + G

### *Boron Clusters in Biomedical Applications: A Theoretical Viewpoint DOI: http://dx.doi.org/10.5772/intechopen.106215*

(d) level leads to interaction energies of −28, −12, −18, and −11 kcal/mol for the cisplatin/C4B32, cisplatin/Li@C4B32, cisplatin/Si4B32, and cisplatin/Li@Si4B32 complexes, respectively. The interaction distance for the cisplatin/C4B32 is relatively short (1.86 Å) in spite of relatively small interaction energy. Also, a blue shift toward lower wavelengths (larger transition energies) was observed from ultraviolet-visible spectra. Noticeably larger adsorption energies (more negative) are found in the solvent phase.

Sun and coworkers [121] explored the adsorption behavior of FU drug on B40 and some derivatives including MB39 and M@B40 (M = Mg, Al, Si, Mn, Cu, Zn). These authors applied calculations using the B3LYP functional in conjunction with the SDD basis set with effective core potential for Cu, Mn, and Zn atoms and 6-31G(d) basis set for the other atoms. Accordingly, the FU drug prefers to attach to the corner boron atom of the B40 through one of its oxygen atoms, resulting in a strong polar covalent B–O bond. The corresponding interaction energy is calculated to be −11 kcal/mol. Additionally, the ΔH and ΔG values for the interaction of FU drug via B40 are both negative. Furthermore, they found that FU-B40 complex exhibits a much larger dipole moment of 9 Debye than those of 6 and 0 Debye for 5-FU and B40, respectively, resulting in an increase in polarity for the whole system, and thus, enhancing the solubility of the resulting FU-B40 in an aqueous medium.

The drug release was also studied through a pH-dependent mechanism approach. The influence of pH on the FU-B40 complex was further examined by approaching a proton to the O atom of FU in complex. As seen in **Figure 6**, the distance between the O and B atoms greatly increases from 1.55 to 4.05 Å during the structural optimization. As a result, the interaction energy of FU-B40 severely decreases from −11 to −5 kcal/mol in the acidic environment, reflecting that the interaction between FU and B40 cluster is distinctly weakened under the attack of a single proton. Therefore, the FU drug can be released from the B40 carrier within the targeted tumor tissue where the medium is more acidic.

#### **Figure 6.**

*Optimization process for the protonation of FU drug adsorbed on B40 cluster. The distances (in Å) between B and O atoms are also given. Figure reprinted with permission from ref. [121].*

**Figure 7.**

*Optimized geometries of the most stable FU-[M@B40] with M = Mg, Al, Si, Mn, Cu, and Zn complexes. The lengths of the newly formed bonds (in Å) are also given. Figure is reprinted with permission from ref. [121].*

**Figure 8.**

*Optimized geometries of the most stable FU-B39M (M = Mg, Al, Si, Mn, Cu, and Zn) complexes. The lengths of newly formed bonds (in Å) are also given. Figure is reprinted with permission from ref. [121].*

Additionally, the substituent and encapsulation effects of Mg, Al, Si, Mn, Cu, and Zn atoms on the drug delivery performance of B40 have been also explored. The FU oxygen atom tends to combine with MB39 or M@B40 cages, which are depicted in **Figures 7** and **8**, respectively. Interaction energies vary in the ordering (values in kcal/mol) –16 (FU-[Al@B40]) –16 (FU-[Mg@B40]) > −15 (FU-[Cu@B40]) > −13 (FU-[Mn@B40]) > −12 (FU-[Zn@B40]) > −12 (FU-[Si@B40]).

Meanwhile, the variation of interaction energies for the substituted complex is in the ordering of −30 (FU-B39Al) –22 (FU-B39Mg) > −13 (FU-B39Cu]) > −12 (FU-B39Zn) > −12 (FU-B39Mn) > −9 kcal/mol (FU-B39Si). The absorption of FU on B39M or M@B40 cages is more favorable than pristine B40 except for SiB39. Therefore, the encapsulation and substitution of impurities can be regarded as an efficient approach to control and/or tune-up the interaction between the FU and B40.

Sun and coworkers [122] explored the potential application of all-boron fullerene B40 as a drug carrier for anti-cancer nitrosourea (NU, cf. **Figure 4**) by means of PBE0/6-31G (d, p) computations. The NU drug tends to combine with a corner B atom of the B40 cage via its oxygen and nitrogen atoms with a moderate adsorption energy of −25 kcal/mol. The *E*g value is decreased remarkably following adsorption

#### *Boron Clusters in Biomedical Applications: A Theoretical Viewpoint DOI: http://dx.doi.org/10.5772/intechopen.106215*

of NU drug because this raises its HOMO and reduces its LUMO level. However, a long recovery time of 52 seconds was predicted for the NU desorption process at 310 K, indicating quite long and difficult desorption of NU from B40 at human body temperature.

Moreover, B40 with a high drug loading capacity can simultaneously carry up to five NU drug molecules. Additionally, the substituent effect of C, N, Al, and Ga atoms on the drug delivery performance of this B40 cluster was investigated. The interaction energies vary in the sequence of −68 kcal/mol (NU-B39C) > −37 (NU-B39Al) > −19 (NU-B39Ga) > −18 (NU-B39N). Also, the dipole moments were greatly enlarged from 1 to 6 Debye of B39M to 15–21 Debye of NU-B39M (M = C, N, Al, and Ga). Therefore, it can be deduced that substitution of one boron atom of B40 by an exogenous atom indeed induces an obvious influence on the interaction between B40 and NU drug. As a result, the substituent effect of foreign atoms can be employed to modulate or tune up the drug adsorption performance of B40 cluster.

Interaction between the FU anticancer drug and the B40 fullerene was also investigated using the PBE-D/DZP level in both the gaseous and aqueous phases [123]. Results indicate that the FU molecule remarkably adsorbs on the top of B40 through its oxygen atom with moderate interaction energy of −24 kcal/mol (cf. **Figure 9**). The energy gap value of the FU-B40 complexes is relatively decreased by 21% as compared to the isolated B40 fullerene. The HOMO-LUMO gap of B40 amounts to 1.8 eV, which is reduced to 1.4 eV in FU-B40. Thus, the adsorption of the FU molecule can be identified from electronic response, resulting from the decrease of electric conductivity. Furthermore, the FU molecule bears a Hirshfeld charge of 0.35 a.u. in complex, resulting in a charge-transfer complex, in which the charge is effectively transferred from the FU molecule to the B40 fullerene.

The capacity of B40 for carrying the FU drug was explored. All the six holes of B40 interact with FU molecules and the corresponding 6FU-B40 complexes in both gas phase and aqueous solution are achieved. The interaction energy was estimated to be −13 kcal/mol per FU drug molecule in both phases. Moreover, the energy gap is

#### **Figure 10.**

*Optimized geometries of (a) 6FU-B40, (b) Na@B40-6FU, and (c) Ca@B40-6FU complexes. Figure reprinted with permission from ref. [123].*

distinctly decreased for this complex. The 6FU-B40 system has *E*g = 0.35 eV in the gas phase and *E*g = 0.71 eV in the aqueous phase.

The effect of Na and Ca encapsulation inside the B40 cluster on the FU adsorption behavior was also examined (cf. **Figure 10**). The interaction energy per FU molecule becomes now about −31 kcal/mol for 6FU-Na@B40 and 6FU-Ca@B40 systems in solution. Noticeably, the dipole moments enhance for the studied complexes in both phases. Further studies are needed to evaluate, in particular the recovery times, as to whether these fullerenes might behave as innovative boron-based candidates as drug delivery systems.

DFT (PBE-D/DZP) calculations were performed to investigate the interaction between the melphalan (MP; cf. **Figure 4**) as a chemotherapy medication and the bare as well as Na and Ca endohedral encapsulated B40 fullerenes (M@B40 with M = Na and Ca) [124]. The interaction energy of one MP drug with B40 was computed to be −15 kcal/mol. This interaction is a charge-transfer type occurring from the drug to the fullerene. The simultaneous adsorption of six MP molecules onto the fullerenes was also studied. An interaction energy of −4 kcal/mol per MP is obtained for 6MP-B40 system. Thus, it is deduced that the bare B40 fullerene suffers from a low adsorption energy per MP molecule in gas phase when it is fully loaded by MP drugs.

In order to improve the absorbency of B40 toward MP drug, the Na and Ca-encapsulated Na@B40 and Ca@B40 could yield some improvement (cf. **Figure 11**). The interaction energy per MP molecule increases now to −9 kcal/mol for the encapsulated fullerene in gas phase. Also, the dipole moment is enhanced in both gaseous

*Boron Clusters in Biomedical Applications: A Theoretical Viewpoint DOI: http://dx.doi.org/10.5772/intechopen.106215*

**Figure 11.**

*Optimized geometries of the M@B40-6MP complexes.*

#### **Figure 12.**

*Optimized geometries of (a) NedaPt-B40 and (b) 2NedaPt-B40 complexes. Figure reprinted with permission from Ref. [125].*

and aqueous phases for the resulting complexes, which is a crucial factor for the design of a drug carrier. The release of the MP drug from the carrier surface could be occurred through a *p*H-dependent mechanism.

The interaction between the nedaplatin anticancer drug (cf. **Figure 4**) with the B40 fullerene was also explored using PBE-D/DZP calculations in both vacuum and water mediums [125]. The nedaplatin molecule remarkably tends to adsorb on the top of B40 through its oxygen atom with an interaction energy of −18 kcal/mol. The adsorption of two nedaplatin molecules onto the fullerene holes has occurred with an interaction energy of −14 kcal/mol per drug molecule (cf. **Figure 12**).

Furthermore, reported results illustrate that the Li and Na encapsulation into B40 greatly increases the adsorption of nedaplatin in both the gaseous and solution


*Boron Clusters in Biomedical Applications: A Theoretical Viewpoint DOI: http://dx.doi.org/10.5772/intechopen.106215*


#### **Table 1.**

*Summary of the interaction energies of boron-based clusters with bio-molecules considered in biomedical applications.*

phases. The adsorption energy per nedaplatin molecule is about −28 kcal/mol for both Li@B40 and Na@B40 fullerene in aqueous solution, which is greater than that of the bare B40 fullerene, which is not favorable to be used.
