The role of carbon nanotubes in antibiotics drug delivery

Carbon nanotubes (CNTs) have a tremendous role as nanocarriers in the area of drug delivery, due to their high surface area and ability to be easily conjugated with many organic and drug groups like anticancer, antibiotics, etc . This review has reported the role of the functionalized CNTs in antibiotics drug delivery from 2017 to 2019.


Introduction
The important goal of enhancing nanocarrier drug delivery systems (DDS) is to develop the therapeutic impact or decrease the toxicity of medically active compounds [1]. Carbon nanotubes (CNTs) discovered by Iijima in 1991, are structures with nanometric diameters [2,3]. There are two types of carbon nanotubes, including single-walled (SWCNTs) and multi-walled carbon nanotubes (MWCNTs). Carbon nanotubes have significant properties, including remarkable electrical conductivity, exceptional tensile strength, thermal conductivity, and the ability to be modified chemically [4,5]. Carbon nanotubes features, including unique surface area, stiffness, strength, and resilience, have led to much interest in the field of drug delivery systems. Also, nanomaterials like CNTs have been employed in different applications such as DNA detection and the improvement of immunoassays for the bacteria detection [6]. CNTs are exposed to adsorb or conjugate with a wide kind of therapeutic materials such as bioactive proteins, peptides, and drugs because of their high surface area. These systems have a splendid potential in the nanomedicine field because functionalized CNTs show low toxicity and not to disturb immune systems [7]. Drug delivery refers to methods, formulations, technology fields, and systems for carrying a pharmaceutical composite in the body, sometimes based on nano compounds such as CNTs [8]. DDS like lipid-or polymerbased nano compounds could be aimed to improve the pharmacologic and therapeutics features of drugs controlled parenterally [9]. Two functionalization methods are used for the modification of CNTs (SWCNTs 1, MWCNTs 2) (Scheme 1). CNTs are able to be oxidized employing strong acids, and as a result, their length reducts while forming carboxylic groups, which improve their dispersion in aqueous solutions [10]. Dissolvability under physiological situations is a key precondition to gain CNTs biocompatible. Furthermore, functionalized CNTs (f-CNTs) 3 or 4 can be bonded to different active molecules, such as proteins, peptides, nucleic acid, and other medical agents. CNTs eternal walls can be functionalized by an efficient method in regard to the 1,3-dipolar cycloaddition of azomethine ylides. CNTs go through the addition reaction while warmed in DMF in front of an aldehyde and an α-amino acid [11]. The rang of this reaction is extremely wide and forms f-CNTs 5 or 6, which have high solubility in an extensive scope of solvents. It can be possible to adjust solubility in aqueous solutions of organic solvents by attentively selecting the reactants [12].
Antibiotics has had a significant effect on human and animals life with the ability of controlling infections during the past century [13].
Weak antibiotic internalization can be solved by carring antibiotics with nanomaterials such as CNTs which are able to effectively interact with the bacterial envelopments [14].

The synthesis of functionalized single-walled carbon nanotubes (f-SWCNTs) SWCNTs functionalized by thioglycoside derivatives
The reaction of 4-Ethynylaniline 7 with di-tert-butyldicarbonate provided tert-butyl(4-ethynylphenyl)carbamate 8, which reacted with azide composition (mannose) 11 or (lactose) 12 respectively in the presence of sodium L-ascorbate and copper sulfate in water to produce 1,4-disubstituted triazole 13 or 14. The deprotection of compound 13 or 14 by treatment with trifluoroacetic acid (TFA) produced the compound 15 or 16, which was treated with a mixture of MeONa/ MeOH to obtain the neutral amine 17 or 18 (Scheme 2) [23].
In the third step, the acid-functionalized SWCNTs compound 3 reacted with aminoporphyrin 26 in N,N'-dicyclohexylcarbodiimide (DCC) to provide the porphyrin conjugated SWCNTs 27 (Scheme 6). The interaction among the porphyrin, as an antibacterial agent, conjugated SWCNTs 27, and the bacterial cells in front of visible light cause the cell membrane ruin. Porphyrin-SWCNTs conjugates could be employed as an antibacterial agent too [25].

SWCNTs functionalized by lysine
SWCNT-Lys-NH 2 29, as shown in Scheme 7 was prepared from SWCNTs 1 and H-Lys(Boc)-OH 28 in the presence of paraformaldehyde (PFA) and TFA to afford lysine-modified SWCNTs 29, which were nontoxic and did not have the primary influence on the microbiota [26,27].

SWCNTs-ciprofloxacin as nano-antibiotic
Ciprofloxacin 30 was reacted with di-tert-butyl dicarbonate (Boc 2 O) in water/dioxane including NaOH to provide N-Boc-   The main strategy was the covalent functionalization of SWCNTs with ciprofloxacin by spacer support to enhance the hydrophilichydrophobic stability and gain a fresh stable nano-antibiotic compound, which is biocompatible (Scheme 11). The antibacterial activity of f-SWCNTs 45 was significantly enhanced in comparison to the ciprofloxacin versus different bacteria such as S. aureus, P. aeruginosa, and E. coli [28].

Malachite green (MG) MWCNT conjugate
MGMWCNT 56 was obtained by the reaction of MG 55 and COOH-MWCNT 4, according to the reported [25] reaction previously (Scheme 16). This article presented the improved capability of a photoactivated malachite green coupled to carboxylated multi-walled CNTs (MGMWCNT) 56 for the antibacterial therapy in front of Staphylococcus aureus and Pseudomonas aeruginosa. This information indicated that the MGMWCNT conjugate 56 could be used as a further approach for removing these both bacteria structures from the medical system [36].

MWCNTs-coated titanium alloy discs:
MWCNTs-coated titanium alloy discs were prepared through the coating of MWCNTs by the hard titanium alloy discs (TiAl6V4), and then immobilizing the encapsulated Ni particles on the MWCNTs surface. Rifampicin is an antibiotic drug which was loaded on the MWCNTs-coated titanium alloy discs to inhibit biofilm formation against Staphylococcus epidermidis [43].

Carboxymethyl chitosan (CMCS)-MWCNTs
Chitosan and NaOH in isopropanol (C 3 H 8 O) as a solvent was put into a flask to alkalize. Monochloroacetic acid (MCA) was solubilized in isopropanol, and added to the reaction mixture to provide CMCS 64 [44]. The mixture of MWCNTs 2 and CMCS 64 were sonicated to afford a homogeneous CMCS-MWCNT 65, which was poured in MeOH to obtain the solid nano bio-compound 65 (Scheme 19) [45]. These nanocomposites display greater antibacterial activity in front of S. aureus and E. coli than the employed standard ampicillin (a penicillin antibiotic) and gentamicin [46].

Electro-conductive CNT hybrid hydrogels
CNTs were produced by aerosol-assisted chemical vapor deposition [47]. Hydrogel including different quantities of CNT, H NTi (i = 1, 2, 3), were produced under SONOPULS method by mixing proper CNT mass in a Gel water mixture 66 [48]. Acrylamide (AAm) 67, polyethylene glycol dimethacrylate (PEGDMA) 68, and ammonium The mixtures 58 and 59 were combined and sonicated. The initiator 2,2-azobis (2-isobutyronitrile) (AIBN) was added to the mixture of reaction to start the polymerization reaction to provide MWCNT@ liquid crystalline molecularly imprinted polymers particles (MWCNT@ LC-MIP) 60, which showed better drug loading ability because of their smaller size, well permeability, and high surface area (Scheme 17). LVF is used in the infection treatment of soft tissue, skin, urinary tract, and respiratory tract. The LVF-imprinted MWCNT@LC-MIP has the potential activity for a gastro retentive drug delivery system (GRDDS) and used as a floating drug delivery systems (FDDS) [37,38].

Polyethylene glycol f-MWCNTs/gelatin-chitosan nano compound
f-MWCNTs (COOH-MWCNTs) 4 was treated with SOCl 2 to give MWCNTs containing acyl chloride (RCOCl) groups 61, which was treated with polyethylene glycol 62 (PEG) to obtain polyethylene glycol f-MWCNTs 63 (Scheme 18). It was added into the chitosangelatin mixture under the sonicated condition to afford polyethylene glycol f-MWCNTs/gelatin-chitosan, which didn't demonstrate any cytotoxicity. Therefore, the ciprofloxacin lactate drug mixture was appended to MWCNTs-COOH/gelatin-chitosan nano compound and MWCNTs-PEG/gelatin-chitosan nano compound to evaluate their antibiotic activities. It can be used as an agent in nanomedicine, targeted thermic tumor ruin, drug delivery, and magnetic battlefield targeting of tumors. It is evident that the transfer of antibiotic drugs like ciprofloxacin can be easily made when it was instantly immobilized on the carbon nanotube surface through H-bonding and π-π stacking [39].

MWCNTs-magnetic nanoparticles
In this process, MWCNTs were reacted with concentrated H 2 SO 4 /HNO 3 to provide COOH-MWCNTs, which were mixed with persulfate ((NH 4 ) 2 S 2 O 8 ) 69 were added to the mixture 66 to provide the polymerization solution 70, which was put among two 5.0 × 5.0 cm 2 glass sheets, disconnected with a Teflon spacer (0.6 mm) to obtain electro-conductive CNT hybrid hydrogels 71 (Scheme 20). The design of electro-conductive CNT hybrid hydrogels could release curcumin (CUR) as an antibiotic drug, which was applied to extraneous voltage as a valuable device for wound curing. The existence of gelatin in the reaction feed is forced to improve the dispersibility of CNT in liquid media [49,50].

Human serum albumin (HSA)-CNTs
CNTs were oxidized using H 2 SO 4 /HNO 3 under the ultrasonic condition to provide COOH-CNTs. In this process, the phosphate buffer was used to dissolve HSA, which was added to COOH-CNTs solution to obtain HSA-CNTs [51]. HSA can facilitate binding and carrying a lot of poorly soluble antibiotic drugs like bendroflumethiazide in water [52].

Star-shaped poly(ɛ-caprolactone) (PCL)-poly(ethylene glycol) (PEG)/CNTs p red. OCl nano compound
CNTs were synthesized using Fe as the catalyst via CVD method [53]. CNTs were functionalized to immobilize some kinds of chemical groups such as OH, COOH, and RCOCl on their surface through threesteps. The first step, the CNTs were reacted with nitric acid under reflux condition to provide partly oxidized CNTs to produce OH and COOH groups. In the second step, carboxyl groups (COOH) of CNTs p oxi were reduced chemically by LiAlH 4 to promote the hydroxyl groups to afford CNTs p red , which were treated with OxCl to obtain CNTs p red-OCl 72 (Scheme 21). In the last step, CNTs p red-OCl were utilized to produce the star-like PCL-PEG/CNTs p red-OCl nano compounds as below. The CNTs p red-OCl 72 were mixed with prepared star-like PCL-PEG copolymers 73, which was prepared by relatively modifying a chemical three-step method [54]. At first, a homopolymer of star-like PCL was produced by ɛ-caprolactone (ɛ-CL), pentaery-thritol (PTOL), and stannous octoate (SnOct 2 ) under reflux condition. In the second step, a prepolymer of star-like PCL-OxCl was obtained by the treatment of OH groups of starlike PCL (stPCL) and acyl chloride (RCOCl) groups of oxalyl chloride (OxCl) under reflux condition. In the next step, a mixture of PEG in dichloromethane was added to avoid unwanted cross-linking reacting over the prepolymer preparation to provide star-like PCL-PEG, which was reacted with CNTs p red-OCl to afford star-like PCL-PEG/CNTs p red-OCl nano compound 74 (Scheme 22). Also, the resulting product was tested against Staphylococcus aureus bacteria and Pseudomonas aeruginosa. were better than the polymeric compound, while their bacterial action was lesser. The molecular scaffold of the star-like copolymer made conceivable poly(ethylene glycol) chains be used to the achievement of bacteria and inhibited their growth [55].

Conclusion
In conclusion, the role of carbon nanotubes in antibiotics drug delivery was reviewed through the functionalization of SWCNTs and MWCNTs to improve their abilities such as drug-releasing, targeting, adsorption, solubility in water. Consequently, f-SWCNTs and f-MWCNTs display better antibacterial activity against bacteria like E. coli, S. aureus, Bacillus subtilis, and etc.