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Using the functionalized carbon nanotubes and other nanomaterials to deliver the antimicrobial drugs, is one of the most applications of carbon nanotubes. Several studies were conducted about this topic.
Amphotericin B (AMB) is one of the first antimicrobials to be delivered with CNTs. Wei Wu et al. studied the Targeted Delivery of Amphotericin B to Cells by using Functionalized Carbon Nanotubes, they used oxidized MWCNTs that were functionalized with AMB and FITC. They found that at equivalent AMB concentration of 10 µg/mL, this CNT conjugate was found to be significantly less cytotoxic to Human Jurkat lymphoma T cells as compared to pristine AMB. This CNT-AMB construct was able to penetrate cells rapidly within 1 h of incubation by spontaneous piercing mechanism without causing cell death. Finally, They evaluated the antifungal activity of CNTs,functionalized with AmB, against three species of fungi(Candida parapsilosis, Cryptococcus neoformans, Candida albicans). In this experiment, they used AmB that was covalently linked to ammonium functionalized multi- and single-walled carbon nanotubes (MWNT-AmB and SWNT-AmB). The functionlized forms was found to be more potent than free AMB possibly due to enhanced drug solubility and the presence of multiple copies of AMB per CNT molecule (i.e. the multivalence effect) leading to improved binding affinity between the drug and its target.177 In another separate paper by the same group, a similar MWCNTs AMB construct and a newly designed SWCNTs-AMB conjugate with PEG linker were prepared with AMB loading of 25% and 10% w/w, respectively. These conjugates were tested for their antifungal activities in comparison to pristine AMB and a conventional colloidal dispersion AMB deoxycholate formulation. Both MWCNTs-AMB construct and SWCNTs-AMB conjugate were considerably more than AMB alone. Some fugal strains which were resistant to free AMB showed a significant response to the MWCNT-based AMB conjugate.178
In another study performed by Pruthi et al., AMB was physically adsorbed on mannosylated MWCNTs inorder to treat leishmaniasis by achieving specific delivery of the drug to macrophages. the mannosylated MWCNTs had high affinity to bind lectins and were able to be uptaken by macrophages in sufficient amount. but the result of this study is unfortunately insufficient to support macrophage-targeting because a control experiment with non-mannosylated MWCNTs was not performed.
Although AMB was adsorbed onto the mannosylated MWCNTs and demonstrated a sustained in vitro release profile, the use of Rh B-loaded mannosylated MWCNTs for intracellular fluorescence imaging of macrophages is inconclusive because Rh B could be detached from the MWCNTs before it enters macrophages, which means that the observed fluorescence is due to free Rh B not the MWCNTs-loaded with Rh B.179
Apart from AMB, dapsone is another example of antimicrobial that has been successfully delivered with CNTs. It is an antimicrobial and anti-inflammatory drug that can be used to treat many diseases such as malaria, leprosy, AIDS-associated toxoplasmosis and other diseases.180 Some bacterial species developed resistance to dapsone so experiments was started to deliver dapsone with CNTs and fortunately it was delivered successfully. Dap-MWCNTs was formed by functionalizing dapsone onto oxidized MWCNTs. Dap-MWCNTs were first tested on rat peritoneal macrophages it was rapidly ingested with predominant endosomal localization without significant cytotoxicity. Dap-MWCNTs showed many advantages as it induced less apoptosis than oxidized MWCNTs and had a lower degree of oxidative stress. On the other hand, apoptosis of macrophages is important for clearance of intracellular pathogen, so the delayed apoptosis seen by Dap-MWCNTs may be counterintuitive in the treatment of infection.181
In anoter study, Pazufloxacin mesylate, an antibiotic belonging to the class of fluoroquinolones, was adsorbed onto MWCNTs functionalized with ethylenediamine. In vitro release suggested that the adsorption of pazufloxacin consists of two phases, the first one is a rapid burst release followed by a second phase of sustained release. The total amount of released pazufloxacin from the amino-functionalized CNTs was higher at pH 5.7 than pH 7.0, due to increase hydrophilicity in acidic condition. This could be advantageous in the treatment of infections, due to the acidic environment of the infected cells.182
In another hand, gentamicin, an aminoglycoside antibiotic, was incorporated into collagen hydrogel doped with 1% w/w CNTs which served as an additive to enhance the physical stability of the hydrogel and retard the release of gentamicin. The retarded release effect had took a place in the formation of irregular CNT network in the hydrogel which impeded solvent diffusion. However, The presence of CNTs can induce a simple chemical attraction between CNTs and gentamicin, and hence improve the drug loading which could affect the drug release rate.183
In addition, chloroquine is an anti-malarial drug that also possesses lysomotropic effect. Due to their ability to cause swelling and rupture of endocytic vesicles, lyosomotropic compounds have been proposed to be used as an additive to enhance gene transfection by enabling timely escape and minimizing degradation of delivered genetic material in lysosomes. For further enhancement of gene delivery with CNTs, chloroquine was loaded onto DWCNTs coated with cationic polymer PEI and plasmid encoding for luciferase. Chloroquine can be released from the CNTs in acidic condition.Coating chloroquine with cationic polymer and plasmid can strongly affect chloroquine loading. Transfection efficiency can be improved up to five folds by introduction of chloroquine compared to a non-chloroquine loaded control. Unfortunately this construct has limited uses as a biocompatible transfecting agent because it was found to have more cytotoxic effects to cells than the non-chloroquine loaded control and free chloroquine. In the future, this construct might prove to be effective as a treatment of intracellular malaria infection and the excellent intracellular delivery of chloroquine can explain the higher observed cytotoxicity.184
In another study, Annamalai Senthil Kumar et al. used an electrochemical route for highly selective immobilization of amoxicillin (AMX) on multiwalled carbon nanotube modified glassy carbon electrodes (GCE/[email protected]), without any linkers and surface functionalization. In order to reveal the immobilization of AMX both on the inner and outer (surface) walls of the carbon nanotubes. They usedX-ray diffraction, transmission electron microscopy and scanning electron microscopy. Finally, they tested its antibacterial activity against Escherichia coli, Staphylococcus aureus and Bacillus subtilis in comparison with the unmodified AMX and MWNT using disk diffusion method. They found that [email protected] has enhanced antibacterial activity against the three bacterial pathogens185
Liangliang Ji et al. studied the adsorption of two sulfonamide to MWCNTs. Nonporous, pure graphite was used as a comparative adsorbent The results revealed thatthe two sulfonamides have a strong adsorption to both MWNT and graphite which can be explained by( π-π electron coupling)186 In another study, Xin Zhang et al, studied the adsorption of sulfamethoxazole on different carbon nanotube typesand compared the results with the adsorption to natural sorbents including soils, sediments and sludges. Many properties of carbon nanotubes contributed to the adsorption process such as surface area, diameters and surface functional groups. They showed that the adsorption coefficients of SMX on CNTs were generally twicehigher in magnitude than other natural sorbents..187 Also, Liangliang Ji et al. studied the effect of aqueous solution chemical characteristics on the tetracycline adsorption onSWNT and MWNTsuch as the effect of ionic strength (NaCl and CaCl2), the results showed that there is an inverse relationship between the ionic strength and the tetracycline adsorption on both SWNT and MWNT. They also studied the effect of Cu2+ion (7.5 mg/L) that showeda higher tetracycline adsorption rate to both SWNT and MWNT due to cation bridging mechanism. They finally studied the effect of dissolved soil &coal humic acids (50 mg/L) , and the results revealed that these acids have a minimal effect on SWNT while on graphite and MWNT it has a suppression effect on tetracycline adsorption.188
According to ciprofloxacin, S.A.C. Carabineiro et al. studied the adsorption capacity of ciprofloxacin on three types of carbon based materials: activated carbon, carbon nanotubes (MWCNTs) and carbon xerogel that were functionalized through oxidation with nitric acid then they were heat treated at different temperatures (between 350 and 900 °C) under a flow of N2. They demonstrated that the adsorption capacity affected inversely when the samples were treated with nitric acid. While thermal treatments, especially at 900°C after oxidation, enhance adsorption performance.189 In another study, S. Ashok Kumar and Sea-Fue Wang studied the stabilizing of multi-walled carbon nanotubes by aqueous solution of ciprofloxacin. It was found that MWCNTs can be stabilized by ciprofloxacinand the dispersions were stable for more than a month.190 Recently, Haibo Li et al. studied the effect of PH and temperature on the adsorption of ciprofloxacin on different functionalized CNTs like: carboxylized (MC), hydroxylized (MH), single-walled CNTs (SW)and graphitized multi-walled CNTs (MG).They found thatSW had the highest absorption rate for ciprofloxacin among all CNTs due to its largest surface area and they found that this is true for all PHs .Also, ciprofloxacinsorption was thermodynamically favorable For SW, while the reverse process was observed for MC and MG. For MH, ciprofloxacin sorption firstly increased then decreased with increasing temperature.191
Apart from using carbon nanotubes to deliver antimicrobial drugs, other nanmaterials were used form the same purpose. For example, Renjis T. Tom et al. prepared Ciprofloxacin-Protected Gold Nanoparticles of two different
mean diameters, 4 and 20 nm. they used different analytical techniques to study the adsorption of ciprofloxacin molecule on gold nanoparticle surface. The voltammetric and spectroscopic studies confirmed that nitrogen atom of the NH moiety of piperazine group can bind strongly to Au nanoparticles. These particles are stable in dry state and at room temperature. This study showed that the release of molecule from the particles depends on the size of particles and is more in the basic medium than in pure water. These particles were found to have many application because their fluorescent nature. Finally, This study shows that metal nanoparticles could be useful carriers for ciprofloxacin and other fluoroquinolone molecules.192 Regarding to liposome, many other examples have also been developed for various applications. For ciprofloxacin, M Magallanes et al. were prepared Liposomes that incorporated ciprofloxacin by dehydration-rehydration procedure to treat Salmonella Dublin in mice spleens. Their results revealed that a single injection of liposome-incorporated ciprofloxacin (LIC) was 10 times more effective than a single injection of free drug at preventing mortality.193 Another example conducted by MURRAY S. WEBB et al. who encapsulated ciprofloxacin into large unilamellar vesicles (LUV) and studied their antibacterial efficacy in vivo against Salmonella typhimurium in mice infected with intracellular S. typhimurium. They noticed that the LUV composed of dipalmitoylphosphatidylcholine-cholesterol (DPPC/chol),
distearoylphosphatidylcholine-cholesterol (DSPC/chol), or sphingomyelin-cholesterol (SM/chol) increased the circulation lifetime of ciprofloxacin after intravenous (i.v.) administration by >15-fold. In another hand, the retention of ciprofloxacin in liposomes in the circulation decreased in the sequence SM/chol > DSPC/chol > DPPC/chol. It was noticed that after the adminsrtation of Liposomal ciprofloxacin,intravenously and intraperitoneally to mice, they conferred significant increases in the longevity of the drug in the plasma after intraperitoneal administration and in the lungs after intratracheal administration in comparison to free ciprofloxacin and the concentration of drug in the liver, spleen, lungs and kidneys is also increased. Also, they concludedthat it extended survival and reduced the number of bacteria in the liver and spleen after studying The efficacy of a single i.v. administration of an SM/chol formulation of ciprofloxacin in a Salmonella typhimurium infection model. The encapsulated formulation resulted in 103 to 104 fold fewer viable bacteria in the livers and spleens of infected mice than was observed for animals treated with free ciprofloxacin. These results confirmed that the utility of liposomal encapsulation of ciprofloxacin improved the pharmacokinetics, biodistribution, and antibacterial efficacy of the antibiotic.194 In another study, when negatively charged liposomes are used, ciprofloxacin efficiently inhibits the growth of M. avium in vitro in a murine macrophage-like cell line and this results also were observed in vivo by using specific stealth liposomes in a mouse model of tuberculosis infection.195
Regarding to Solid Lipid Nanoparticles (SLNs), a study conducted by D. Jain and R. Banerjee to develop single dose delivery systems based on nanotechnology for prolonged antibiotic release in a controlled manner. In this study they prepared ciprofloxacin hydrochloride-loaded nanoparticles using four different natural carrier materials: albumin, gelatin, chitosan (CS), and lipid [solid lipid nanoparticles (SLNs)] . They compared them on the basis of particle size, electro-kinetic stability, entrapment efficiency, and drug release. Their Results suggested that CS nanoparticles and SLNs were found to be promising formulations for sustained ciprofloxacin release especially for local delivery in ocular and skin infections.196
Finally, concerning to polymeric nanoparticles as nanoantibiotics to deliver ciprofloxacin, several studies were carried out. Fawaz et al. encapsulated the synthetic drug ciprofloxacin in polyisobutylcyanoacrylate (PIBCA) nanoparticles. Thay studied their pharmacokinetic after intravenous infusion to the rabbit. The results revealed that ciprofloxacin-loaded PIBCA/NP led to increased AUC, t1/2 and Vd, and to a decreased Cl as compared with free form of drug. In addition, they tested these nanoparticles against a M. avium infection in a human macrophage culture, it was found that ciprofloxacin-loaded PIBCA/NP was more effective than unbound ciprofloxacin. In spite of this, the efficacy of ciprofloxacin associated with nanoparticles was much lower than anticipated due to the cytotoxicity of the polymeric material that was observed at concentrations higher than 80 mg of PIBCA per ml.197 another study carried out by Dillen et al. to prepare Poly(lactide-co-glycolide) nanoparticles incorporating ciprofloxacin HCl by using W/O/W emulsification solvent evaporation method. They used poly(vinylalcohol) as a stabilizer. They studied of different preparation factors on the physicochemical properties of nanoparticles. Thee microbiological activity on two types of microorganisms, Pseudomonas aeruginosa and Staphylococcus aureus, was tested. the activity against P. aeruginosa and S. aureus of the nanoparticles and aqueous solution was comparable.198 While Rosemary et al. investigated the antibacterial activity of ciprofloxacin-encapsulated silica nanoshells that were synthesized from [email protected] core-shell nanoparticles. In the case of Escherichia coli DH5R better antibacterial activity was showed in comparison with free ciprofloxacin, but the same activity was observed for Lactococcus lactis MG 1363. Also, nanoparticles were shown to enter the bacterial cell to exert their antibacterial effect by fluorescence imaging studies that conducted using fluorescein [email protected]199 Last study carried out by Abeylath et al. where they synthesized glycosylated polyacrylate nanoparticles that had covalently-bounded three antibiotics (N-sec-butylthio b-lactam, ciprofloxacin, and a penicillin ) within their framework. The results of the microbiological test showed that the N-sec-butylthio b-lactam and ciprofloxacin nanoparticles both had powerful in vitro activities against methicillin-resistant Staphylococcus aureus and Bacillus anthracis, while the penicillin-bound nanoparticles had no antimicrobial activity
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