Carbon Nanotubes: A Novel Cargo System for Drug Delivery and Targeting

Abstract

Carbon nanotubes (CNTs) are one-dimensional nanomaterials, mostly considered second-generation carbon allotropes. Since the majority of them are composed entirely of carbon, they tend to arrange themselves in a hexagonal manner, creating a cylindrical tube-like structure. Its unique mechanical, electromagnetic, thermal, and spectroscopic properties attracted medical researchers' attention. Low solubility of pristine nanotubes can be effectively overcome by functionalization by different functional moieties. The needle-like feature of functionalized CNTs and large surface area helps to develop covalent or non-covalent bonds between molecules and themselves by attaching to the surface of CNTs. The unique structure of the nanotubes provides extended space for higher entrapment of the drug. Because of their unique form, CNTs can pass through the membrane of the cell and deliver drug molecules to specific locations. This makes them highly flexible and thus more likely to deliver drugs into cells. CNTs have large interior volume so can be encapsulated with drugs having medium and high molecular weights. The CNT can be effectively functionalized to achieve the target specificity which increases the efficiency of drug and with reduced adverse effect. The present work focuses on the different types, production methods, purification methods, functionalization and biosafety of the carbon nanotubes. It also focuses on the patent of carbon nanotubes.

Keywords

Introduction

Figure 1: Structure of CNTs (a) SWCNT (b) MWCN

CNT TYPES BASED ON THEIR CHIRALITY 

Chirality is a critical factor in the crucial electrical properties of CNTs. Based on chirality, we can categorize CNTs into three types: chiral, zigzag, and armchair. All three of the above-mentioned forms are depicted. In distinction to the first two arrangement types, the zigzag perceptive of bonds has a V-shape opposite to the tube's league and is also chiral or helical. In the armchair arrangement, the chiral vector encompasses chairs that are at right angles to the tube's axis.[26] Both the electrical charge and conductivity properties aid in the construction of a wide variety of nano electronic devices and serve as commissioner indicators of the presence of chirality in CNTs. [27] Specifically, CNTs are categorized into many groups according to their solubility properties, preparation method, and structural changes, such as functionalized, solvent-dispersed, surfactant-assisted, and bimolecularly assisted nanotubes, among others.[28]

SYNTHESIS OF MULTIWALLED CARBON TUBES

Iijima's 1991 paper on helical microtubules of graphitic carbon started the current carbon nanotube report in materials science, as did the subsequent discovery of single-walled carbon nanotubes (SWNTs) in 1993, independently by Iijima and Ichihashi and Bethune et al. The original discovery of multi-walled carbon nanotubes (MWCNTs) was recently credited to Radushkevichto and Lukyanovichi in 1952.[29] It is feasible to create carbon nanotubes with single and multiple walls using general procedures that have been adapted to one type of tube. Many synthesis techniques have been developed during the past 20 years, and MWCNT synthesis is now a verified process that has been successfully scaled up to a commercial level.[30] Arc discharge and laser ablation must also be taken into consideration, even if catalytic chemical vapor deposition (CVD) is now the most practical and popular production technique.[31]

Arc Discharge

An electric arc between two graphite electrodes in a gaseous atmosphere produces a plasma in arc discharge carbon nanotube synthesis reactors. This plasma then evaporates and condenses as a filamentous carbon product on the cathode. The manufacture of carbon nanotubes and fullerenes has been accomplished successfully using this technique. By means of altering the current density, the process mode can be controlled. The process can be modified by adjusting the density. The method works well for large-scale manufacturing because the helium flows throughout the reactor at a controlled rate and pressure.[32] A metal catalyst-filled drilled hole in the anode graphite rod may facilitate the creation of MWCNTs. Increasing the hydrogen concentration of the chamber gas, conducting the synthesis in liquid nitrogen or a magnetic field, refining the quenching procedure, or using the plasma-rotating arc discharge approach can increase the crystallinity of MWCNTs produced by arc discharge.[33,34] The process has significant drawbacks, including high energy consumption and postproduction purification procedures, but it also offers benefits, such as simplicity and adaptability in terms of carbon source material and catalyst.[35]

Laser ablation 

The process of laser ablation, which uses a laser beam to vaporize a carbon target—often one that contains transition metals as a catalyst component—marked the start of the nanocarbon revolution in the 1980s.[36] The second harmonic of a Nd:YAG laser pulse is directed onto a graphite target that has 1%–2% catalyst metal in a standard laser ablation experiment.[37]  The process of laser ablation, which started the nanocarbon revolution in the 1980s, is utilizing a laser beam to evaporate a carbon target, usually one that contains transition metals as a catalyst component.[38] In a typical laser ablation experiment, the second harmonic of a Nd:YAG laser pulse is focused onto a graphite target that contains 1%–2% catalyst metal. The target is heated in an electric furnace to 800-1400 °C while an inert gas flow is maintained. The target is evaporated into a plasma by the laser, producing carbon nanotubes.[39] The inert gas stream sweeps the generated nanotubes onto a cold finger collector, where they are regularly extracted from the reactor. Laser ablation is the favored synthetic approach for many fundamental studies because it produces high-quality nanotubes, despite its unsuitability for bulk manufacturing.[40]

Catalytic chemical vapor deposition Methods 

Catalytic chemical vapor deposition, or CCVD, is a popular technique for creating carbon nanotubes. A volatile carbon source is introduced into a reactor, where it breaks down on an appropriate catalyst surface and its carbon content is recrystallized as carbon nanotubes.[41] Carbon nanotubes with one or more walls can be created using this procedure. Both homogeneous (the catalyst and carbon supply are both volatile) and heterogeneous (the catalyst is supported in the solid phase) designs are possible for the CCVD process. A volatile organic chemical can be used to create the metal catalyst in situ or prefabricated. The degradation of the carbon source can be powered by heat, microwaves, or plasma.[42] Cost-effectiveness, scalability, continuous operation, and a comparatively low operating temperature are some of the benefits of the CCVD technique. However, it also has drawbacks, like the requirement for a post-synthetic purification step and lower-quality synthesized nanotubes.[43] The preparation of multi-walled nanotubes (MWNTs) is typically carried out at high temperatures, with the deposit nature and yield controlled by various parameters such as metals and supports, hydrocarbon sources, gas flows, reaction temperature, and reaction time.[44]  The catalyst support's quality is essential; materials including Silicon, Magnesium, and Aluminium are appropriate but unsuitable for the formation of CNTs. Because of their high carbon content, acetylene, ethylene, and benzene are the hydrocarbons most commonly used.[45] Different temperature ranges for metals and supports, high temperatures promoting appropriate graphitization, and homogenous pyrolysis becoming excessive above a certain temperature makes determining the ideal reaction temperature a challenging task.[46]

Certain catalyst preparation techniques have been used to create helical-shaped nanotubes. It has been discovered that when acetylene is broken down at 700 °C, silica and alumina-supported co-catalysts generate a significant number of helical tubes. The pH of the original solution and the pretreatment used during catalyst preparation determines the quality of these tubes. Acidic-centered samples exhibit little action.[47] Over catalysts made from pH 7 solutions, carbon nanotube production is seen; however, when the catalyst surface is neutral, selectivity for helical carbon nanotubes abruptly increases. The quantity of spiral nanotubes grows dramatically with increasing pH. This might be because co-acetate is well soluble at low pH, which produces symmetric catalytic centers and symmetric particles on the silica surface. Cobalt hydroxide starts to precipitate as the pH rises, and some solid, most likely asymmetric particles land on the catalyst's surface.[48] There is ongoing discussion over the function of asymmetric catalyst particles in spiral carbon nanotube development. For use in flat-panel displays, arrays of aligned multi-walled nanotubes have been created.[49,50]

PROPERTIES OF MULTIWALLED CARBON NANOTUBES

Mechanical Properties 

MWCNTs are weaker in the radial direction, with a radial Young's modulus of 30 GPa and up to 40% radial deformability,[51] but they have exceptional mechanical properties in the axial direction, with a tensile strength of 60 GPa and a Young's modulus in the TPa range. The outermost shell is the only load-bearing element due to the incredibly low friction between the MWCNT walls, and the cross-sectional area of MWCNTs is not reduced before mechanical failure.[52,53] The mechanical properties of MWCNTs are complicatedly affected by defects, which can improve load transfer between walls while weakening individual shells. The spring constant of MWCNT cantilevers can be as low as 0.001 N/m by adjusting the nanotube's length.[54] In the low-strain area, carbon nano-coils exhibit elastic spring-like behavior with a spring constant of 0.12 N/m and can be extended to 42% of their initial length. Coiled MWCNTs have a fundamental resonance frequency between 100 and 400 MHz, which can be used to create resonators that are sensitive to changes in mass within the sub-atto-gram range.[55] MWCNTs are readily altered by mechanical forces because of their low radial strength. While chemical treatment and ultrasonication can be replaced by ball milling, only chemical treatment yields adequately separated, individual nanotubes. The end morphology of mulled carbon nanotubes is a major problem; when bending, kinks form, and during milling, open ends form, which weakens the material and makes it the perfect place for breaking.[56]

Electromagnetic Properties 

Although the electronic components of multi-walled carbon nanotubes (MWCNTs) have not been thoroughly investigated, they have been shown to be largely successful in featherlight line and string operations.[57] While the exterior layers dominate the transverse response, the longitudinal polarizability of MWCNTs is governed by the sum of the polarizabilities of the constituent tubes. At low bias and temperature, the MWCNT parcels are determined by the helicity of the furthest wall.[58] In addition to supporting incredibly high current consistency, MWCNTs can withstand incredibly high temperatures. An individual nanotube may carry current up to 106 A/ cm², according to early measurements; tube-enhanced CVD-derived MWCNTs push this limit to 108 A/ cm².[59]  The absence of standardized, essence-catalyzed nanotube samples makes the glorious moment of MWCNTs a contentious topic. Nevertheless, it is possible to thoroughly examine the glitzy packages of bedded transition-essence patches. The ¹³C NMR signal of multiwalled carbon nanotubes (MWCNTs) broadens correspondingly with the number of walls,[60] making direct nuclear magnetic resonance (NMR) compliances on MWCNTs delicate. The electron paramagnetic resonance (EPR or ESR) diapason of MWCNTs is different from that of SWCNTs, exhibiting a single narrow asymmetric peak. The findings of ESR measurements have varied significantly based on the size distribution, answer items, and degree of metallic pollution and junking.[61]

Thermal Properties

Dresselhaus and Eklund's work on phonons in carbon nanotubes set up that aligned MWCNT flicks have a thermal conductivity of 15–25 W/(m K), operating at an effective normal of 200 W/(m K). For MWCNT carpets, Gaillard et al., reported thermal conductivities ranging from 180 to 220 W/(mK).[62] Chiu et al., established ballistic phonon transport in MWCNTs and calculated the phonon mean free path and thermal conductance ⁶³. According to Yan et al., reduced heat conductivity in MWCNTs may be caused by a strong inter tube coupling. The specific heat of MWCNTs was built up to be equivalent to graphite but substantially informed by the arrangement of the nanotubes. A 0.6 vol% suspension of MWCNTs in water boosted water's thermal conductivity by about 38.[63,64]

Spectroscopic Properties

Raman spectroscopy is a crucial tool for examining carbon nanotubes, particularly single-walled carbon nanotubes (SWCNTs). The Raman spectrum of MWCNTs is dominated by two peaks: the D band at 1350 cm−1 and the G band at 1590 cm⁻¹. These peaks correspond to the nanotube wall airplane tangential stretching C-C climate.[65] The intensity of the D and G bands is a widely used method for assessing the general chastity of a multi-walled carbon nanotube sample. In contrast to SWCNTs, the chirality of the remotest shell has no bearing on the optical spectrum of MWCNTs, which spans the ultraviolet (UV) to infrared range. The reflectivity of MWCNTs is determined by the phase topology of the bulk nanotube and the polarization exposure relative to the applied field [66,67].

PURIFICATION OF MWCNT

The synthesis techniques and the purification of MWCNTs have been developed concurrently. For the majority of CVD-grown nanotubes, liquid-phase oxidation followed by acid leaching seems to be a good overall solution. An effective soft purification method was proposed by Alvizo-Paez et al. and is advised for applications where maintaining the nanotube structure is essential.[68]

Elimination of Catalysts and Supports for Catalysis

MWCNTs are formed by employ supporting metal catalysts, usually cobalt, iron, and nickel, to catalytically break down hydrocarbons. These catalysts are made by impregnating metal salts into oxide-like supports, such as zeolites, silica, or alumina. After 48 hours of leaching in hydrofluoric acid, zeolite and silica supports can be removed from the carbon product by filtering and washing. [69] Sodium hydroxide solution is used for extraction rather than alumina. The most economical method is growth on a water-soluble substrate, such as the wash-and-go advance. The metal components of the catalysts are typically carried into the solution while the metal particles embedded in the carbon nanotubes remain intact. MWCNTs can be uncapped by oxidation or treatment in a molten lithium chloride – potassium chloride eutectic.[70]

Amorphous Carbon Elimination

By-product-containing carbon nanotubes Colorful chemical and physical methods can be used to purify carbon material. Advanced chastity goods are impacted by chemical methods, although they usually permanently alter the raw material.[71] While carbon can be oxidized to generate irregular structures in the gas or liquid phase, reduction is carried out at high temperatures in the hydrogen environment. Sulphuric acid/ nitric acid (H2SO4/HNO3), ammonium persulphate (NH4S2O8), hydrogen peroxide (H2O2), ozone, chlorine water, and concentrated HNO3 treatment are all factors in other liquid-phase oxidation processes. Ultrasound or microwave oven treatment can improve oxidative digestion.[72] To make the nanotubes accountable and facilitate their separation from contaminants, intentional functionalization techniques such as bromination, 1,3-dipolar cycloaddition of azomethine ylides, and HNO3 oxidation can be employed. After sanctification, the original MWCNT structure should be restored by reduction or high-temperature annealing.[73] Remaining carbonaceous patches and metallic contaminants are eliminated by post-tube-enhanced CVD (PECVD) hydrogen tube treatment. Unformed carbon can be burned out in air through precisely regulated oxidation without causing harm to the nanotubes.[74] For further sanctification of nanotubes, centrifugal separation is typically used. Soots with a high yield of nanotubes can be separated using microfiltration. Recently, electrophoretic techniques and size exclusion chromatography (SEC) have been used to distinguish between various MWCNTs.[75]

CARBON NANOTUBES' OPENING

Both physical and chemical ways can be used to purify carbon nanotubes. Chemical ways include functionalization ways including bromination, oxidation in the gas or liquid phase, and reduction in the hydrogen atmosphere.[76] The original structure is restored via high-temperature annealing. Remaining carbonaceous patches and metallic adulterants are barred by hydrogen tube treatment in post-tube- enhanced CVD (PECVD). For fresh sanctification, centrifugal, microfiltration, and size exclusion chromatography (SEC) ways are employed.[77]

FUNCTIONALIZATION

Since single-walled and multi-walled carbon nanotubes absorb similar chemical packages, they can both be functionalized still, MWCNTs are less reactive due to their larger external fringe and lower curve. The carbon nanotube packages are controlled by three factors sp2 hybridization, π orbital misalignment, and sp3 disfigurement patches.[78] A clear correlation between addition response affinity and nanotube periphery is suggested by the fact that the π orbital misalignment approach and pyramidalization angle scale identically with tube periphery. MWCNTs are smoothly transformable in chemical responses due to their high sp3 disfigurement attentiveness, which serves as a precursor to subsequent chemical transformations.[79] Although Hauke and Hirsch's chapter is quite comprehensive, functionalization reviews are also provided by Musso et al. and Karousis et al.[80] To functionalize and dispense MWCNTs, researchers employ a variety of methods, such as the following:

Non-covalent functionalization

Non-covalent functionalization can disperse nanotubes in solutions without degradation of their electrical properties and the aromatic structure. This method consists of filtration-centrifugation-ultrasonication. In many cases, surfactants, including polymers are employed to adsorb molecules onto the surface of the nanotube. Nonionic, anionic, and cationic surfactants were utilized to disperse nanotubes however their distribution ability is not improved.[81] Furthermore, the serum nuclease cleaves down DNA molecules adsorbed on MWCNTs yielding that no directly physically adsorbed CNT can make it in vivo stable. The water dispersion of CNTs may be significantly enhanced by the π-π interaction, which forms one hydrophilic and one hydrophobic link between the side walls of the nanotubes. Surfactants have been used as dispersants in processes to improve the compatibility of composite materials, stabilize CNT dispersions for spectroscopic examination, and clean raw carbon materials.[82] However, they can cross the plasma membranes which can be harmful for the biological system. Therefore, the desired surfactant should be non-toxic to be biocompatible with biological systems and generate stable complexes with MWCNT that are also established in vitro as well as in vivo. This is not true for non-covalent functionalization, where phospholipids are a relevant class of plasma membrane constituents and can serve as anchoring groups. Due to their excellent mechanical strength and biocompatibility in the accepted organism, these carbon nanotubes (CNTs) can serve a wide array of biomedical applications such as targeted drug delivery systems biosensors or imaging.[83]

Covalent Functionalization 

Chemical functionalization of multiwalled carbon nanotubes (MWCNTs) involves lastingly attaching chemical groups to the plane of the walls or tips of the nanotubes. These groups can be linked to the external layer or ends of the nanotubes, offering profit such as covalent association with polymeric materials and dispersion in various solvents. However, this method can lead to the formation of flaws on CNTs.[84] Covalent functionalization can be indirect on the surface with the carboxylic acid group or direct on the side walls. SWCNTs are easier to functionalize due to their larger outer layer diameter and shielded inner layers. The carbon nanotube is not very reactive, requiring exaggerated conditions for reaction. The surface chemistry of MWCNT’s surface chemistry does not characteristically respond to the added group or moieties.[85] 

Reaction of cycloaddition

It differs from the response described above in that it occurs along the wall's sides rather than subsequently to its split ends or defects. This method of covalent functionalization is also widely employed. Three categories may be complete out of this reaction: 

1. A photochemical reaction with azides is involved in photoinduced cycloaddition.
2. The Bingal reaction, which produces carbenes, happens while a strong base is present in the reaction. An additional name for it is the 2 + 1 cycloaddition reaction.
3. A popular method for functionalizing carbon nanotubes is the 1,3-dipolarcycloaddition reaction.[86] 

MWCNTs functionalized with polymers 

Typically, polymer molecules are employed to get better the dispersion of carbon nanotubes (CNTs) and create CNT-based complexes for testing novel properties. Through in-situ monomer polymerization, in which the monomer reacts with the entities present on the MWCNT's surface, the polymer has been stuck to the surface while initiators are present ⁹¹. Functionalized MWCNTs were distributed in an appropriate diffusion medium during the first phase. The second step involved dispersing the complex into a pre-made polymer matrix to acquire a functionalized MWCNT polymer complex, and the last step involved modifying the composite using a radiation process. Compared to earlier physically mixed polymer composites, the resulting composite has enhanced chemical, physical, and electrical characteristics without attaching itself to the carbons on the surface of the nanotubes.[87] Figure 2 indicates different approaches for the functionalization of carbon nanotubes.

Figure 2: Functionalization of CNTs for target specificity

Figure 3: Application of functionalized MWCNTs

PATENTS ON MWCNT DRUG DELIVERY SYSTEM

These patents underline the increasing interest towards exploitation of CNTs, particularly MWCNTs for creation of more sophisticated drug delivery systems. Below exist a few interesting examples of patents that reflect different strategies on how to use CNT in medicine: 

1. United States Patent: US20150196650A1 – Carbon nanotube-drug complexes for the treatment of cancer. The present invention provides a novel method for preparing a carbon nanotube drug complex capable of treating cancer. This invention relates to conjugating anticancer drugs, e.g., doxorubicin with MWCNTs for their targeted delivery and release at tumor cells. Nanostructure drug delivery in combination with specific targeting moieties to functionalize the nanotubes ensures that drugs are specifically delivered at a high concentration payload into cancer cells, minimizing toxicity toward normal tissue.
2. Patent:  WO2010000990A2 – Gene delivery with carbon nanotubes: Described herein is a method for functionalization of carbon nanotubes and use thereof in delivery to cells of an nucleic acid, encoding protein. The disclosure includes an invention that has to do with the use of MWCNTs functionalized using conjugation with nucleic acids, comprising DNA and/or RNA for gene therapy applications. The patent reflects that the technology is a promising tool for gene therapy with improved gene transfection efficiency relative to conventional modes of gene delivery and confirms the use of MWCNTs.
3. US Patent for Carbon nanotube-based drug delivery to the brain and treatment of neuro-infections, US9603891B2- This patent addresses a carbon nanotube-based delivery method for the effective treatment of neurological disorders. Here, we highlighted the functionality of MWCNTs with ligands for targeted delivery to help neuroprotective drugs across BBB, and thus may be promising in future management. This creation is especially beneficial for treating degenerative mental conditions like Alzheimer's and Parkinson's, in which drug supply to the brain works a vital role.
4. Patent US8263126 — Ocular Drug Delivery with Carbon Nanotubes This patent covers the application of carbon nanotubes for ocular drug delivery. Functionalization of MWCNTs allows for better solubility and ocular tissue penetration in the eye. This invention is intended for the treatment of ocular diseases such as glaucoma, uveitis, and age-related macular degeneration by introducing a new way to deliver ophthalmic drugs with improved bioavailability (through extended/permeable residency) and sustained release.
5. Patent-EP2568567B1-CNT-based-Antimicrobial-Coatings-for-Medical-Devices: This patent is related to CNTs (MWCNTs) as a coating in medical devices. Catheters, stents, and prosthetics are medical implants with a special coating of the antimicrobial agent on them to prevent bacterial invasion. The functionalization can be useful in inhibiting infection-causing bacteria which has entered into respiratory airways through inhalation of hazardous bacteria. The patent promotes the advantage of using MWCNTs in reducing infection rates and providing longevity benefits for medical devices.

CONCLUSION

The CNTs are emerging as important medical delivery vehicles because they have a high loading capacity and can be functionalized for targeted conditions, combined with their ability to transport various therapeutic entities. Due to their unique tubular structure, they have the ability to load drugs into this lumen using waterborne molecules inside out and others on outside in the shell. Functionalization further improves the productivity of MWCNTs in drug delivery applications by improving solubility, biocompatibility, and targeting certain types of cells or tissues. Functionalization can make MWCNTs more soluble in biological fluids, shortening their half-life time and, therefore, decreasing the likelihood of unwanted human exposure and toxicity. Targeting the desired cell can be achieved by aging ligands such as antibodies, peptides, or folic acid to the CNTs. The accumulation of non-functionalized MWCNTs in a natural habitat mainly triggers toxic responses, oxidative stress, and inflammation. Safety concerns arise from enterprises regarding the long-term destiny of MWCNTs in biological systems due to a partial understanding of their metabolization and concurrence from the body. Thus, from the study, it can be concluded that the CNTs are the novel and reliable components for drug delivery to desired sites.

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