INTRODUCTION:

Carbon nanotubes can be described as graphite sheets that are rolled up into cylindrical shapes. The length of CNTs is in the form of micrometers with a diameter of about 100 nm. Carbon nanotubes (CNTs) are considered as a derivative of both carbon fibers and fullerene with molecules composed of 60 atoms of carbons arranged in particular muffled tubes. The discovery of carbon nanotubes in 1991 by iijima presented transmission high resolution electron microscopy (HREM) observations of elongated and concentric layered microtubules made of carbon atoms, nowadays which were called carbon nanotubes (CNTs).

In order to understand the structure of a carbon nanotube possess various interesting chemical and physical functionalization methods of properties, have been extensively used in biomedicine¹. Functionalized carbon nanotubes with water solubility and biocompatibility are able to cross cell membranes, shuttling a wide range of biologically active molecules including drugs, proteins, DNA and RNA into cells^3-7. The cytotoxicity of carbon nanotubes is largely dependent on their surface functionalization, with minimal toxic effects for well functionalized, serum-stable nanotubes^8-9.

Carbon nanotubes:

CNTs is one of carbon allotropes such as diamond, graphite, graphene, fullerene and amorphous carbon. But, it is the one-dimensional carbon form which can have an aspect ratio greater than 1000 makes it interesting. The bonding in carbon nanotubes is sp², with each atom joined to three neighbours, as in graphite. CNTs are rolled-up graphene sheets (graphene is an individual graphite layer). This type of structural bonding, which is stronger than the sp³ bonds found in diamond, provides the molecules with their unique strength. Under high pressure, nanotubes can merge together, trading some sp² bonds for sp³ bonds, giving the possibility of producing strong, unlimited length wires through high pressure nanotube linking. The properties of nanotubes depend on atomic arrangement (on how the sheets of graphite are ‘rolled’), the diameter and length of the tubes, and morphology or nanostructure¹⁰.

Advantages of carbon nanotubes:

In the particular context of drug delivery applications CNTs may offers following advantages¹¹.

1. Highly uniform ordered structure with high aspect ratio.

2. Ultra light weight and easy availability.

3. Photoluminescence property.

4. Biocompatibility and non-immunogenicity.

5. Highly elastic nature.

6. Ferromagnetism and non-linear property.

7. Cellular internalization via endocytosis and passive diffusion mechanisms.

8. Biodegradable.

9. Exhibit minimum cytotoxicity based on the in vitro in vivo studies.

10. Excretion through biliary pathway (urine 96% and remaining 4% by feces).

11. Cell membrane penetration due to its tiny nanoneedle tubular structure

12. Open ends on both sides of CNTs make the inner surface accessible and further incorporation of bioactives within the tubes

13. Longer inner volume for endohedral filling relative to diameter.

14. High mechanical strength, thermal conductivity, superconductivity metallic or semi-metallic behavior.

15. Rare retention of well functionalized CNTs (f-CNTs) in reticuloendothelial system (RES) due to small size (<1μm).

Disadvantages of CNTs:

Apart from the various advantages some drawbacks are also associated with CNTs as given below:

1. Low aqueous solubility in organic or non-organic solvents.

2. Pristine CNTs exhibit some toxicity, hence un-suitable for drug delivery.

3. Bundling/aggregation phenomena.

4. Accumulation in liver.

Limitations of CNTs:

Apart from having numerous applications CNTs also have certain limitations:

1. CNTs are not soluble in most of the solvents and their incompatibility in biological milieu restricts their use in medical science.

2. It is almost impossible to produce structurally and chemically reproducible batches of CNTs with almost identical characters, so batch to batch variation in properties may take place.

3. Difficulty in maintaining high quality and purity standards¹².

Applications of CNTs:

a. Carrier for drug delivery:

Many researchers have contributed in proving the effectiveness of CNTs as a possible carrier for drug delivery systems¹³. Amphotericin B (an antifungal drug), when incorporated with carbon nanotubes, reported enhanced targeting¹⁴. Cisplatin (anticancer drug), when incorporated with oxidized SWNHs, have reported to slow down the delivery of cisplatin in aqueous milieu, which increases the residence time of drug in the liver, which has been reported to be effective in terminating the growth of human lung cancer cell¹⁵. Polyphosphazene platinum, an anticancer drug when given assimilated into nanotubes showed increased distribution, permeability and retention in the brain because of guarded lipophilicity of nanotubes. Doxorubicin, an antibiotic when given assimilated into nanotubes showed increased intracellular penetration. Oral Erythropoietin (EPO) administration has been made possible because of CNT- based carrier system, which was not possible earlier due to the instability of EPO in the gastric environment. The gelatin- CNT mixture (hydrogel) has been utilized as a potential carrier system for biomedical. CNTs can also be utilized as lubricant and glidant in pharmaceutical industries due to sliding nature of graphite layers bound with week Vander wall force¹⁶.

b. In genetic engineering:

In genetic engineering, CNTs and CNHs are used to manipulate genes and atoms in the development of bioimaging genomes, proteomics, and tissue engineering. The unwound DNA (single stranded) winds around SWNT by connecting its specific nucleotides and causes a change in its electrostatic property. This creates its potential application in diagnostics (polymerase chain reaction) and in therapeutics. Wrapping of carbon nanotubes by single-stranded DNA was discovered to be sequence-dependent, and hence can be used in DNA analysis¹⁷.

c. Biomedical applications:

Bianco et al.¹⁸ have prepared soluble CNTs and have covalently linked biologically active peptides with them. This was established for viral protein VP1 of FMDV exhibiting immunogenicity and eliciting an antibody response. In chemotherapy, drug entrapped nanotubes attack directly on viral ulcers and kill viruses. No antibodies were produced against the CNT backbone alone, suggesting that the nanotubes do not possess fundamental immunogenicity. The combination of all the described features of the vaccine system with the actuality that the capacities of the anti-peptide antibodies to neutralize FMDV have been enhanced has indicated that CNT can have a valuable part in the making of novel and effective vaccines¹⁹.

d. Artificial implants:

CNTs can be utilized as artificial implants without the problem of any host body rejection reaction. Normally host body shows rejection reaction for implants with post administration pain but when CNHs and CNTs have used incorporation with proteins and amino acids they successfully avoid all rejection reaction. This approach is being utilized with calcium filled CNTs, which can act as a bone substitute²⁰.

e. Preservatives:

CNTs and CNHs are having antioxidant properties. So they can be utilized for the preservation of drugs which are prone to oxidation. Their antioxidant properties are being employed in anti-aging cosmetics with zinc oxide as sunscreen to prevent oxidation of important skin components.

f. Diagnostic tool:

Nanotubes have a specific property of showing fluorescence when incorporated with any biomolecule. Therefore protein-encapsulated or protein/enzyme-filled nanotubes have fluorescent properties which can be utilized as implantable biosensors. For diagnostic purposes, CNTs can also be incorporated with magnetic materials, radioisotope enzymes which can be utilized as biosensors²¹.

g. CNTs role in cancer therapy:

Many studies investigated that CNT was used for the cellular adsorption²².Therefore, the diffusion of nanotubes interred and crossed cell membranes via an energy-independent non-endocytotic process. There are many fabricated neon drug target have been purposed for the folate receptors²³.

h. Magnetic nanoparticles assembled CNTs:

From the long-timedecades, nanoparticles have been used for the many targets. MagneticCNTs have also showed encouraging outcomes as a MRI difference agent with elevated nuclear magnetic resonance relaxivities, catalysisand little cytotoxicity. CNTs engaged more professionally in bioimagingor biomedical applications^24-28.

Classification of CNTs:

CNTs are classified into single-walled carbon nanotube, double-walled carbon nanotube, and multi-walled carbon nanotube according to the rolling layers of graphene sheets^29-31.

The tubular cylindrical CNTs have been classified into following four categories:

1. Single-walled Carbon Nanotubes (SWCNTs):

Single-walled carbon nanotubes (SWCNTs) were synthesized in 1993³². The milestone discovery of CNTs has opened new frontiers in the field of nanoscience, nanotechnology and nanomedicines. SWCNTs are characterized by the presence of single graphitic sheet cappedat both ends in a hemispherical arrangement of carbon networks. SWCNTs have diameter range from 0.4 to 3.0 nm and length 20 to 1000 nm³³. SWCNTs consist of a single cylindrical carbon layer with a diameter in the range of 0.4-2 nm, depending on the temperature at which they have been synthesized. It was found that the higher the growth temperature larger is the diameter of CNTs^34-37.

2. Double-walled Carbon Nanotubes (DWCNTs):

DWCNTs are another type of CNTs that resemble SWCNTs due to similar morphology. DWCNTs consist of exactly two concentric cylindrical layers³⁸.

3. Triple-walled Carbon Nanotubes (TWCNTs):

TWCNTs are characterized by the presence of three walls³⁹.

4. Multi-walled Carbon Nanotubes (MWCNTs):

The CNTs were discovered earlier by Bacon in 1960, while the first successful synthesis of multi-walled carbon nanotubes (MWCNTs) was witnessed by the TEM microphotograph of a Japanese Microscopist, Sumio Iijima. MWCNTs consist of 2-10 concentric cylindrical layers of graphene shell shaving diameter range from 1.4 to 100 nm, and length range from 1 to 50μm^40-44. The various types of carbon nanotubes.

Fig. no.1: Various types of carbon nanotubes: (a) Single-walled, (b) Double-walled, (c)Triple-walled, and (d) Multi-walled carbon nanotubes.]

Table no.1: Comparative Study of SWNTs and SWNTs

Sr. No	SWNTs	MWNTs
1	Discovered by Donald bethune, in 1993	Discovered by SumioIijima, in 1991
2	SWNTs have their outer diameter in the range 0.6-2.4nm.	MWNTs generally have their outer diameter in the range of 2.5-100 nm.
3	Made by rolling single layer of grapheme	Made by rolling multiple layers of graphene with an inter layer separation of about 0.3nm.
4	Catalyst is required for production	Can be produced without catalyst
5	Bulk synthesis is difficult since it requires proper control over growth and atmospheric conditions.	Bulk synthesis is easy.
6	Purity is poor	Purity is high
7	Chances of defect are more during functionalization.	Chances are less but once happened it is difficult to improve.
8	Fewer conglomerations in body.	More conglomerations in body.
9	Characterization and evaluation is easy	It has very complicated structure
10	It can be easily tangled and more flexible.	It cannot be easily tangled.

Functionalization CNTs:

The pristine CNTs are inherently hydrophobic in all kind of solvents or biological milieu. In order to utilize their full promising potential in biological systems; CNTs can be chemically engineered by the attachment of different functionalities. The surface modifications, performed to overcome the major limitations associated with nanotubes are referred as functionalization⁴⁵.

Fig. No. 2: Functionalization CNTs

Non covalent functionalization:

Non covalent functionalization involves Van der Waals interactions, π–π interactions, and hydrophobic interactions of biocompatible functional groups with the surface of the CNT. One of the main advantages of this type of bonding is the minimal damage caused to the CNT surface. It has been suggested that noncovalent attachment preserves the aromatic structure and thus the electronic characteristics of CNTs. On the other hand, because noncovalent bonding provides a weak force between the functional group and the CNT, it is not suitable for targeted drug delivery applications⁴⁶.

Covalent functionalization:

Covalent binding of biocompatible groups to the surface of the CNT is another method of functionalization. Using this method, the surface of the CNT can be modified by different techniques, creating a suitable platform on the surface of these materials, enabling covalent attachment of biocompatible groups to the surface of CNTs. Oxidation of CNTs using strong acids is a method commonly used for generating covalent functionalization. Briefly, concentrated nitric acid, concentrated sulphuric acid, and CNTs are sonicated and heated. This process allows for side-wall covalent functionalization, and carboxylic acid groups would be attached, rendering CNTs water-soluble⁴⁷.

Fig No. 3: Carbon nanotubes (CNT) before and after oxidization using a combinationof nitric and sulfuric acid. This method resulted in chemical modifications of carbon nanotubes and formation of carboxylate groups on the surface.

Figure no.3 shows a transmission electron microscopic CNT image before and after oxidization using a combination of nitric and sulfuric acid. These modifications would provide a suitable platform for the covalent attachment of biocompatible functional groups to the surface of the CNT, and the presence of a carboxylic group can improve CNT biocompatibility⁴⁸.

Cancer detection and diagnosis:

The various properties of CNTs can be manipulated to create a variety of components that can be applicable in a nanosensor and can be useful as biomarkers and detectors. CNTs can be used in two ways as effective cancer combatants: First is nanosensor in which identifiers and biomarkers are used to detect cancer. Second is drug carriers in which sensors, capsules are utilized for the transfer of drug in our body. CNT-based nanosensors consist of sensing units, nanoactuators, nanotransistors, nanoantennas, storage units, powerunits. The sensing units of nanosensors can beused to monitor the level of a specific substance inthe body. Different nanosensors distributed throughout the body defining the human body nanosensor network can be used for the detectionof chemical components like sodium, glucose, Various health problems like cholesterol, blood pressure and the presence of potential diseases inthe form of cancer markers, foreign bodies can be detected via nanosensors in cancer detection and diagnosis can be used as tumor detectors and image sensors. Tumor markers are used to recognize, diagnose, and manage some types of cancer. Tumor marker levels may be measured before treatment to help doctors plan the proper therapy. In some types of cancer, the level of a tumor marker reflects the stage (extent) of thedisease and the patient’s outcome or course of disease. Tumor markers may also be measured eriodically during cancer therapy. A drop in the level of a tumor marker or a return to the marker’s normal level may demonstrate that the cancer is responding to treatment, whereas no change or an increase may indicate that the cancer is not responding.” A large number of tumor markers a recurrently being identified for a wide range of cancer types such as such as alpha-fetoprotein (AFP) for liver cancer and germ-cell tumors, Beta-2-microglobulin (B2M) for leukemia and some lymphomas, prostate specific antigen (PSA) for prostate cancer, and HE4 for ovarian cancer. Since CNTs exhibit distinctive electronic, mechanical andthermal properties, they have been proposed as a promising tool for detecting the expression of evocative biological molecules at early stage of cancer⁴⁹.

Drug delivery using CNTs:

CNTs have been scrutinized as potential nanocarriers for the delivery of drugs, genes, and proteins. Nano sensors as drug-delivery systems can overcome problems associated in the case of free drugs, such as limited solubility, poor biodistribution, shortage of selectivity, adverse pharmacokinetics, and healthy tissue damage. Nanovectors and nanoactuators can be used to release a specific drug in unreachable positions ofour body⁵⁰. CNTs have been explored as novel drug delivery vehicles with low toxicity and immunogenicity. Chemotherapeutic agents are often compromised by their systemic toxicity due to lack of selectivity. In addition, limited solubility, poor distribution among cells, inability of drugs to cross cellular barriers, and especially a shortage of clinical procedures for overcoming multi drug resistant (MDR) cancer. These all factors limit the chemotherapeutic agents in cancer therapy. Functionalized CNTs can cross the cellular barriers by endocytosis or other mechanisms⁵¹. When used in antitumor chemotherapy, the high surface area of CNTs allows for efficient loading of chemotherapy drugs. For this purpose a technique named as SWNT based tumor-targeted drug delivery systems (DDS) have been developed which consist of three parts: functionalized SWNTs, tumor focusing ligands and anticancer drugs. Cancer cells over express folic acid (FA) receptors and several research groups have plotted nanocarriers with engineered surfaces to which FA derivatives can be attached. Nonspherical nanocarriers (e.g., CNTs) have been reported to be retained in the lymph nodes forlonger periods of time in contrast to spherical nanocarriers (e.g., liposomes). Thus, CNTs might be used for targeting lymph node cancers⁵². In thesestudies, magnetic nanoparticles containing the anticancer cisplatin were entrapped into folic-acid functionalized MWNTs. An exterior magnet as employed to drag the nanotubes to the lymph nodes where the drug was shown to be delivered over several days and the tumor to be selectively inhibited. The magnetic properties of the nanotube scan be used to prevent cancerous cells from migrating to other parts of the body to move them to less dangerous places in the body. Also, these magnetic properties can be used in combination with the carbon nanotube’s ability to interact with bio molecules to move certain cancer fighting drugs through the body⁵³. By attaching a peptide that is specifically attracted to tumor cells to the SWNTs, they can navigate themselves to the tumor cells. Once at the tumor, the amphilic nature of the carbon nanotube permits them to be swallowed up by the cells through there permeable membranes and the drugs are released into the cells which kills them. The large surface areas of SWNTs (up to 2600 m²/g) permits large quantities of cancer fighting drugs, like doxorubicin, to be stored in the SWNTs and released to kill as many cancerous cells^54-58.

Fig no.4: Drug Delivery in Cancer Cells

CONCLUSION:

CNT's properties and characteristics are still being extensively studied, and scientists have barely begun to explore structural potential. They will move via membranes, deep into the cell, bringing pharmaceutical drugs, vaccines and nucleic acids to previously unattainable targets. Overall, recent CNT studies have shown a very positive glimpse of what lies ahead for medicines in the future. Multiwalled carbon nanotubes is used for the detection of cancer as well as for treatment. There are several obstacles yet to be addressed before this class of optical biosensors can be used in a clinical environment, including the stigma surrounding its biocompatibility. CNT should be considered in the same way as other biopersistent fibers in workplace risk assessments which suggest similar control and assessment approaches until better knowledge becomes accessible. Difficulties in applying PCOM methods, however, mean that assessment based on electron microscopy should be strongly taken into consideration. There is obviously a need for more studies to gain insight into the mechanisms of these adverse effects and the best ways to test CNT in the air to protect those exposed to this new content.

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Received on 12.08.2020 Modified on 31.08.2020

Res. J. Pharma. Dosage Forms and Tech.2020; 12(4):301-307.

DOI: 10.5958/0975-4377.2020.00050.6