INTRODUCTION:

Nontechnology ("nanotech") is the intersection of matter at atomic, atomic and supermallicular scales. The most detailed, detailed description of nanotechnology is the mention of specific technological goals of using atoms and atoms to produce macro-scale products, which are now also called nuclear nanotechnology. A more generalized description of nanotechnology was then established by the National Nanotechnology Initiative, which defined Nano technology as the goal of detecting at least one dimension 1 to 100 nanometers. Due to this definition, quantum mechanical effect is important in this quantum-ralam scale and hence the definition has been diverted from a particular technical objective to the research category with all types of research and technology which is related to the specific properties of the substance below the given size threshold. Therefore it is common to see "Nanotechnologies" and "Nanoscale Technologies" as a plural form to refer to general property size searches and a wide range of applications. Due to the variety of potential applications (including industrial and military), the government has invested billions of dollars in Nano technology research. NanoTechnology, as defined by size, is naturally very broad, which includes various areas such as surface, science, organic chemistry, nuclear biology, semiconductor physics, energy storage, micro-manufacturing, nuclear engineering etc. Related research and applications are equally different from the traditional mechanics of physics with a new approach based on a nuclear self-assembly, from the development of new materials with the direct control of the molecular scale on the nanoscale dimensions.

Scientists currently discuss the future effects of Nano technology. Nanomedicine Nanomedicine, Nanotechnology, Biomaterials, Energy Generation and Consumer Products, Nanotechnology can be able to create new content and devices with large applications. On the other hand, nanotechnology raises issues like nanomaterials and the effect of the poisoning and environmental effects of the world economy and speculation about the world's day-to-day situations like many new technologies. There has been debate between the lawyers' groups and the government about whether these concerns require special regulation of nanotechnology.^[1]

The concept of nanotechnology plantation was first used in 1959 by renowned physicist Richard Feynman in his speech. There was plenty of room in the room below, in which he suggested the possibility of synthesis through the direct handling of molecules. The word "nano-technology" was first used by norio taniguchi in 1974, although it is not widely known.

Comparison of Nanomaterials Sizes

In this way, the rise of Nano technology as an area of the 1980s was due to the convergence of Draclear's theoretical and public work, which developed a conceptual framework for nano technology and made popular and high-visibility experimental progress, so that the potential for nuclear control was given extra attention. Regardless of the popularity of the 1980s, many nano technologies have been examined in various ways by the number of atomic mechanisms for making mechanical devices.

In the 1980s, due to the growth of nanotechnology in modern age, two major achievements were added. First, the scanning tunnel microscope in 1981, which provided unprecedented molecular visibility of independent nuclear and bonding, and successfully used to handle personal nuclear in 1989. Microsecope developer Gerd Binig and Henrik Rohrer have received the Nobel Prize at IBM Zurich Research Laboratory. Physics in 1986. Binnig, Quoute and Gabor discovered that atomic nuclear force microscope that year.

Secondly, in 1985, Harry Crito, Richard Smiley and Robert Curl invented the florence, who won the Nobel Prize in Chemistry in 1996. Initially the C60 was not described as nano technology; The related work related term used to describe related graphene tubes (called carbon nanobubes and occasionally called book tubes), which advocates possible applications for nanoscale electronics and devices.

In the early 2000s, this field attracted scientific, political and business attention, which led to both controversy and progress. There was a debate about the definitions and potential consequences of Nano Technologies, as mentioned in the report of the Royal Society for Nano Technology. Challenges have been raised about the probabilities of the applications of atomic nanotechnology advocates, which in 2001 and 2003 saw a public debate between Drexler and Smiley. Meanwhile, commercialization of products based on the progress of nanoscale technology has emerged. These products are limited to the large number of applications of nanomaterials and do not include molecular control of the substance. There are some examples in some examples, such as using carbon nanoparticles for antibacterial agents, nanoparticles-based transparent sunscreen, carbon fiber reinforcement using silica nanoparticles and carbon nanobews for stains-resistant cloth. In addition to the National Nanotechnology Initiative in the United States, governments in the nanotechnology research and funding have come forward to formalize the size-based definition of nano technology and funded research on nanoscale and research in Europe and research through European European Framework Program and Technical Development.^[1]

NanoParticles (NP) are one of the most commonly used nanotechnology-based products used in biomedicine that can be either organic or inorganic. Organic NP contains liposomes, dendrimer, chitosan, viruses, solid-lipid NP and polymeric NPs; Cancer diagnosis and therapy have increased their ability. Inefficient NPs include gold, silver, silica, magnetic particles, ceramic particles, quantum dots (QDs) and carbon particles. Inefficient NPs have also been identified as vector components for cancer treatment. Carbon Nanotebus (CNT) is hollow fiber carbon atoms that were found on the ground of the Arco-Burned Graphite. Their high percentage ratio, large surface area, rich pages have been tested for various applications, such as chemical efficiency and size stability in nano-scale, CNTs electromagnetic interference shielding, storage capacitors, shimble and structural reinforcement. In particular, CNTs are considered as the practical choice of materials in biomedicine applications and attractive candidates for biomeolyol and drug delivery are transporters. Indeed, through chemical implementation, CNT is used as a nano-carrier so that anticoagulants carry drugs, genes and proteins for chemotherapy. They are used for the use of agents for almost infrared (NIR) flow urosene emissions, photocostic (PA) imaging, Raman scattering and magnetic resonance imaging (MRI). That's why, in this review, we show prominently on CNT representative applications for cancer therapy and diagnosis, focusing on their work as a delivery vector and contrast precursors in biomedical imaging modalities. The different perspectives and related comparisons between CNT-based and polymeric NP-based applications described in this review are summarized in Table 1 and 2. Men and women account for 47.2% of all cancer in top five cancers; These can be cancerous, can be examined and / or treated early and can be treated. It can significantly reduce the mortality rate of this cancer. U.S. The skin cancer of all types is the most common form of cancer and the number of cases is increasing. Abnormal skin cells are uncontrolled growth. Rapid growth of tumor results is either mild (inefficient) or fatal (cancer).^[2]

Carbon nanobubb has been synthesized a long time for the production of catalyst actions of hydrocarbons from thermal demolition. Nanofilants, which were found in transmision electron microscopes micrograph published by Redushwitch et al in 1952, were the first evidence that nanobubants were made - they showed the inside cave.^[2,3]

A Graphical Representation of a Carbon Fullerene With 60 Carbon Atoms

A History of Carbon Nanotubes

Single-walled nanobews, geometrically, there is no oblation on tube diameter. However, the computation has shown that pushing the single-wall tube in a flattened two-layer ribbon is more favorable than ≈ 2.5 nm diameter rather than maintaining tubular morphology. On the other hand, it is easy to understand that SWNTs with a diameter of 0.4 nm have been successfully synthesized, although the radius of curvature, tension and energetic expenditure are small.

≈ 1.4 Energized sensitization has been achieved for nm, even when the high SWNT ensures the state of the product, even though the synthesis technique (based on at least solid carbon sources) is even rare diameter. There is no restriction on nanobube length which depends only on the limitations of preparation methods and the specific conditions used for synthesis (thermal grandiens, residences and so on). Experimental data is compatible with this statement because the terms of SWNT use high SWNT products. There is no restriction on nanobube length which depends only on the limitations of the preparation methods and the particular conditions used for synthesis (thermal grandiens, dwelling and some others).^[3]

To date, carbon nanobubes (CNT) are the most modified materials for which there is an international objective of increasing the industrial quantity due to their excellent properties used in many applications in medical or other potential applications. . In these compound parts, only small size and amazing optical, electric and magnetic properties have become increasingly popular in different areas. It is often described as a graphene sheet made in cylinder shape. To make sure, they are 12 nm diameter graffiti cylinders and finally include pentagon rings. Carbon nanobews has potential therapeutic applications in the field of drug delivery, diagnosis, and biosensing. Functionalized Carbon Nanotubes can also function as vaccine distribution system.



The basic concept is to connect the antigen to carbon nanotubesb, while retaining its structure, to respond to antibiotics with appropriate specifications. There is a hope that many applications of CNT will be examined in future due to the increased interest shown by Nano Technology Research community in this field.

Carbon Nanotebus (CNT) is a class of nanomaterials in which carbon atoms have two-dimensional hexagonal networks and they are connected in one direction so that the hollow cylinder is formed. Carbon nanobubes are one of the most comprehensive components of carbon, especially a square of floren, intermediate between goatball (closed conch) and graphene (flat sheets). In addition to these single-wall carbon nanotechnos (SWCNS), the name for the multi-wall (MWCNT) variants is also included with graphene-strips embedded in multiple layers, such as two or more nested nanobews or scraps. Personalized nanobules naturally align themselves into "ropes", which are compounded by relatively weak Van der Waals forces. Most of the other nanobugs of design are focused on carbon issues; So that the "carbon" qualifier remains in vogue and names are shortened by NT, SWNT and MWNT. ^[5]

Many of these materials and applications are focused on nuclei, whose girth increases from some graphene cells up to a few hundred cells, ie 0.25 to 25 nm diameter. Normal production method means carbon length is probably uncertain, but its diameter is much longer than normal. The nanobubes have been made half a meter long, which is 100,000,000:1  in diameter. For most purposes, carbon nanotubes can be considered to be infinite.

Thanks to their nonstructure and the strength of the bonds of atoms, these cylindrical carbon molecules have exceptional mechanical rigidity and tension strength. They also have medium chemical stability, high electrical conductivity and unusual thermal conductivity. These properties are expected to be valuable in most parts of the technology, such as electronics, optics, composite materials (space for carbon fiber or supplements), nano technology and other applications of literature.^[6] Long and narrow properties of carbon nanotechnology (for example, whether it is a metal or a semiconductor) are determined by its diameter and the "rolling" angle between the gravin nets and the cylinder axis. These parameters are limited so that the type of nanotubes can be described by two small complete ones. Most of the nanotube types are sparrows, which means that a tube can not rotate and its mirror image is transliterated to match it. In addition, carbon nanobugs are extremely symmetrical: In atomic nanotechnology, each atom is similar to any other atom. ^[7] The carbon nanotechnos (or in general, the fullerenes) are due to the exclusive power orbital hybridization, which can be the sp2 type between the essential carbon atoms. These bonds, which are grampeps, are more powerful than spawn impurities in Alcan and Diamond..^[7] Nanotube is a nanometer-scale tube-like structure. Nanobub is a type of nanoparticle and may be large enough to work as a pipe through which other nanoparticles can be transmitted or on the basis of the material, electrical conductor or electrical indicator can be used.

Carbon nanotube (CNT) and recent events have revolutionized new areas of nano technology and have contributed a lot to both basic science and engineering. For this reason, most developed countries have invested heavily in CNT and Nanomaterial research programs and found many interesting results. Because of this, more research has been done in this area, however, in the limited budget for all science projects, different countries are encouraged to spend better in this area. Countries have a scientific effect according to publications and research costs ^[8]. In the previous study, the CNT research and development period has been reported ^[9]. Carbon nanobubes are hollow cylinders made of graphite carbon atoms that are nanoscale (10-9 m), which are much smaller than the width of human hair. They are members of the CNT Fullyn Structural Family and their ending is limited to the sphere of the Bucky Ball Structure. Due to their nanosecisation, CNT has a broad range of electronic, thermal and structural properties that may vary with their length, diameter, and chilliiness. Show high value of CNT thermal conductivity. Young modules, large surface area, high current density, ballistic transport on submicron scales, and massless tariff fermion charge capability, which make them capable of expanding applications in a wide range of applications such as photovoltaic devices, sensors, transparent electrodes, super capacitors, and compounds. Prior to the introduction of carbon nanoteobes in 1976, Cronus' Morinobu Endo saw the hollow tubes of frozen graphite sheets synthesized by a chemical vapor-enhancing technique. ^[10] The first samples seen later can be known as single-wild carbon nanotubes (SWTS) ^[11]. A single scientist is the first three scientists to show images of nanotubes with walls. ^[12]

Due to their unique properties, their synthesis, purification and applications have become an attractive and interesting research area in the area of CNT Nano Technology. It has been proven that instead of using anti-synthesized CNTs, their properties increase the use of electrolytes, biology and energy storage if their pages are converted into chemical compounds or made functional. Carbon nanobubes are classified as multi-volume nanobubes (MWNTs) or single-light nanotubes (SWNTs). SWT is a single-rolided graphene and MWNT is a multi-rolled graphite. This paper offers a preview of combined carbon nanotube applications and their future challenges which provides information for further research.^[13]

CNTs are well-ordered, hollow, carbon graphic nanomaterials, with a range of properties. Some of these are high ratio, high surface area and ultra light weight. Generally, CNTs are classified as Single-Diwold (SWCNT) or Multivol (MWCNT). SWCNT creates a cylindrical carbon layer with a diameter of 0.4-2 nm, in accordance with the temperature it has been synthesized. It has been found that the high rise temperature gives a larger diameter. On the contrary, MWCNTs are made from most carbon straps, which are formed from the diameter of 1-3 nm for the inner tube and 2-100 nm for external tubes. Regarding the structure of two types of CNT, it has been stated that the original carbon arrangement of SWCNT is different from the MWCNT. SWCNT is composed of armchairs, zigzags, chirars or helical systems.

On the other hand, according to the arrangement of graphite sheets, the design of MWCNT can be divided into two types. One is the design of "Russian-doll" where the graphite sheets are concentrated and the other is a parchment-like model where a graphite journal is rotated around itself. CNT synthesis can be done by heating carbon black and graphite controlled flame. Using this method, the big problem is the irregularity of the size, size, mechanical strength, quality and accuracy of the CNT obtained. To avoid these problems, techniques such as electric arc discharge, laser ablation, or hydrocarbons have been suggested. Depending on the type of synthesis, different types of CNTs can be synthesized with different properties.

 

Proper fictitious technique can be used for the purpose of CNT. For example, if CNTs are required for electric vehicles, then SWCNT should be used instead of MWCNT. The reason for this is that SWCNT can be semiconductor or metallic if MWCNT is semiconductor. In drug delivery, SWCNTs are known to be more efficient than MWCNT. This is due to the one-dimensional structure of SWCNT and the effective area of the ultrahide surface due to the effective drug-loading capability. 26 has been shown that SWCNT-Antikensar Drug Complex has a time of blood circulation more than an antiksar drug. Drugs can be retained for a long time by the tumor cells through their own, increased permeability and retention effectiveness.

Various reports have suggested that once the activated SVCN drops in a specific area, gradually the body recedes backwards and eventually out of the stool. This suggests that SWCNS is the right candidate for drug delivery and there are supportive nanoplatores for future future cancer therapies. SWCNT can also be used for idling. Single-molecular fluorescence spectroscopy and Raman spectroscopy techniques can be used to analyze the fluorescence and structural properties of SWCNTs. Fluorescence spectroscopy of independent nanobubes with similar structures have emissions and line widths emitted by defects in local environments. MWCNT is more useful than SWCNT for thermal treatment of cancer. This is due to the fact that Mwgawats left the ultrasonic power after the display of Infrared Light almost. The release of this energy in tissues produces local temperatures, which can be exploited to destroy cancerous cells. MWCNT contains more electrons per particle, and there are more metallic nozzles than SWCNT, so they absorb nearby infrared radiation at a rapid distance. ^[14]

Carbon nanobews has unique properties due to their structure and size, which will be discussed in this section. Many recent research has been done using carbon nanotubes (CNT), for example, brain is using CNT as an electrical electrode for research, where scientists have bundled millions of CNTs in micron-sized threads. n Nanoprob, the unique properties of nanobub have also become very high in size, high conductivity and high mechanical strength. Such probes can be used in various applications such as drug delivery, nanoelectrodes, high resolution imaging, sensor and field emission equipment.

Nanotubes are a unique category of content because their properties depend on geometry, not just on their designs. Diameter, number of walls, length, charity, van der Waals forces and quality affect the properties and performance of nanotubes. This reliance on geometry creates scaling-up nanotubes so that bulk content is so much more challenging. 

Nanotubes are also unusual because they come together to make a bundle together. Nanobubes upper fiber content are fibrous compounds of nanobub and strands. The hope and dream of researchers around the world is that wide applications and engineering designs will change in nanotubes superfiber content. There are two types of carbon nanotubes, open end and close. Close tips are more efficient in field emissions compared to the open end, which is against what was expected. High Field Enhancement Components, because of an effective effective curvature of open-ended tubes. However, after testing the test, it is thought that other molecules like oxygen atoms connect to free dubling bonds at the end of the open tube, so the electrons do not emit so the fertile energy creates a localized electron state with lesser degree of energy.

Fabrication Methods:

Here is a basic summary of the processes used to fabricate nanotubes and the types of nanotubes produced.

Arc Discharge Process

A simple method designed to produce multi-walled nanotubes. One successful set-up uses a graphite (c-cathode) cathode and a Molybdenum (Mo) anode. An arc is created when the chamber is initially evacuated to 0.01kPa and then helium pumped in to increase the pressure to 25kPa, when the arc is ignited by contacting the electrodes. This is maintained for 1 second at an arc distance of 1mm using a current of 60A. The nanotubes are created on the C-cathode surface near the centre where several craters form. The number of tubes decreases with an increasing distance away from the craters.

Arc Discharge Set-up

Laser Ablation Process

Use to get higher purity single-walled nanotubes. The impurities that could be associated with nanotubes are:

1.	Amorphous carbon
2.	Graphite particles
3.	Catalysts
4.	Fullerenes
5.	Silicon and various hydrocarbons

The best-known conditions for this process are: using argon at 67kPa, a flow rate of ~3mm/s and a 25mm inner tube.

Laser Ablation Set-up.

The process works by having a 12mm diameter graphite target, containing 1 at. % of nickel and cobalt. The tube and target are both inside a 56mm tube, all seated in a 1473K furnace.

Two Nd (Neodymium) lasers are fired along the axis of the tube to ablate the target end with energies of 0.3J/laser. A plume is then produced and as it expands the temperature drops from the original 3000-4000K and visible emission decreases. The plume propagates upstream and carbon nanotubes are formed.

High Pressure Carbon Monoxide Process

Use to produce single-walled nanotubes, producing up to 450mg of SWNT an hour. The process involves flowing carbon-monoxide mixed with a small amount of Fe(CO)₅through a heated reactor. Products of the Fe(CO)₅ decomposition produce iron clusters in the gas phase where the nanotubes nucleate and grow. Normal conditions for this process are 450psi (30 atm) at 1050^oC and are described by the reaction of:

Chemical Vapour Deposition (CVD) Process

Produces both multi-walled nanotubes and single-walled nanotubes. This process has the advantage that SWNT can be grown at specific areas on the substrate at lower temperatures than other processes and with simpler equipment. However the SWNT vary with quality and have a large deviation in their diameter. The two catalysts used in this process are:

Catalyst A = 1mg iron nitrate seeds dissolved in 10ml isopropanol.

Catalyst B = 15ml methanol, 15mg aluminium oxide, 20mg FE(NO₃)₃·9H₂O and 5mg MoO₂(acac)_2.Once these are prepared and a silicon substrate predefined by an e-beam lithography or optical lithography, a drop of catalysts is placed on the substrate. These are then spun at 2000r.p.m. for 40 seconds and baked for 5 minutes at 150^oC, followed by a lift off. Growth of the nanotubes is then done in a quartz furnace at 750- 1000^oC (atmospheric pressure). During the heating and cooling of the furnace, a flash of argon is used to reduce the contamination of the materials. MWNT are formed at the lower temperatures of 750 to 850^oC and SWNT are predominant at 850 to 975^oC

Factors found to affect CNT toxicity

A list of factors that have been found to have an influence on the degree of toxicity of CNTs follows below:

· Concentration / dose of CNTs.

· SWCNTs or MWCNTs.

· Length of the tubes.

· Catalyst residues left over during synthesis or functionalization.

· Degree of aggregation.

· Oxidization.

· Functionalization.

The development of such a system is not dependent only on the identification of special biomarkers for neoplastic diseases but also on the constructing of a system for the biomarker-targeted delivery of therapeutic agents that avoid going into normal tissues, which remains a major challenge report, more emphasis is put on advancements made in the scientific aspect of CNTs and their production. Targeted drug delivery is a method of delivering the drug to the site of action in a concentration relatively higher than other parts of the body. Nanotubes are most useful as drug loaded carriers and when coupled with targeting lagans to increase the drug efficacy at the site of infection. The major critical stage in the targeted drug delivery involves finding a proper target for particular disease, finding a drug to treat that disease and finding the non-immunogenic, site specific drug carrier to enhance selective interaction with wit5h the tissue of interest.

Progress in CNT productions

A variety of production methods for CNTs are available, and now chemical modification, fictionalization, and characterization of individual CNTs are possible.

1. Microstructure variation

MWNTs were grown by spray pyrolysis of acetylene as the carbon source in the presence of Au–Co as catalyst precursors. A high yield of

network-shaped carbon nanotubes with further purification has been obtained under optimal conditions. The optimum synthesis parameters included a synthesis temperature of 700 °C, growth time of 30 min, and a flow rate of acetylene and hydrogen of 40 and 300 sccm, respectively.

2. CNT composites

CdS-decorated MWNTs as a material for new devices are reported. Cadmium Sulfide nanoparticles were successfully grown on MWNTs via a simple chemical reaction. The CdSMWNTs sample was afterwards characterized with SEM/TEM and X-ray Diffraction. The obtained images show clearly the decoration ofMWNTs by the CdS nanoparticles, and the XRD measurements indicate the CdS structure as a Zinc blend type.

3. Growth rate

Another important parameter in CNT production is the growth rate. Dense, vertically aligned multiwall carbon nanotubes were synthesized on TiN electrode layers for IR sensing applications. Microwave plasma-enhanced CVD and a Ni catalyst were used for nanotubes synthesis. Since the length of the CNTs influences sensor characteristics, they studied the effects of changing Ni and TiN thickness on the physical properties of the nanotubes.

4. Functionalized carbon nanotubes

The reactivity of p-toluenesulfonyl, methylsulfonyl and trimethylsilyl nitrene, derived from the corresponding azides, was studied towards SWCNT prepared by arc or high-pressure CO conversion methods. The functionalized SWCNTs were analyzed by Raman, IR, and VIS/NIR spectroscopy.

5. Catalyst effect

In a study, the decomposition of ethylene on an iron catalyst to obtain CNTs and their purification system is reported. That paper describes the preproduction and characterization of carbon nanotubes using ethylene as a carbon source and iron as a catalyst. An additional purification procedure of carbon nonmaterial is presented, and the purification was conducted in two stages. The effects of confinement in carbon nanotubes on Fischer-Tropsch (FT) activity, selectivity and lifetime of CNT supported iron catalysts are reported. A method was developed to control the position of the catalytic sites on either inner or outer surfaces of carbon nanotubes.

Advantages of Carbon nanotubes

1. Extremely small and lightweight, making them excellent replacement for metallic wires

2. Resources required to produce them are plentiful and many can be made with only a small amount of materials

3. They are resistant to temperature changes, meaning they fuction almost just as well as in extreme cold as they work in extreme heat.

4. Have been in the R & D phase for long time now meaning most of the kins have been worked out.

5. As a new technology, inventions have been pilling into these R&D companies, which will boost the economy

6. High electrical and thermal conductivity

7. Very high tensile strength

8. Highly flexible and elastic (~18% elongation before failure)

9. High aspect ratios

10. Good field emission

Disadvantages

1. Newer technology so not as much testing has been completed

2. Lower lifetime (1750 hours compared to 6000 hours for silicon tips)

3. Higher potentials required for field emission as the tubes are not so well localised so the extractor electrode must be further away.

4. Despite all the research, scientist still don’t understand exactly how they work

5. Extremely small, so are difficult to work with it

6. Currently the process is relatively expensive to produce the nanotubes.

7. Would be expensive to implement this new technology in and replace the older technology in all the places that we could.

8. At the rate this technology has been becoming obsolete, it may be a gamble to bet on this technology.

Factors found to affect CNT toxicity

A list of factors that have been found to have an influence on the degree of toxicity of CNTs follows below:

· Concentration / dose of CNTs.

· SWCNTs or MWCNTs.

· Length of the tubes.

· Catalyst residues left over during synthesis or functionalization.

· Degree of aggregation.

· Oxidization.

· Functionalization.

Methodology/ Material method

Method

Being one of the fundamental measures to be an expedient delivery system, drug loading is the process wherein active drugs are combined with the carriers to give the final form of the drug delivery system. CNTs are distinctly privileged from this aspect because their spherical shape and high surface area to volume ratio grant a tremendous potential to accommodate drugs. Besides, loading capacity can be improved through decorating hydrophilic or amphiphilic polymers on the surface, as a result of which some extra space is acquired. Another distinction of these nanomaterials is the fact that they are in position of carrying pharmaceutical agents through multiple ways, such as encapsulation inside the cavity, tethering on the surface upon functionalization, and adsorption on the wall or among the walls of CNTs. In overall, CNTs have been widely utilized as delivery system for many drugs because of these benefits

Functionalization of Carbon Nanotubes the Carbon Nanotubes were covalently functionalized by subjecting them to three types of treatments.

(a) Treatment with conc. Hydrochloric acid

This method simply purified the CNTs. In this method 500mg of MWNCTs was placed in a 500 ml round bottom flask and 200 ml of HCl was added. The mixture was stirred using magnetic stirrer for 2 h, then diluted in water, filtered, washed with ultrapure water and then dried in vacuum at 400C overnight.

(b) Initial acidic Treatment

Followed by treatment with hydrochloric acid it was used to produce covalently functionalized MWCNTs. In this method the initial acidic treatment with nitric acid and sulphuric acid produced oxidized MWCNTs and then the treatment with hydrochloric acid produced carboxylated MWCNTs. 500 mg of MWCNTs were added to a 200ml mixture of 98% H2SO4 and 65% HNO3 (V:V = 3:1) and agitated for 12 h at room temperature. The MCWNTs were thoroughly washed with ultrapure water and dispersed in HCl and refluxed for 24 h, then collected by filtration and washed with ultrapure water to neutral pH. The product was then dried in vacuum at 400C overnight.

(c) Initial basic treatment

Followed by treatment with hydrochloric acid it was used to produce covalently functionalized MWCNTs. In this method the initial basic treatment with ammonium hydroxide and hydrogen peroxide produced oxidized MWCNTs and then the treatment with hydrochloric acid produced carboxylated MWCNTs. 500mg of MWCNT was dispersed in 25 ml of the mixture of ammonium hydroxide (25 %) and hydrogen peroxide (30%) (V: V=1:1) in a 100 ml round Bottom flask equipped with a condenser and the dispersion was heated to 800C and kept for 5 h. After that, the resulting dispersion was diluted in water and filtered. Then the resulting residue was washed with ultrapure water up to neutral pH and the sample was dried in vacuum at 400C overnight.

Selection of the best method for functionalization:

This selection was made on the basis of dispersion stability. For this 10 mg of functionalized Nanotubes were dispersed into 10 ml of phosphate buffer solution pH 7.4 by sonication for 2 minutes and these dispersions were then kept in sealed vials, the dispersion stability was visually analyzed after a period of 15 days.

Covalent bonding

Covalent chemical bonding of polymer chains to CNTs results in strong chemical bonds between nanotubes and the attached molecule. Various covalent reactions have been developed to graft molecules based on their varying properties and can be further classified as Grafting to or Grafting from reactions, which involve the addition of preformed polymer chains or the polymerisation of monomers from surface derived initiators on CNTs, respectively. Both to and from methods involve reaction to the surface of CNT by functionalisation reactions. Molecules or polymer chains reacting with the surface of pristine, pre-functionalised or oxidised CNTs are the three main methods used to attach molecules covalently.

Non-covalent bonding

Non-covalent bonding of molecules to CNTs is generally the more widely used method of drug delivery according to the literature. An ideal non-covalently functionalised CNT should have specific properties; the more closely matched, the greater the usefulness in biological roles. This can be carried out by creating micelle-type structures where amphiphilic molecules are coated to the CNT. Another common form of functionalisation is π-π bonding achieved by stacking pyrene molecules onto the surface of the CNT. This type of bonding can also be applied to single strands of DNA by virtue of the aromatic DNA base units. This was shown to be unstable as it is cleaved by nucleases and consequently the biological applications are so far limited. Non-covalent bonding does not disrupt the π – network where, except for a shortening of length, the physical properties of the CNTs are essentially preserved, showing great promise for imaging and photothermal ablation.

Preparation of drug loaded carboxylated CNTs: The drug loaded CNTs were prepared by using three methods which are mentioned below:

a) Fusion Method: Physical mixtures of 6-MP (100 mg) and functionalized-CNTs with different weight proportions were prepared in accordance to the ratio in the formulationand heated above the melting point of the drug at 3300C (as determined by melting point apparatus using capillary tube method) for 5 min. After this initial heating, the mixture was vortexed for 1 min and returned to 3300C for 5 min. The process was then immediately transferred to a bath of ice water. The powders were kept at 400C for 24 h.

b) Incipient Wetness Impregnation Method: A concentrated solution of 6MP (100 mg in 10 ml) was prepared in two different solvents (0.1N NaOH and ethanol: water 1:9) in accordance to the ratio in the formulation (Table 1) and this solution was added to carboxylated-CNTs. Continuous agitation, using ultrasonicator, was applied during the addition of the 6MP solution. The solution thus obtained was stirred for 2 hrs and then the dispersion obtained was filtered using vacuum filtration assembly fitted with membrane filter (0.5 μm, Sigma Aldrich), and then the residue was washed with ultrapure water. The products were dried at 400C for 24 hours.

c) Solvent Method: A mixture of 6MP (100 mg) and carboxylated-CNTs was prepared in accordance to the ratio in the formulation (Table 1) and added to 10 mL of two different solvents 0.1N NaOH and ethanol: water (1:9). The solution obtained was agitated for 4 hrs using ultrasonicator, and dispersion was filtered using vacuum filtration assembly fitted with membrane filter (0.45 μm; Sigma Aldrich, Germany) and the residue was washed with ultrapure water. The product was finally dried at 400C for 24 h.

1. Purification and acid oxidation:

Single walled carbon nanotubes were first purified by incubation in concentrated nitric acid at 95 °C for 2 h. In a second step, the sample was oxidized by incubation in a 3:1 mixture of concentrated nitric and sulfuric acid at 95 °C for 2 h. then the oxidized SWCNTs were washed by vacuum-assisted filtration using 0.2 μm polycarbonate filters. Until the eluate was clear and of neutral pH. Oxidation debris was removed by washing with sodium hydroxide (0.01 M) and three centrifugation steps at 75,000g were performed to remove big agglomerates and bundles. The concentration of the resulting dispersion was determined gravimetrically by filtering a known volume of oxSWCNT suspension using 0.2μm polycarbonate filters, drying the filter for 1 h at 110 °C, and weighing the amount of oxSWCNTs on the filter paper using a microbalance. Finally, the concentration was adjusted to 200 μg/mL.

2. Sample characterization

The obtained oxidized Single walled carbon nantubes were then characterized by atomic force microscopy (AFM), UV/vis absorption spectroscopy and Raman spectroscopy. For AFM sample preparation, oxSWCNTs were diluted with water to obtain a concentration of 10 μg/mL and a droplet was placed onto a freshly cleaved mica substrate (1 cm2) and dried in air. AFM measurements were performed using a PicoPlus instrument. Data analysis was carried out using “Gwyddion 2.9”, a free SPM data visualization and imaging tool released under the GNU General Public License. UV/vis absorption spectroscopy was carried out using a Helios Alpha UV/Vis spectrophotometer from Thermo Scientific. Raman spectroscopy measurements were performed using a Renishaw microRaman instrument at an excitation wavelength of 785 nm. Acid-base titration to determine the number of total acidic sites was carried out as described in the supporting information.

3. Drug release over time at different conditions

In order to measure drug release over time at different conditions, the drug were loaded onto oxSWCNTs functionalised with branched PEG 2500- NH2 at a drug/CNT weight ratio of 1:2, which guarantees 100% drug binding. After incubation over night at 4 °C, the samples were mixed with 100 mM sodium phosphate buffer pH 5.5/7.4 or cellular growth medium (MEM, phenol red-free) and incubated at 37 °C for 24 h, 48 h, or 72 h. After each time point, 500 μL of each sample were filtered using 300 kDa Pall Nanosep® centrifugal devices and the amount of drug in the eluates analysed by UV/vis absorption spectroscopy (at 479 nm for doxorubicin or at 608 nm for mitoxantrone).

4. Confocal microscopy

Cultured cells in single cell suspension were seeded into 24-well tissue culture plates containing cover slips at a density of 75,000 cells per well. After an incubation period of 24 h under standard tissue culture conditions, the medium in the wells was replaced with a 1:1 mixture of the respective nanotube sample in cell medium and the plate incubated for 1 h, 3h, or 5 h at 37 °C. Afterwards, the medium was aspirated off, the cells washed twice with PBS and incubated with 4% formaldehyde for 10 min. Next, ToPro3 nuclear stain in a 1:10,000 dilution (1 mL) was added to each well and the plate left to incubate for 10 min. Finally, after abundant washing, the cover slips were mounted onto glass slides using VECTASHIELD® fluorescent mounting medium and sealed with nail polish. Confocal microscopy was carried out using a Zeiss LSM 510 confocal microscope in multichannel mode. Fluorescein-labeled structures were excited at 488 nm and emission detected at 500- 550 nm, doxorubicin excited at 488 nm and detected at 650-710 nm, and TOPRO excited at 633 nm and detected at 650-710 nm.

Product Evaluation/ Standardization/ Characterization of Nanotubes by Application of critical Parameters

Evaluation

In-Vitro evaluation.

1. Mechanical testing

1. Tensile test

All printed vascular conduits were soaked in the CaCl2 solution for 24 h in order to minimize the effect of residence time in the CaCl2 solution. Three different random segments for each sample were fabricated to evaluate mechanical characterization using a Biotense Perfusion Bioreactor (ADMET, Inc. Norwood, MA). The mechanical testing unit consisted of a linear actuator, sample grips, a bioreactor frame and a 250 g load cell. The load cell and closed-loop servo-controlled actuator can measure a maximum tensile load of 2 N and provide a stroke of 25 mm, respectively. Load-displacement data was recorded at 1 Hz through a data acquisition system (MTest Quattro System, ADMET, Inc. the samples were mounted in the grips between pieces of sandpaper (to minimize Slip), leaving a sample gauge length of 6-8 mm for mechanical loading. The vascular 17 conduits were loaded to failure at a rate of 10 mm min ˉ¹. Samples that failed at the edge of grips were discarded from analysis.

2. Burst pressure

The estimated burst pressure (BP) was calculated from ultimate tensile strength (UTS) measurements by rearranging the Laplace law for a pressurized thin-walled hollow cylinder, where BP is the estimated burst pressure (mmHg), T represents the wall thickness (μm) of conduits, and LD represents the unpressurized lumen diameter (μm)

3. Perfusion test

The main function of vascular conduits is to provide nutrients and oxygen to surrounding tissues as well as take away the waste. In order to develop vascular conduits biomimetically, it is essential to evaluate the permeability capability of the engineered vascular conduits. Thus, a perfusion system, which consisted of a media reservoir, a peristaltic pump (ISMATEC, IDEX Corporation, Glattbrugg Switzerland) and a perfusion chamber (with a cover to prevent evaporation), was developed. A peristaltic pump was selected to provide pulsatile media flow, and cell media was perfused from the media reservoir, through the pump and the vascular conduit, and pumped back to the media reservoir. Gauge 25 (0.25 mm I.D., 0.52 mm O.D.) needles were inserted into the fabricated vascular conduits. Surgery clips were used to fix the vascular conduits during perfusion without leakage. Several combinations of fabrication parameters (i.e., composite dispensing pressure and CaCI2 dispensing rate) were tested to obtain the ideal core diameter to obtain a best match for a gauge 25 needle. The criteria for the fabrication parameter selection was that the lumen diameter of the dispensed vascular conduit should be exactly same as the size of a 25 gauge needle’s outer diameter, such that the needle could be inserted into the vascular conduit tightly and no leakage should be allowed at the connection of the conduit and the needle.

4. Dehydration and swelling studies

All printed vascular conduits were soaked in 4% CaCl2 for 30 minutes, hence all the conduits were fully cross-linked. For the swelling and degradation studies, we first needed to dehydrate the vascular conduits by having them at room temperature for 4 days.

5. Dehydration study

The experiments were conducted for an alginate vascular conduit after dehydration in order to find out the dimensional characterization. Only alginate vascular conduit diameter was measured since the wall thickness and lumen section were not visible under microscope. No statistical significant difference was observed between groups.

6. Swelling and degradation studies

These studies were conducted to show how MWCNTs influence the alginate vascular conduit swelling and degradation properties.

7. Cell viability

The printing process caused some cell damage; quantitative red fluorescent labeled dead cells were observed from the fluorescence image along the conduit channel wall. Compared with the initial control, cell viability was decreased from 75.6 ± 0.04% to 53.3 ± 0.01% for plain alginate vascular conduits, and from 72.2 ± 0.02% to 53.9 ± 0.01% for MWCNT reinforced upon printing

8. Tissue histology

The long-term biocompatibility of vascular conduits with MWCNT reinforcement was evaluated through histochemistry study by checking cell morphology and tissuespecific ECM formation. The tissue histology study showed different characteristics between MWCNT-free (the positive control group) and MWCNT-reinforced conduits. In MWCNT-reinforced conduits, damaged cells within the conduit wall can be easily identified by broken cell nuclei.

9. Cell cultures and cell culture tests

Cell cultures: PC 12 neuronal cell line was cultured in RPMI 1640 media (Sigma Aldrich) supplemented with 5% fetal bovine serum, 10% horse serum(both heat inactivated), and 1% penicillin/streptomycin. Cells were grown in suspension in an incubator with humidified atmosphere with 5% CO2 at 37°C.

Cellular uptake: For the translocation test, cell suspensions were prepared at a final concentration of 10,000 cells/ml in 1ml media containing FITC labelled riluzole loaded CNTs. The concentrations of MWCNT-riluzole-FITC were 0.002, 0.02 and 0.2 mg/ml. Untreated cells and unconjugated FITC were used as controls. The cells were incubated at 37°C for 1 hour. After incubation the cells were washed twice in phosphate buffered saline (PBS), resuspended in 300 μl PBS, loaded on to a 96 well plate and analyzed with the victor X3 UV-vis mode at a wavelength of 492 nm. The distribution of FITC was given in terms of absorbance units. The media and untreated cells were used as controls.

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Received on 14.10.2019 Accepted on 02.12.2019

Int. J. Tech. 2019; 9(2):54-66.

DOI: 10.5958/2231-3915.2019.00012.9