Fullerenes, their Properties, Medical Applications of them, and their Role in Drug Delivery

Fullerenes, their Properties, Medical Applications of them, and their Role in Drug Delivery

Fullerenes, their Properties and Production

Abstract

In 1985, three scientists produced a fullerene, named C60, in fewer quantities by vaporizing the graphite in the arc or the laser beam or with an electric current in a low-pressure argon or helium atmosphere. Since then, they have gained significant attention in different fields. The newly found molecule was named by these scientists after Richard Buckminster Fuller, in 1967, he made a dome of shape like the carbon cluster, whereas, in 1970, the possibility of fullerenes existence was predicted. Later, it’s observed that fullerenes occur in interstellar dust and also in Earth's geological formations, only in the ppm-range. Fullerenes, also known as buckyballs, are carbon's new allotrope and their appearance also resembles soccer balls. Fullerenes consist out of 20 hexagons and 12 pentagons with a carbon atom in each edge of this lattice structure. Fullerenes also exist in different stones, naturally. Earlier, on the cave walls, they were deposited as soot. In 1990, fullerenes were produced on a larger scale for the first time. In this article, the making of fullerene is explained properly, and the fact that fullerenes unique structure joined with immense derivatization makes them a possible agent for many therapeutic applications, including free radical scavenger, anti-HIV- protease activity, antimicrobial action, photodynamic DNA cleavage, and their use as the diagnostic agents and in biomedicine.

Introduction

Fullerene is an allotrope of carbon with molecules that consist of carbon atoms joined by double and single bonds to make a partially closed or closed mesh, with fused rings of 5 to 7 atoms. Carbon's allotropes were limited to graphite, diamond, etc. but then, carbon's third form called fullerenes got discovered. An experiment was done in which laser irradiation vaporizes graphite's surface into plasma containing free ions and atoms. Due to the collision with helium atoms, those free atoms and ions were chilled down. Clusters containing numerous amount of carbon atoms were made because of the collision, ranging in size from 20 carbon molecules and larger. It's also discovered that Carbon 60 molecules concentration was increased by permitting the plasma to react longer, a mass spectrometer examines the clusters, and it was seen that clusters having 70 to 60 carbon atoms dominated, making up Carbon 60, 40-times more as compared to carbon's other structures. These were the most studied fullerenes. In the beginning, only less than 10-15 g was prepared, but in 1990, new preparative methods for high yielding of fullerenes were developed. Fullerenes got named after an architect, Richard Buckminster Fuller, who made a so-called geodesic dome structure of hexagonal and pentagonal cells in 1967, which is very similar to the fullerene molecules. Fullerenes exist in nature, particularly where high energy and carbon exist and close to volcano craters. They are even formed when gas burns in the household cooker, in regular lighter's flame or in places of ancient carbon rock accumulation. In 1999, C60 fullerenes were found in schungite.

Stereographic projection of C60 fullerene[1>. (Note: To visualize the 3D image, the picture must be held about 15 cm from the eyes and the eyes must focus at infinity).

Figure 1: Stereographic projection of C60 fullerene[1]. (Note: To visualize the 3D image, the picture must be held about 15 cm from the eyes and the eyes must focus at infinity).

The C60 molecule showing single bonds (a5) and double bonds (a6)

Figure 2: The C60 molecule showing single bonds (a5) and double bonds (a6) [2].

Fullerenes are not self-inflammable and mostly yellow in color. Under ignition source influence, fullerenes are flammable (dust explosion). Fullerenes are the only carbon modifications that are not soluble in water, but soluble in organic solvents. Hydrated C60 fullerene helps an organism in returning to its "normal condition" in the case of any negative changes, and it does that for the maintenance and restoration of those structures it has generated as a matrix in the process of life's origin. The C60 fullerenes are the smallest ones like the buckyball, C70 is the next larger fullerene having the shape of a rugby ball. Nowadays, most of Carbon 60 is synthesized in the laboratory by treating soot with organic solvents, to extract carbon 60. The soot is made between two carbon electrodes by using an electric arc. Extracted Carbon 60 can be separated and then purified using chromatography, along with other fullerenes. C60 molecules are incorporated into frames and shafts to achieve very thin-walled and lightweight, robust structures of carbon. These are highly used in medical fields and have various applications in biomedicine.

Properties

Topology

Schlegel diagrams are usually used for viewing closed-shell fullerenes 3D structure. A closed fullerene of the sphere-like shell should have some heptagon or pentagon cycles at-least. Open fullerenes, e.g. graphene and carbon nanotubes, consist entirely of rings of the hexagon. In theory, a long nanotube with joined ends forms a torus-like closed sheet that could also consist entirely of hexagons.

Bonding

Three neighbors were connected with each carbon atom, so it is usual to label those bonds as a mixture of single and double covalent bonds.

Encapsulation

Endohedral fullerenes are one of the fullerene derivatives having small molecules or ions incorporated inside the cage atoms.

Aromaticity

Scientists have increased the reactivity of the fullerene by assigning active groups to their surfaces. Super aromaticity is not exhibited by fullerenes. C60 diameter is 0.7nm, and, is just like a soccer ball, due to which, it is usually called a "soccer ball molecule". Comparing one such molecule's dimensions with the Earth, one finds, that the soccer ball-fullerene relation resembles the relation between the Earth and soccer ball. Fullerenes have a very low density of 1,68 g/cm³ in comparison with, graphite having a density of 2,1-2,3 g/cm³, or diamond having a density of 3,51 g/cm³, that is because of their hollow ball shape. C60 is the smallest stable fullerene because of the two pentagons that are side by side. C60 molecule's important property is high symmetry because there are 120 symmetrical operations, like rotation around the axis and reflection in a plane, which maps the molecule onto itself. Bond lengths are of 2 types in the fullerene: C5-C6 double bonds (hexagons) and C5-C5 single bonds (pentagons). Each C atom makes bond via sp2 hybridization with three other adjacent atoms.

Fullerene Products

A C60 molecule has a diameter of 7 Å. C60 molecules form a solid of weakly bound molecules together. Fullerites are fullerenes' crystalline state. It looks like a yellow powder, but after dissolving in toluene, it turns to pink. The molecule is quite stable, chemically. The temperature of over 1000°C is required to break the balls. In the absence of air, fullerenes can transform into graphite when heated up to 1500C. C70 looks more like a rugby ball and has 25 hexagons. When hexagons are removed or added from the structure of the soccer ball, the roundness begins to lose. Giant fullerenes appear in the shape of a pentagon. Smaller fullerenes appear as asteroids. Carbon 60 is the most stable one. A loss of stability comes with the loss of roundness. Other than C60 and C78, C70, C86, C76 C84, have been separated and discussed in detail. Carbon disulphide, toluene, and xylene are good solvents.

Applications

See below application in pharmaceutics to get a detailed information

Fullerenes are hollow, inert, and indefinitely modifiable. They are not absorbed in water-soluble form when given orally, but they get quickly distributed to various tissues of the body when given through IV. They are excreted by the kidney without any change. Fullerenes are widely used for many biomedical applications like photodynamic therapy, and gene and drug delivery, etc.

Click Images to Read More about Fullerenes

Analyzed: Enormous Sphere Fullerene Types of Fullerenes and their specific uses (C60, C70, Fullerenols) Applications of Fullerenes

Tumor research

In cancer research, HeLa cells were used in recent experiments. This includes the production of new photosensitizers which get absorbed by cancer cells and still trigger the death of the cell. To prevent damage to the cell, the body shouldn't contain a new photosensitizer in it for long. When cancer cells absorb them, and they get exposed to light radiation, creating reactive oxygen that damages the lipids, proteins, and DNA that makes up the cancer cell. The cellular level damage leads to the cancer cell going through apoptosis, which causes a reduction in tumor size. When the light radiation treatment ends, free radicals will be reabsorbed by the fullerenes to prevent tissue damage. The treatment may penetrate deeper into the body and be absorbed effectively by cancer cells in the near future.

Diagnostic applications

Endohedral metallofullerenes have metal ion fixed inside the cage of fullerene. Water solubilized forms are used as Magnetic Resonance Imaging (MRI) and X-ray contrast agents, and radiopharmaceuticals. One of these derivatives has been studied in detail as a radioactive tracer for diseased organ imaging and to kill the cancerous tumors. Inside the carbon shell, there is a stable radioactive metal that is very resistant to the body's metabolism. Metallo-fullerenes are not toxic, and they allow imaging of the circulatory system by staying in the body for at least an hour.

Anti-HIV activity

Wudl et al. hypothesized that Carbon60 has the almost same radius as of the cylinder which explains HIV-Protease active site, a chance exists for a strong hydrophobic interaction between the active site surfaces and C60 derivatives. HIV-Protease inhibition in C60 presence was explained through experimental observations and molecular modelling studies. Inactivation of virus assays proved fullerene derivatives' activity against HIV-2 and HIV-1.

DNA photo-cleavage

C60 derivatives cytotoxicity was mediated by its DNA cleaving capability. So, other usages of fullerenes are related to its easy photoexcitation, that's why Photodynamic compounds, which are fullerene-based, are being established for cancer treatment.

Free radical scavenger

Fullerene compounds have a unique cage structure, combines in the core with numerous conjugated double bonds, interacts with the biomolecules, and have avid reactivity with free radicals. Fullerene derivatives protective effect is explained in numerous systems, containing reduced injury on the ischemia-reperfusion intestine, protecting different types of cells from going through apoptosis, reducing the free radical level in organ perfusion, and neuroprotective effect. Derivatives of fullerene have shown good results in pre-toxicity studies. Also, both water and lipid-soluble derivatives are possible, and this point has increased their importance as an antioxidant in health and personal care products, e.g., burn creams, nutritional supplements, and skin creams.

Antimicrobial activity

Monomethoxy triethylene glycol (mTEG) substituted fuller-pyrrolidines shows inhibition of M. tuberculosis and Mycobacterium Avium. Carboxy-fullerenes inhibits E. coli-induced meningitis by lessening the damage which is caused by infiltrating neutrophils on the blood-brain barrier. Later, it was observed that carboxy-fullerenes could insert into Gram+ve cocci's cell wall, disrupt its cell wall structure, and cause the death of bacteria. The gram-ve organisms' cell wall has an outer membrane consisting of lipo-poly-saccharides, phospholipids, and lipoproteins. Fullerenes can't assess it. This advises that carboxy fullerenes could be taken against Gram +ve cocci as new antimicrobial agents

Osteoporosis

Fullerene derivatives in bones, i.e. poly fluoro-bi-phosphonated derivatives are being considered as a bimodal drug for osteoporosis

Medical Applications of Fullerenes and Its Role in Drug Delivery

Introduction

Fullerene is carbon's third allotrope after graphite and diamond, are carbon molecules inside closed-cage, produced in the gas phase during graphite's laser desorption. Fullerene has molecules that consist of carbon atoms joined by double and single bonds to make a partially closed or closed mesh, with fused rings of 5 to 7 atoms. Carbon's allotropes were limited to graphite, diamond, etc. but then, carbon's third form called fullerenes got discovered. C60-fullerenes (CFs) constitute a fused-ring structure of carbon atoms, comprising of 12 pentagons and 20 hexagons. Fullerenes can be used in lipid-like systems, serving as a reservoir and even crossing membranes of cell and blood-brain barrier. The behavior of controlling the drug-disease rate, high loading of the drug, substantial biocompatibility, immuno-neutrality, mononuclear phagocytic system bypassing capability, nature of long circulation, and extraction of tissue by virtue of retention effect and enhanced permeability are the major promises.

Fullerenes can serve as stages for the transportation of drugs and imaging agents. Fullerenes, when surface functionalized, can have direct antioxidant activity. They also serve as drug vectors or scaffolds of drug delivery with covalent or non-covalent linkages between bioactive moiety and Fullerene. A fullerene subclass is known as, Endohedral fullerenes, offer a robust shell and in their interior spaces, they contain atoms that are supposed to be prevented from contacting against the body, for example, in contrast, enhancement for MRI, and as radionuclides carrier. C60 is of soccer ball shape, and it's the archetype fullerene of the family. Higher fullerenes have larger cases, including C74, C78, C70, C84, C76, etc. Cages of fullerenes are comprised of pentagons and hexagons, with alternating carbon-carbon bonds of single bond character (at the pentagon-hexagon junctions) or of double bond character (at the hexagon–hexagon junctions). Also, the larger the cage of Fullerene, the more possible structural isomers. With the help of their all-carbon surfaces, minimum derivatization is needed to use them for the delivery of drugs. The effectiveness of the drug is increased due to the properties of nanomaterials, including, a specific size, characteristics of the surface, a rare spherical structure with a strong a-polar character, and compositions of material are well recognized to provide potentially valuable advances over traditional drug delivery.

Properties

Fullerenes due to their remarkable properties and structure attracted many different scientists. Properties like symmetric nature, nano-metric size, chemical tailoring opportunities, thermal conductivity, photoconductivity, and capabilities to load drugs are the reason why fullerenes are good in applications of drug delivery. Fullerenes also have neuroprotective, antiviral, MRI contrast, antioxidant, and anti-inflammatory properties. Fullerenes and its derivatives also provide enormous promises in drug delivery, especially to the cancerous cells due to its benefits therapeutically and chemical modifications. The highly symmetrical C60 sphere, have an elegance and beauty that excites the imagination of scientists, as they cover aesthetic gaps between the architecture, sciences, and the visual arts. Fullerenes have a broad range of properties in both mechanic and electric field and are also, great conductors of electricity and heat, and have astonishing tensile strength. Due to such properties, they have a great future in the field of medicine, pharmacy, structural materials, and electronics.

Applications in pharmaceutics

C60 Fullerenes non-toxic antioxidant

Anti-tumor Drugs

Monoclonal antibody usually targets Melanoma tumors. By combining a monoclonal antibody with multiple fullerenes, multiple drugs can be delivered to different tumors. Normally, multiple targeting agents are used in other methods, to deliver individual drug-loaded nanoparticles to malignant cells, but the new way is better. It's proved that melanoma tumors get anti-cancer drugs delivered inside them through gp240 which is a tumor protein and ZME-018 binds itself to this protein, while the Rice group has been developing fullerenes as drug delivery agents.

Topical drug delivery

Fullerenes are used in cosmetic applications and transdermal delivery because of its antioxidant activity and its interactions with epidermal keratinocytes which provides many spectacular abilities to them. Due to these properties, different forms are used often, like anti-inflammatory substances, moisturizers, cytoprotective, barrier-repair agents, UVB inhibitory, anti-melanoma-genesis agents, and hair growth stimulators. In the drug delivery area, fullerene-based peptides showed satisfactory penetration, in comparison with mechanical flexion. Isopropyl myristate/transcutol formulations with basic cosmetics without tough organic solvents proved to be good for cosmetics and biopharmaceutical applications. There are also a few publications on the use of fullerenes and non-covalently adsorbed drugs (fullerenes displaying stability at room temperature); that's why, when at optimum concentration, efficient and acceptable transdermal drug delivery is presented.

Crossing the blood-brain barrier

A blood-brain barrier is made of the tight endothelial junctions that inhibit the para-cellular permeability, thus creating it a big task to deliver drugs into the central nervous system. Fullerene and its water-soluble derivatives have a high potential to complete that task. In research, fullerene and hexamethonium' complex systems were established, and it was compared with the delivery system of the only hexamethonium. 40-times boosted potency was showed as a result of a complex delivery system of drugs. Also, neuro-degeneration because of amyotrophic lateral sclerosis (ALS), can be treated by carboxy-fullerenes. Brain's tight complex structure doesn't allow any chemical to pass through the barrier naturally, but delivery systems that are fullerene-based don't obey this and deliver the drug through their tight complex structures.

Cancer therapy

Targeted delivery is required when it comes to cancer therapy; fullerenes offer that more efficiently. One other drawback in normal cancer therapy is that the use of multiple drugs is needed, but Fullerenes' remarkable structure gives it the capability to carry a payload of multiple drugs, which could solve many of the chemotherapy's side-effects. Doxorubicin side effects like cardiomyopathy make it an applicant for conjugation with Fullerene and then after conjugation, their outer surface attaches with the hydrophilic shell, developing a new strategy 'on-off' for delivering drug which causes the formation of novel, new drug delivery systems which are very stable in physiological solutions even in the 'off' state with a pH 5.5; by contrast, the ROS generation by Fullerene leads to two types of treatment in the 'on' state. First, oxygen species generation, which causes cell death (PDT) and, second, the ROS-sensitive linkers to get broken, which enables doxorubicin's exploding release (chemotherapy).

Nucleic acid delivery

Targeted delivery to cells that has a deficiency in a nucleic acid is important. Mostly, viral delivery is used. In some researches, due to their high efficacy, low cost and non-immunological reactions, fullerenes, especially cationic ones, were used to transport small molecules. These complexes form micrometer particles by agglutinating in the bloodstream further, with plasma proteins. The agglutinate rapidly clogs capillaries of lungs, releasing siRNA into cells of the lung to silence the targeted cancer genes expression and after delivery of siRNA, it is rapidly cleared from the lung. It is proved that conjugated nucleic acids are used with fullerene-based delivery systems to increase the efficacy in a target-specific manner.

Photodynamic therapy

PDT is important in the treatment of diseases from a small infection to cancer. PDT's key limitation is that many photosensitizers have poor water solubility. Fullerenes have great advantages, some of them including their PDT potential – visible light's absorption combined with an efficient intersystem crossing to a long-lived triplet state which on illumination, cause fullerenes to generate ROS and act as photosensitizers. In past years, many substances have been produced that are conjugated with fullerenes. The major problem was that the effect on cancer cells and the healthy cells were equal, but delivery systems based on Fullerene increases the absorption in cancerous cells and decreases it in healthy cells, thus, solving the problem.

Radical scavenging and Antioxidant activity

Antioxidant activity and the body's balanced oxidation are to avoid diseases and toxicities that are caused by excess free radicals, e.g. atherosclerosis and cancer. Fullerene cage has many double bonds inside, which makes them capable of reacting with free radicals, e.g. hydrogen peroxide, hydroxyl radicals, and superoxide. Recently, C82 and C60, two fullerenes, were used as an antioxidant when conjugated with three transition metals (gold, copper, and silver). Results showed that in metal presence, fullerenes' anti-radical capacity was boosted. Fullerenes antioxidant abilities are also applied in skincare products and cosmetics, as an anti-aging agent. One of the major problems today is oxidative stress, which the fullerene-based systems are expected to balance. The fact that Fullerenes can reduce apoptosis in cortical neurons and can also block receptors of glutamic acid has been reported. Tri-mesic acid (TMA) fullerenes and Hexa (sulfo-butyl) fullerenes also displayed their capability of trapping free radicals and efficiently helps in neurodegenerative diseases' treatment, such as Alzheimer disease. Various studies revealed that fullerenols and malonic acid fullerenes, which are water-soluble derivatives, can react with superoxide free-radicals and hydroxyl, lessening the degeneration of neurons related to ROS.

Anti-HIV activity

Several reports are made on fullerenes' ability to inhibit the activity of HIV-1 protease. Fullerene enters into the pocket, and then through van der Waals interactions attaches to the active site causing antiviral activity. Some fullerene derivatives inhibit the HIV-1 viruses that have resistance against multiple drugs. During treatment with these compounds, no toxicity occurred. That's why they should be in next-generation for the treatment of HIV. Pyridine/pyridinium-type fullerene derivatives with no carboxylic acid inhibit HIV-1 reverse transcriptase in an environment that's cell-free. Results displayed fullerene cage important role without any cytotoxicity sign.

Antibacterial activity

Many functionalized fullerene derivatives demonstrated satisfactory effects of inhibition on bacteria. Carboxy-fullerene suppresses S. pyogenes growth and the fact that its administration can prevent ¼ mice from dying. In addition, more activity was exhibited against Gram +ve bacteria, and none on Gram –ve bacteria. Fullerenes can interact directly with biomolecules, e.g. anti-cancer drugs or aromatic mutagens.

Conclusion

In this review, Fullerene and many of its derivatives have been stated along with their uses in different pharmaceutical applications. Fullerenes has a specific structure, and it helps in the treatment of some diseases. What makes Fullerene good for delivering the drug is the ability to, cross the blood-brain barrier, carry the load of multiple drugs, deliver to the targeted cells, not dissolving before reaching the targeted cells. Fullerenes are used to deliver anti-tumor drugs, drugs for cancer therapy, and drugs that need to enter the brain. They can inhibit HIV-1 and also Gram +ve bacteria. Fullerenes and their derivatives are widely used in the medical field.

Fullerene-C60, Purity: 99.9%  Fullerene-C60, Purity: 99.5%  Fullerene-C60, Purity: %99  Fullerene-C60, Purity: 98%Fullerene-C60, Purity: 95%

Fullerene, namely C60, named after Architect Richard Buckminster Fuller, was produced by vaporizing graphite in the laser beam. Fullerenes are soluble in organic solvents and not in water. C60 fullerenes are the smallest ones like the buckyball; meanwhile, C70 has the structure of a rugby ball. Nowadays, most of Carbon 60 is manufactured in the laboratory. The remarkable carbon cage structure makes them a potential therapeutic agent for many potential therapeutic applications, in biomedicine and diagnostics.

References

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https://www.ijpsonline.com/articles/fullerenes-an-...

https://pubmed.ncbi.nlm.nih.gov/30703542/

https://pubs.rsc.org/en/content/articlelanding/201...

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30th Sep 2020 Arslan Safder

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