Fullerene Applications in Biomedicine: A Comprehensive Review - Nanografi

Fullerene is a carbon allotrope present in the form of a mesh consisting of five to seven atoms of carbon bonded together. 

Fullerene can be present in different sizes and shapes depending upon the category they belong to. However, it mostly presents in the form of a pentagon or a hexagon. Fullerene exhibits remarkable properties and characteristics because of which their applications have only increased over the past years. The major portion of their applications can be found in the medical field. Fullerene is used in various ways all of which are presented below in which they are wide range of applications in the medical industry.

Introduction

One of carbon's allotrope, fullerene, is made up of carbon atoms that are joined by double and single bonds for creating a partially closed or closed mesh, with 5-7 atoms, fusing and forming fused rings. A molecule of fullerene can be of any size or shape, it can be a tube, an ellipsoid, or a hollow sphere. Graphene however is a flat mesh of the regular hexagonal rings. Graphene is the family’s extreme member. 

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Structure and Topology of Fullerene

Topology of Fullerene

Informally, those Fullerenes who have a closed mesh topology are denoted by Cn, which is their empirical formula and is commonly written as Cn. In Cn, the number of carbon atoms is denoted by n. Although, there is more than one isomer for some 'n' values.

Buckminster Fuller named buckminsterfullerene (C60) which is the family's most famous member, and the whole family was named after it. Due to their resemblance with the soccer ball, the closed fullerenes are also known as buckyballs. Bucky onions are the name for nested closed fullerenes. The names, buckytubes or carbon nanotubes are used for the cylindrical fullerenes. Fullerite is mixed or pure fullerene’s bulk solid form.

Fullerenes have been discovered for a long time but they were detected in outer space and nature in 1985. The number of carbon allotropes increased after fullerene was discovered. Previously, the allotropes of carbon were amorphous carbon like charcoal and soot, diamond, and graphite, but now fullerene is added to the list of carbon allotropes. Due to their technological applications in nanotechnology, electronics, and materials science, and their excellent chemistry, fullerenes have gained a lot of attention.

Structure of Fullerene

The structure of fullerene has pentagonal and hexagonal rings (heptagonal at times). Pentagonal rings are important for the molecule’s curvature. Each carbon atom in the fullerene is connected to the other carbon atoms in the fullerene by two single bonds or one double bond. In fullerene, each carbon is sp2 hybridized. C60 is the smallest fullerene as in C6, two pentagons don't share an edge, making C60 the most common. Truncated icosahedron has the same structure as that of C60. A pentagon (five-membered ring) replaces each vertex, due to which all of the twenty former triangular faces are converted into hexagons (six-membered rings), with a bond along each edge, and in each hexagon's corner, there is a carbon atom. Those structures that avoid the edge-sharing (contiguous) pentagons are stable. The most minor carbon clusters are C70 and C60.

Chemical and Physical Behavior

Instead of electron-rich aromatic systems, fullerenes behave physically and chemically as electron-deficient alkenes. In organic solvents, fullerenes are soluble. Fullerenes accept electrons easily. If the hydroxyl group, for instance, fullerenes, is added to modify fullerenes, it can enhance its solubility in water. Nanotubes are cylindrical, very thin, and long carbon structures that have graphite molecules attached to their edges. Fullerenes are similar to rolled-up graphene sheets. There is a chance of the nanotubes have single, two, or more concentric cylinders.

Following are the characteristics of the nanotubes, the length of the cylinder, the radius of the cylinder, the number of concentric cylinders, and the thickness of the wall. Chirality is a characteristic possessed by some nanotubes. Chirality is a manifestation of longitudinal twisting. The structure of the nanotubes determines whether the nanotubes act as semiconductors or have a metallic character, and therefore can offer chances of creating semiconductor–metal, and semiconductor–semiconductor junctions, which is very beneficial in devices.

Thermal Conductivity

Fullerenes have excellent thermal conductivity and are very strong materials. Nanomachines are the microscopic mechanical systems in which fullerenes are assembled. Nanotubes can be utilized for building transistors, diodes, inductors, capacitors, or microscopic resistors because graphite can act as a semiconductor. Due to the capacitance among layers, electric charges might be stored in the concentric nanotubes, aiding in the formation of high-density memory chips. New co-polymers having particular mechanical and physical characteristics can be created with the addition of fullerenes into the polymer structures as fullerenes are chemically very reactive.

Properties of Fullerene

Topology

Due to 2-dimensional projections not being enough and ideal for clarifying closed-shell fullerenes’ 3-dimensional structure, people use Schlegel diagrams for clarifying the structure of the closed-shell fullerene. The closed-shell fullerene’s combinatorial topology can be displayed as a convex polyhedron; particularly its 1-dimensional skeleton which consists of its edges and vertices. Schlegel diagram is the skeleton’s projection onto the polyhedron’s faces through a point that is just outside the polyhedron’s face, for all the other vertices to be projecting inside that face. Closed fullerene’s Schlegel diagram is a 3-regular and planar graph.

Closed Fullerenes

A closed fullerene that has a shell-like sphere should have some cycles at least that are heptagons or pentagons. Especially if there are faces that have 5-6 sides, it follows V−E+F=2, known as Euler's polyhedron formula. In that formula, F is the number of faces, E is the number of edges, and V is the number of vertices. If fullerene has seven-atom (heptagonal) cycles, similar constraints exist.

Open Fullerenes

Graphene, carbon nanotubes, and other open fullerenes consist of hexagonal rings. If you join two long nanotubes by their ends, a closed torus-like sheet can be formed and it is completely made up of hexagons.

Bonding

Instead of 4, each carbon atom in fullerene is joined with only 3 of its neighboring atoms, making it important for describing those bonds as a mixture of double and single covalent bonds.

Encapsulation

Endohedral fullerenes have small molecules or ions encapsulated inside the cage atoms.

Research

In the development and research field, fullerene's physical and chemical characteristics were famous at the start of 2000. Fullerene’s usages in armor were discussed in Popular Science. Some other heavily studied characteristics in the nanotechnology field are superconductivity and heat resistance.

Calculations

Ab-initio quantum methods have been used to do many calculations that are implemented to fullerenes. UV, Raman, and IR spectra can be obtained by using TD-DFT and DFT methods. The conclusions of such calculations can be compared with the experimental results. In various organic reactions like the Bingel reaction, the unusual reactant is fullerene. Researchers learned about the Bingel reaction in 1993.

Aromaticity

Fullerene’s reactivity can be increased by attaching the active groups to the surfaces of the fullerenes according to the researchers. Superaromaticity is not displayed by buckminsterfullerene, meaning that there’s no delocalization of the electrons in the hexagonal rings over the whole molecule.

Spherical Fullerene

The atoms in spherical fullerene can freely delocalize and have n pi-bonding electrons. Spherical aromaticity’s 2(N + 1)2 rule for spherical aromaticity is Huckel's rule's 3-dimensional analog. This rule would be satisfied by the 10+ cation and will be aromatic. If quantum chemical modeling is used, one can see that strong diamagnetic sphere currents exist in the cation. In conclusion, two more electrons can be picked up by C60 in water, turning it into an anion. If C60 tries to produce a loose metallic bond, nC60 may result which is described below.

Applications of Fullerene in Biomedicine

Fullerene has a wide range of potential applications in various industries such as electronics, energy, medicine, and more, which makes it a growing market. Additionally, with the advancements in nanotechnology and materials science, the potential uses and demand for fullerene-based products are expected to increase in the future. In various biomedical applications, for instance, in gene and drug delivery, photodynamic therapy, X-ray imaging contrast agents, and high-performance MRI contrast agents, there has been extensive usage of the fullerenes. All such applications in biomedicine are summarized in various reviews below.

Medical Research on Fullerene

Fullerenes were being studied in 2003 for potential usages in medicine. They bind particular antibiotics to target resistant bacteria’s structure and can also target specific cancer cells like melanoma. Fullerenes were described as the light-activated antimicrobial agents in the article in the October 2005 issue of Chemistry & Biology.

Fullerene in Tumor Research

Even though radiation therapy was involved in past cancer research, the more important therapy to study is photodynamic because, in the treatment of tumor cells, breakthroughs provide various options to various kinds of patients. In cancer research, many latest experiments used HeLa cells. All recent experiments involve the production of new photosensitizers which have enhanced the capability of being absorbed by cancer cells and can still trigger cell death. To make sure that no unwanted cell damage occurs, the photosensitizer doesn’t remain for long in the body. HeLa cells can absorb fullerenes if made for it. L-arginine, folic acid, and L-phenylalanine among other functional groups can be used to deliver C60 derivatives to the cells.

Mechanism of Functionalizing Fullerene in Cancer Cells

The fullerenes are functionalized for increasing the molecule’s solubility by the cancer cells. These molecules are taken up by the cancer cells at an increased rate due to the upregulation of transporters in the cancer cell. Here, fullerenes functional groups, L-phenylalanine and L-arginine will be brought up by amino acid transporters. C60 derivatives, after being absorbed by the cells, will react to light radiation by transforming the molecular oxygen into reactive oxygen, triggering apoptosis in cancer cells and the HeLa cells, basically, all the cancer cells that can absorb the fullerene molecule. According to this research, cancer cells can be targeted by a reactive substance and light radiation can also trigger it, therefore reducing the damage to the surrounding tissues while the surrounding tissues undergo treatment.

Reactive Oxygen and Apoptosis Triggered by Fullerene in Cancer Cells

Reactive oxygen is created when cancer cells absorb fullerenes and expose them to light radiation. In the process of the creation of reactive oxygen, damage occurs to lipids, proteins, and DNA that make up the cancer cell. Damage at such a level causes apoptosis of cancer cells, resulting in a lessening in the tumor's size. To lessen the chances of damage to other tissues, free radicals will be absorbed by fullerene once the treatment of light radiation is finished. If the cancer cells of the patient are in light radiation’s reach then this treatment is a good option as it focuses mainly on the cancer cells. Maybe with time, the treatment will go deeper inside the body, and cancer cells will absorb them more efficiently.

Fullerene as Photosensitizers in Medical Application

Fullerenes' photoexcitation is C60's other potential medical application. Photoirradiation can be used to excite fullerene from the ground state to 1C60. Then, intersystem crossing can be done to readily convert this short-lived species (1C60) into a long-lived 3C60. In oxygen’s presence, fullerene can decay to the ground state from its triplet, transferring its energy to oxygen, and producing singlet oxygen 1O2, which is known as a highly cytotoxic species. Also, in oxygen’s presence, one electron can be transferred by the fullerene radical anion, forming a hydroxyl radical –OH and a superoxide anion radical O2•-. Moreover, the high-energy species 3C60 and 1C60 are remarkable acceptors, and in the donor’s presence, they can undergo a different process, and electron transfer helps in easily reducing them to C60•-.

Excited Fullerene and Its Biological Effects

In the presence of guanosine and other biological reducing agents, excited fullerene can be lessened under biological conditions. Also, Superoxide radical anions and singlet oxygen are famous reactive species towards DNA. For fullerenes to be utilized in photodynamic therapy (PDT), this fullerene’s characteristic renders them potential photosensitizers. Many fullerenes conjugate with various functional groups possess a biological affinity to proteins or nucleic acids and are currently under investigation for activity against cancer cells. Specifically, conjugates of C60 and complementary oligonucleotide or acridine, which interacts with nucleic acids, have been made to increase the cytotoxicity.

Fullerene's Antioxidant Activity and Radical Scavenger Property

Malonic acid C60 tris adduct and dendritic C60 monoadduct’s toxicity was explored on Jurkat cells, and when they are exposed to UV light, there was a drop in cell number by almost 19 percent in 2 weeks. C60(OH)x’s biodistribution and tumor uptake was studied by Ji et al by using radiotracer 125I-labeled C60(OH)x in tumor models of five kinds.

Water-soluble Polymers

A water-soluble C60- N vinyl pyrrolidine copolymer was introduced in 2006 by Iwamoto and Ymakoshi as an agent for photodynamic therapy. Radical polymerization was done to incorporate C60 covalently into a poly (vinylpyrrolidone) chain. To date, the most water-soluble fullerene is this nanoparticle and this method can also generate aqueous solutions of higher concentrations as compared to the attention of saturated C60 in toluene.

Antioxidant Activity

According to recent publications in 1999, fullerenes can be biological antioxidants as they have the characteristics of an antioxidant. They possess low-lying lowest unoccupied molecular orbital (LUMO) and conjugated double bonds in large amounts so they can take up an electron easily, therefore can help radical species in making an attack easily. According to the reports, in one C60 molecule, there are up to 34 methyl radicals added and this quenching process is catalytic.

Moreover, there can be a reaction of fullerene with various super-oxides without fullerene itself being consumed. Fullerenes are the most effective radical scavenger of the world because of such characteristics. Fullerenes are also known as radical sponges according to Krusic et al. in 1991. If you use fullerenes as medical antioxidants, it has many advantages, the major one being fullerene’s capability to localize to mitochondria and other cell compartment sites within the cell, but if the patient is sick or ill, free radicals are produced instead.

Experiments on Rats and Liver Protection by Fullerene

This excellent trait was proved when Najla Gharbi and coworkers experimented on rats. According to them, when you don’t use polar organic solvent in the preparation of aqueous C60 suspensions, they prevent their livers from free-radical damage and have no sub-acute or acute toxicity in rodents. When CCl4 intoxicates rats, it results in the production of trichloromethyl radical CCl3•, triggering damage to the liver on a large scale in a reaction with oxygen. When C60 pre-treats and CCl4 intoxicated rats, the rats displayed no damage to their liver. When utilized in a manner where it’s dependent on dosage, pristine C60 can be a powerful liver-protective agent considering biological tests and histopathological examinations.

Fullerene in Drug and Gene Delivery

Biomolecules and drugs can be directly delivered into cells through the cell membrane and this has gained a huge amount of attention and helped in making people focus on developing safe and effective carriers for the transportation of drugs or genes. The main complication is the transportation of any compound into an intact cell's nucleus. The nuclear membrane, endosomal membrane, and cell membrane are the 3 membrane barriers that limit the transfer of any compound into an intact cell's nucleus. Therefore, understanding the mechanism via which the carriers cross into the cells is extremely significant.

Four Major Groups

Inorganic nanoparticles, recombinant proteins, viral carriers, and organic cationic compounds are 4 main groups of gene and drug carriers according to researchers in 2005. Many nanoparticles can be utilized for cellular delivery as carriers due to their useful characteristics, for instance, controlled release of carried drugs, selectively targeted delivery, and good biocompatibility. Fullerenes come from an inorganic nanoparticles class and they are broadly available because of fullerene’s biological activity and small size (1nm). This carbon’s allotropic form performs many biological activities, all of which are determined by the characteristics of the fullerene core and the core’s chemical modification.

Core of Fullerene and Its Hydrophobicity and Hydrophilicity

The core of the fullerene is extremely hydrophobic, whereas the attached functional groups add more complexity to the fullerene molecule’s behavior. Fullerene can carry genes and drugs for delivering them and can become water-soluble by attaching hydrophilic moieties. In 2002, Foley et al. demonstrated how can the derivatized fullerene cross the cell membrane and bind to the mitochondria. According to a study in 2003, DNA-functionalized fullerenes can enter COS-1 cells and displays relatively better efficiency as compared to the lipid-based vectors that are commercially available. A protective sheath is formed around bound DNA by the fullerene reagent, thus increasing DNA’s time of life in endosomes, and therefore supporting their chromosomal incorporation. Aminofullerenes are used to attach the DNA sequences preferably.

Detachment of DNA

One can achieve DNA detachment in the cytoplasm either through the loss of the amines' binding ability or its amino groups by transforming them into neutral compounds. In 2005, Zakharian et al. designed a lipophilic drug delivery system that releases the drug slowly and uses fullerene derivatives for improving the therapeutic efficacy in this tissue culture. In 2006, Ryman-Rasmussen et al. observed fullerene’s capability of penetrating through the intact skin and how it is broadening fullerene’s application in the delivery of genes and drugs.

Fullerene Peptide in Penetration of Skin

Rouse et al synthesized a fullerene-based peptide and observed its capability of penetrating through unflexed and flexed skin. To perform this study, scientists used porcine skin as a model for human skin. Mechanical flexion alters the skin’s structural organization and increases the penetration by compromising the epidermis’s permeability barrier. Fullerene's toxicity in the living organism and cell culture is not well-known.

Diagnostic Application of Fullerene and Endofullerenes

An unstable atom can be carried by a fullerene cage due to its potential of being an 'isolation chamber', for example, a metal atom, inside the molecular cage's interior, producing metallofullerenes/endofullerenes. Reactive atoms can be isolated by metallofullerenes/endofullerenes from their environment. Fullerene cages show resistance toward the body's metabolism and they are comparatively non-toxic according to various studies. Fullerenes can be used in diagnostic applications better than metal chelates. You can use endo-fullerenes as radiopharmaceuticals, X-ray imaging agents, and magnetic resonance imaging contrast agents.

Conclusion

As fullerene is present in various shapes and sizes so depending upon its variance, the applications of fullerene are quite vast in the medical industry. Fullerene is providing benefits to the field of medicine through its remarkable working mechanics and ever since it is being used, it has only provided efficiency and productivity to the medical field. By purchasing Nanografi's cutting-edge Fullerene products, projects and academic research and businesses can ensure consistent quality and exceptional performance. Our Fullerene materials are designed to meet the highest standards, helping to enhance your brand reputation and boost customer satisfaction.

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