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1. Introduction
Cells carry out the complex cellular function of disintegrating themselves by considering various cellular mechanisms and pathways. This process is caused by a diversity of signals within the cell. This process is essential for the homeostasis of organisms [1]. The importance of apoptosis in cancer treatments cannot be overstated. It is the key to the current strategies. However, the resistance of chemotherapeutic agents to apoptosis is a significant hurdle. This is why it is so inspiring to test and discuss anticancer compounds that do not have standard mechanisms of cell death [2].
Apoptosis is a natural homeostatic mechanism that permits cell populations to be maintained and controlled. Any change or damage to the cell’s DNA will produce cell death through this process. This function is a defense mechanism that occurs when the cell is damaged. However, when this process does not work, cells grow out of control, and cell division occurs, developing cancer cells (Figure 1). Cancer cells could be described as predators, so to control them, different treatments such as radiation, drug-based therapies, and immunotherapy are used [3].
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Currently, there are several treatments focused on trying to mitigate this disease. Still, these have the characteristics of being very aggressive with the patient since they cannot differentiate between healthy and diseased cells [4–6]. Because of this, it has been proposed to investigate alternative therapies that increase the prevalence rate of cases and, in turn, reduce all those adverse effects that affect the integrity of the patient. It is known that the primary suppressive mechanism to prevent the development of tumors by precancerous cells is the induction of apoptosis. In this case, the immune system detects the mutated cells, and signals are generated to trigger apoptosis signaling in these cells [7].
This has led to an interest in carbon-based nanopolymorphisms. Polymorphism is the quality that some compounds have when exposing different crystalline forms. An example of this type of condition is the case of carbon; as it is a pure element, they are called allotropes. Four allotropic forms are distinguished: diamond, graphite, fullerene, and nanotubes [8]. These particles have different geometrical shapes, like spherical, cylindrical, or flat [9]. Studies have shown that these have properties capable of inhibiting cancer cells or being used as supportive treatment conjugated with chemotherapeutics [10–12]. However, although there are different efforts to describe the type of nanoparticles (NPs) used for the treatment of cancer [3, 13–17], any document explains the mechanisms of cell death induced by different NP systems. This manuscript aims to show the cell death mechanisms that carbon-based nanomaterials can induce. Figure 2 shows the tendency of published articles based on the English search for keywords such as NPs, nanodiamonds (NDs), fullerenes, carbon nanotube (CNTs), graphene, and cell death mechanisms since 2000.
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2. What Are NPs?
NPs have a size between 10 nm and 1000 nm [19]. NPs are structures similar in size to biological molecules. Their implementation led to the creation of nanomedicine, a branch of nanotechnology specialized in diagnosing, treating, and preventing diseases and injuries that affect humans, relieving pain, preserving and increasing human health, and implementing the tools and molecular knowledge of human physiology [20].
NPs measuring around 50 nm are more accessible to absorb by cells; those more significant than 50 nm have higher penetration times, and those smaller than 25 nm require a higher concentration to enter the target cells. Another factor considered is the type of cell they are targeted toward. Also, the NPs’ form, structure, and dimension determine the cell’s action to enter them. They can be synthesized to acquire a specific form. The most prominent shapes are spheres, bars, stars, and tubes. Commonly, spherical forms have a broad spectrum of penetration into target cells compared to other forms [21]. Subtypes of existing nanomaterials are classified in different ways. They differentiate between anthropogenic nanomaterials, which man has manufactured or the result of human activities, and natural nanomaterials, which can be found in nature [22].
In recent years, NPs have garnered significant attention. Their excellent performance is due to their characteristics since they have a relevant functional surface about their size. In addition, compounds, drugs, or proteins can be coupled or adsorbed to this surface, giving them great versatility and allowing them to guide the action of nanomedicines toward the specific site of action after their administration (Figure 3) [23, 24].
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NP-based drug delivery systems have shown potential due to their ability to deliver substances directly to tumor sites, sustain and regulate drug release and resistance, protect the drug from degradation, and facilitate a combination of therapies. In cancer treatment, activating apoptotic pathways is crucial. This can be achieved by promoting proteins that facilitate apoptosis, such as Bcl-2-like protein 4 and Bak, and interfering proteins with anti-apoptotic properties. Notably, NPs have demonstrated their potential to overcome the limitations of drugs used for lung cancer treatment, like resveratrol. They enhance the bioavailability, enable specific release, increase stability, and control release, thereby emphasizing their ability to penetrate the tumor tissue [25].
2.1. Carbon-Based NPs
Carbon is an abundant element in the biosphere. It is nonmetal and exists in allotropic forms, including zero- and three-dimensional structures [26]. Carbon-based NPs, whether natural or artificial, are captivating materials composed primarily of carbon. These particles’ diverse properties, structures, and functions result from their unique hybrid orbitals, such as sp, sp2, and sp3. These hybrid orbitals, formed by the intriguing mixing of atomic orbitals, dictate the bonding and shape of the carbon atoms, thereby influencing the properties of the NPs in a fascinating manner [27].
Carbon nanomaterials, a subset of inorganic nanomaterials, are not just functionalized; they are transformed to enhance their biocompatibility or introduce other unique properties. Their remarkable ability to absorb strongly in the near-infrared window has made them popular, opening exciting possibilities for deeper exploration of their properties and prospective applications [28, 29]. Figure 4 introduces the classification of carbon-based NPs, such as fullerenes, graphene, NDs, nanotubes, and others. According to the dimensionality of the material, they could be classified as 0D (carbon dots, graphene quantum dots), 1D CNTs, and 2D (graphitic carbon nitride, graphene oxide) [31].
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The term 0D refers to materials with all dimensions confined to the nanoscale, such as quantum dots (QDs) (2–10 nm in diameter), fullerenes (molecules about 0.7 nm in diameter), and NDs organized in a face-centered cubic crystal structure, featuring facets with dimensions under 100 nm [32]. The 1D is characterized by having one dimension at the nanoscale, such as CNTs (diameters of approximately 0.4 nm and lengths ranging from nanometers to millimeters). The 2D has dimensions in the nanoscale in two dimensions, such as graphene [33].
Graphene is a stable form of carbon made of a hexagonal pattern of benzene rings in each layer with a sp2 hybridization [34]. It is often hailed as the foundation of allotropic graphitic forms and showcases its influence in myriad ways. For instance, when a sheet of graphene is cleverly packaged in a spherical shape, it gives birth to fullerenes. Similarly, graphite is formed when multiple graphene layers interact through π-π interactions and van der Waals bonds. This intricate interplay of graphene’s structure and its derivatives provides a fascinating insight into the interconnectedness of these materials, leaving us enlightened [35].
The hybridization process between sp2 and sp3 orbitals is not just a key but a pivotal aspect in understanding the formation of carbon-based nanomaterials. This hybridization allows carbon atoms to combine, producing hexagons and pentagons in closed three-dimensional structures, giving rise to fullerenes, CNTs, and carbon nanofoams. The bonds of type σ and via sp3 hybridization result from hybridizing the 2s orbital with the three 2p orbitals, producing four arranged orbitals. These orbitals are then formed into a tetrahedron-shaped structure, creating solid structures with three-dimensional, rigid, and isotropic shapes, such as diamonds [36].
Carbon-based nanomaterials, with their remarkable properties, have found applications in diverse fields. They have been used in adhesives [37], sensor applications [31], such as human virus detection [38], reforming of polymers [39], filler material in concrete and cement [40, 42], environment and energy applications [43, 44], supercapacitors [45], and drug delivery carriers; these nanomaterials hold immense promise [46]. Carbon-based nanomaterials hold tremendous promise in various applications, but it is crucial to consider their potential toxicity and usefulness in medical applications. Several studies have evaluated these aspects, highlighting the need for further research and understanding [46–55]. It is of utmost importance to explore the complicated interactions between these materials and living cells.
2.2. Graphene
Graphene is an allotropic configuration of carbon formed by covalent bonds that originate from the superposition of sp2 hybrids of carbons that lie conjugated [56]. Some research on methods of obtaining is micromechanical exfoliation (“scotch-tape” method), where graphene in the free state was extracted for the first time. It is also the most efficient and reliable method for producing high-quality graphene sheets. The next is known as exfoliation; this is the solution obtained from a solid’s outermost layers. In graphite, the graphene layers are weakly constituted through van der Waals forces and are separated using adhesive tape to extract fragile flakes [57].
Graphene, a semiconductor with a zero-band gap, holds unique electronic and optoelectronic characteristics, so the development of graphene nanoribbons (GNR) and graphene quantum dots (GQP) are promising for their practical uses [58]. Graphene’s two-dimensional structure, compared to the hexagonal structure of a honeycomb, is a marvel. Its carbon atoms are organized in a monolayer constituted by benzene rings, giving it outstanding properties that continue to intrigue researchers [59].
Graphene and its derivatives (Figure 5) have been used for different studies focused on biomedicine; graphene oxide has stood out for having specific properties for drug release, making it a potential element for various medical treatments. Graphene oxide is highly soluble in water, allowing it to make covalent modifications. Graphene oxide has also been shown to promote the growth and proliferation of cells in contact with it. This is because the groups found on the surface increase the material’s biocompatibility, facilitating a direct exchange with the cell membrane and promoting cell adhesion and growth [60].
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Graphene oxide and reduced graphene oxide possess remarkable properties, including high mechanical strength, enhanced electrical and thermal conductivity, and a large surface area with numerous oxygen functional groups [61].
Graphene oxide’s versatility is evident in its use as a nanocarrier, thanks to its large surface area, capacity for surface modification, and robust mechanical strength. These properties have applications in drug administration, photothermal therapy, and imaging. The NPs derived from graphene oxide can also play a role in autophagy, either inducing or inhibiting it. This dual function is particularly intriguing, as stimulating autophagy can enhance the reactiveness of cancer cells to cancer drugs while weakening autophagy flux can reduce cell proliferation and increase the inflammatory response.
Stimulating autophagy can increase the responsiveness of cancer cells to cancer drugs, whereas impairing autophagy flux may decrease cell proliferation and elevate inflammation. The production of reactive oxygen species can induce DNA damage and facilitate cancer cell apoptosis [62]. Nevertheless, the extensive use of graphene oxide carries potential risks, particularly neurotoxicity. This was demonstrated in a previous study, where the use of rat astroglioma-derived F98 cells led to excessive cell apoptosis, highlighting the need for caution and further research in this area [63, 64].
2.3. NDs
In recent years, NDs have become more relevant in multiple areas, such as physics, chemistry, and biology [65]. NDs, with their distinctive truncated octahedral structure, are carbon NPs that have captured significant attention. The particles, measuring less than 100 nm, boast a larger surface area per particle unit than other NPs, making them a fascinating subject of study [65]. NDs are obtained by explosions in an enclosed enclosure and an inert atmosphere of classical explosives (e.g., trinitrotoluene or TNT, exogenous, or RDX) and their mixtures. After cooling, the product obtained from this explosion is a carbon black (soot) in which the NDs lie dispersed and surrounded by layers of graphite. There is debate on how to purify the product obtained by detonation. The most common procedure consists of two steps: (1) Addition with an oxidizing acid (e.g., HNO3) that dissolves soot to some extent, and (2) Grinding with zirconite balls to disseminate NDs fully [66].
Many applications attributed to NDs are based on the electrical and optical properties intertwined with diamond defects. These defects, irregularities in the diamond’s crystal lattice, can be intentionally introduced during the synthesis process or occur naturally. They are essential to the distinctive properties of NDs, including their fluorescence and electrical conductivity [67–69]. Its wide range of applications stems from its physical and chemical qualities: fluorescence resistance, extreme mechanical resistance, chemical inertness, easy production, and biocompatibility [70]. To use NDs more extensively in drug delivery, it is necessary to consider their basic properties, processing, surface modification, and potential cytotoxicity problems. While NDs have shown promising biocompatibility, there are still concerns about their long-term effects and potential toxicity (Figure 6). Therefore, thorough toxicity studies and risk assessments are essential before widespread use in biomedical applications [71].
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This nanomaterial is created by adding and repeating carbon atoms, all exhibiting a hybridization of type sp3. This hybridization entails the combinations of one s and three p orbitals, leading to a tetrahedral arrangement of the carbon atoms. This forms a crystal network that covers the three spatial dimensions and is joined by covalent bonds, forming an angle of 109°. This unique structure gives NDs different properties, such as colorlessness, insulation, and the densest and hardest known materials. However, this structure can transform into graphite at high temperatures or when subjected to high-energy radiation [72–74].
It has been reported that NDs have a minor impact on cell viability compared to other carbon-based particles. This is a significant finding, as it indicates that NDs may have a lower potential for causing adverse effects in biological systems [75].
2.4. CNTs
The discovery of new types of nanomaterials has significantly expanded their prospective applications in the biomedical field. Among these, CNTs (Figure 7), with their cylindrical structure and physicochemical characteristics, hold immense promise as a potential game changer in cancer treatment [50, 52, 76, 77]. Moreover, CNTs stand out as stable nanomaterials with unparalleled physical, mechanical, and chemical properties, underscoring their potential in various fields of research [78]. These carbon NPs have properties such as exceptional electrical conductivity, improved young module, and a large surface area, which makes them very attractive for various applications in biomedical research [79]. Its two main applications in treating cancer are the selective delivery of drugs, which refers to the ability of CNTs to deliver therapeutic agents directly to targeted cells, and photothermal therapy. This technique uses materials that absorb light, like CNTs, to select and destroy cancer cells by applying heat through infrared or visible light [80]. They can also function as contrast agents in medical imaging techniques, such as positron emission tomography (PET) and magnetic resonance imaging (MRI), to diagnostic tumors [79].
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They can also function as contrast agents in medical imaging techniques like MRI or PET to detect and visualize tumors.
CNTs are characterized by their storage system when combined with DNA molecules, making them helpful in treating diseases through nanomotors. Nanomotors are tiny machines powered by chemical reactions or external energy sources. CNTs can serve as components of these nanomotors, contributing to their function [81].
CNTs are essentially carbon atoms arranged in cylinders, with diameters mainly in nanometer order [82]. These carbon materials have different tubular structures with diameters in the arrangement of the nanometer and lengths that become incredibly long about their diameter. They also appear as tubular carbon atom arrangements in a benzene polycyclic network. The qualities of the different types of CNTs depend primarily on their diameter, length, walls, and chirality, which refers to the carbon structure in the tube and can significantly influence the properties of the CNT [83, 84].
Depending on the specific need, CNTs have been used as nanocarriers of anticancer drugs such as carboplatin, camptothecin, paclitaxel, doxorubicin, and genes such as RNA/DNA aptamers, minor interference RNA, and plasmid DNA [85].
One of the most robust CNT approaches is targeted drug delivery, designed to treat tumors [86]. There are two categories of CNTs: single-walled and multiwalled. These molecules are primarily synthesized using electric arc discharge, laser ablation, and chemical vapor deposition [87, 88]. CNTs possess high mechanical strength, exceptional aspect ratio, and electrical and thermal conductivity, which is particularly noteworthy [89, 90]. All these attributes have made CNTs unique materials for various applications, mainly in the biomedical area. The most cited problem with this nanomaterial is that it lacks solubility in water and presents toxicity; this problem has been partially solved by modifying the surface, making it more dispersed in water, which increases its biocompatibility [91].
If we can overcome the current obstacles, such as not uniform size, cytotoxicity, not uniform load of drug–CNT, and control of release, CNTs could potentially become one of the most powerful tools in our biomedical and health arsenal. They hold immense promises as cancer therapies [85].
Despite the significant strides in utilizing CNTs for cancer treatment, it is crucial to note that they may also exhibit toxic effects on human cellular structures. This underscores the need to delve deeper into their biocompatibility and interaction mechanisms with cells. However, the number of reports investigating the influence of CNTs on tumors, healthy tissues, or embryonic and their interaction mechanism remains limited [92].
2.5. Fullerenes
The most stable carbon structures are diamond, graphite, and fullerene. In 1985, researchers Harold Kroto and associates unveiled a third allotropic form of carbon, a substance where each molecule had 60 carbon atoms. The challenge of finding a stable geometric arrangement for such a molecule was overcome, leading to the representation of the C60NP, which had a molecular structure akin to a soccer ball (Figure 8) [93, 94].
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The associations between fullerenes are guided by intermolecular forces of the van der Waals type, which are weak attractive forces between molecules. Other “conglomerates” called “major fullerenes” have been discovered, such as C84, C82, C80, C76, C72, and C70, and the “minor fullerenes” of the type: C20, C22, C24, C26, C32, C36, and C50 [66].
The atoms of fullerenes are arranged in a unique polygon of 60 vertices that form an icosahedron, in which each vertex is an atom. When it has 60 carbon atoms, it is called C60, which has 32 faces, giving it a distinct soccer ball shape. This intricate geometric arrangement is a testament to the complexity and beauty of fullerenes [95, 96].
Fullerenes are made through a series of steps: First, an energetic pulse of a laser impinges on an area of carbon, and the atoms are absolved in the form of gas; then, an inert gas, usually helium, is added to it, and together, they form more than hundreds of atoms. Next, the mixture is introduced into a vacuum chamber, where the gas is expanded and cooled a few degrees above absolute zero [97].
Fullerenes have diverse applications, including lubricants and optics. They can even alter their properties under ultraviolet light [98]. Initially, C60 was produced in limited quantities. However, a significant breakthrough occurred in 1990 when Krätschmer and collaborators devised a method to produce fullerene C60 in large quantities, revolutionizing the field [93, 95, 96, 99]. The current approach for obtaining fullerenes requires an electric arc between two graphite electrodes or a laser sublimating graphite. These molecules become very abundant; they could even be more abundant than those of graphite and diamond since they can be found in the smoke of fire and even in red giant stars (with low surface temperatures and large diameters) [100].
Fullerenes and their derivatives have found numerous applications in nanomedicine, showcasing their versatility. They are used in photodynamic cancer therapy, as suppliers of small molecules, as antioxidants for neurodegenerative diseases, and as MRI/PET contrast agents, among other uses [101].
Fullerenes possess physicochemical and photosensitizing characteristics, making them highly effective in cancer treatment. These properties, such as their ability to scavenge free radicals, their small size enabling tumor penetration, and their capacity to inhibit proto-oncogene activation, tumor growth, and angiogenesis, underscore their potential in nanomedicine and their significant role in advancing cancer therapies [102].
Fullerenes have been explored in theranostic nanoplatforms, such as fullerene/photosensitizing nanovesicles (FCNVs), which offer a range of benefits. These nanovesicles, based on a fullerene trimalonate derivative C70 and the chlorine e6, demonstrate high Ce6 loading efficiency and high sensibility to light; the chlorine e6 has enhanced endocytosis efficiency, in vitro and in vivo biocompatibility and good absorption in the 700–2500 nm electromagnetic light region. Importantly, they are eliminated from the body [98], highlighting their potential in imaging and treating tumors.
3. Mechanisms of Cellular Death
Cellular death is considered a dynamic process that expresses the loss of a strategic war in which survival factors and cytotoxic signals are involved [103]. Multiple forms of cell death exist based on characteristics such as cell type, morphological appearance of various subcellular compartments, stimulus that induces it, and causal mechanisms. [104]. Cell death, a fundamental process, plays a pivotal role in conserving balance in the body. The body continually produces many cells, which must be equally eliminated to ensure this balance [105, 106].
Cell death can be classified into accidental cell death and regulated cell death. Extreme temperatures, mechanical forces, chemical exposure, or osmotic stress can cause unintentional damage. The immune system detects this response, and an inflammatory response is triggered. On the other hand, regulated death is a methodical process that involves specific signaling pathways and molecular mechanisms. Regulated death can include apoptosis, pyroptosis, necroptosis, autophagic cell death, cuproptosis, NETosis, and ferroptosis [105, 107–109]. Each type has unique mechanisms of cell death and can elicit distinct physiological responses [107], due to that they are biochemically, morphologically, genetically, and bioenergetically different [110].
In this context, the type of nanomaterials significantly influences the cellular response, triggering a spectrum of toxicological effects, from physical membrane injury to intracellular modifications [105, 111]. The modulation of the different forms of cell death in response to a foreign agent is crucial for the protection, prevention, delay, or progress of diseases and, therefore, of their treatment [112]. For example, several studies have shown that evasion of apoptosis induced by parasite species or the prevention of deaths such as pyroptosis is a key to controlling certain parasitic diseases [113] or to identifying therapeutic prospects for diabetic kidney disease [112].
3.1. Apoptosis
Apoptosis is an essential process for maintaining cellular homeostasis and regulating the organism. It is a programmed cellular event in which oxidative stress has been proposed to play an important role [108]. Its deregulation, whether by genetic, environmental, or induced mechanisms, may result in pathological conditions, such as excessive cell loss (as seen in autoimmune and neurodegenerative diseases) or cell accumulation that can lead to cancer [114, 115].
Apoptotic cells have unique morphological characteristics: blister-like fragmentation, eliminating these residues by other cells, and nuclear–cytoplasmic condensation. Activation of cysteine–aspartic proteases during apoptosis generates protein fragments characteristic of cleaved polymerase. Apoptosis is responsible for most of the cell death that is regulated by homeostasis [104]. Contrary to necrosis, apoptosis does not generate toxic cellular debris, which prevents inflammation and, therefore, does not affect surrounding cells [116]. Apoptosis controls cancer development by balancing cell growth and death. It is relevant to mention that cancer cells avoid apoptosis, allowing unchecked growth. Targeting and inducing apoptosis in these cells can kill them without harming nearby healthy tissue. Therefore, the cell cycle and apoptosis are crucial for the progression of tumor cells, and it is desirable that a treatment proposal for a disease like this be carried out without harming healthy tissues [117].
The key distinction between apoptosis and necrosis lies in DNA fragmentation and preserving cell wall incorruptibility until the phases of cell death. Apoptosis is a mechanism that depends on energy and the synthesis of new proteins, unlike necrosis, which occurs when there is a failure in the supply of energy and protein synthesis. Apoptosis progresses through several phases, starting with phase D1, where molecular mechanisms initiate the process, followed by phase F, where DNA fragmentation occurs, and phase D2, where nuclear and cytoplasmic destruction originates. Macrophages then phagocytose the remnants [118–121].
Apoptosis is a highly regulated and meticulously organized biological process. It begins with the fragmentation of nuclear DNA and continues with the formation of small vesicles derived from the cell membrane (apoptotic bodies), which consist of internal cellular components. These apoptotic bodies are then phagocytosed by specialized cells. In essence, apoptosis is a precise mechanism that allows cells to safely eliminate those no longer needed or damaged, thus contributing to maintaining and balancing tissues and organs in the body [122]. This process is illustrated in Figure 9 of the document.
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Apoptosis, the process of cell death, is a complex phenomenon with two distinct routes: intrinsic and extrinsic. A stimulus from Bcl-2 proteins triggers the intrinsic route, while the extrinsic route begins with the death of ligands that send signals upon binding to specific receptors. This intricate interplay of molecular events is a fascinating area of study in cancer biology and treatment [123].
Activating apoptosis involves the crucial role of caspases, which are “cell death effectors” or cysteine proteases. These caspases are turned in when the life–death balance is disrupted through the interaction of “cell death activators,” extracellular or intracellular [124].
A significant obstacle in cancer treatment is the resistance of cancer cells to apoptosis, which allows them to evade death and become immortal. However, chemotherapy holds promise in overcoming this resistance and inducing cell death mechanisms in cancer cells, thereby underscoring the critical role of apoptosis in cancer treatment [125].
Apoptosis is initiated by the interactions between a ligand and the receptor in the plasma membrane; the receptors are situated in the cytoplasmic membrane; these establish connections in the extracellular environment and, in turn, constantly receive signals from the outside and neighboring cells. These participate in the processes of cell death and are classified into two groups: Those whose activation always leads to the death of the cell are known as “death receptors”—as are the tumoral necrosis factor receptor and Fas receptor—as are those that play a physiological role, but if overactivation occurs, it can also lead to death (glutamate receptors, thrombin receptors, and voltage-gated ion channels [126]). Most anticancer drugs are designed to induce apoptosis in this type of cell; treatments with different mechanisms of action can cause this type of cell death focused on causing DNA damage [127].
The delicate balance between apoptosis and cell proliferation is a key determinant of tumor growth. Understanding this equilibrium is crucial in our collective efforts to combat cancer. The molecule caspase-3, often utilized as a marker for apoptosis in cancer, serves as an executioner of caspase, further emphasizing its significance in this process [10].
3.2. Necrosis
Necrosis is a process that leads to the cytoplasmic membrane rupture, resulting in the exit of intracellular material and, in turn, triggering an inflammatory reaction. Also, necrosis is an event after cell death. Consequently, necrosis is uncontrolled cell death that leads to inflammatory responses in surrounding tissues, which favors the dissemination of different pathogens in a host in susceptible conditions. Conversely, apoptosis is a controlled cellular death process that occurs in response to specific signals and does not trigger an inflammatory response. It is a natural part of the body’s growth and development, and preserving the balance between cellular death and proliferation is essential. [128]. The digestion of antholytic or heterolytic enzymatic type and protein denaturation causes necrotic cells to appear. The nonspecific apoptosis, the process of cell death, is a complex phenomenon with two distinct pathways: intrinsic and extrinsic. A stimulus from Bcl-2 proteins triggers the intrinsic pathway, while the extrinsic route begins with the death of ligands that send signals upon binding to specific receptors. This intricate interplay of molecular events is a fascinating study area in cancer biology and treatment [123].
It has been shown that some proteins are involved in necrosis induction.
1. RIPK1: This induces TNF-dependent necrosis [127].
2. Cyclophilin D: It is a protein found in the mitochondrial matrix, which is linked in the channel openings of the mitochondrial membrane, causing depolarization [106].
3. Other proteases: Sometimes, the stimulus that causes necrosis induces an increase in intracellular calcium, thereby bringing the activation of calpains and cathepsins after permeabilizing the lysosomes. These proteases inside the cytoplasm cause death in different ways [129].
Figure 10 demonstrates the necrosis process, a sequence of events that includes the swelling of organelles, an increase in cellular volume, and the bursting of the cytomembrane, leading to the loss of intracellular content. This process culminates in the release of cell fragments into the environment. Cellular debris, a significant outcome of necrosis, can trigger an inflammatory response in surrounding tissues, thereby contributing to further damage and inflammation in the affected area. Understanding this process is crucial as it can help mitigate the potential damage and inflammation [131].
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Necrosis, often considered an uncontrollable form of cell death called necroptosis, can now be managed. This management is facilitated by specific signaling routes, with a critical player being the RIP1 serine/threonine kinases [132].
4. Discussion
The nanomaterials that stand out most when applied in medicine are the so-called NPs; they have unique chemical and physical properties intertwined with their size. Some of these properties are magnetic, optical, electrochemical, and catalytic. Similarly, the chemical composition and NP shape influence the properties [133]. Nanotechnology used for biomedicine proposes new strategies to increase diagnostic techniques, using NPs as contrast components applied to cancer therapies. In addition, the delivery systems are made up of three components: The first of these is directed to the system with ligands that have a preference for molecules that are expressed in cancer cells, the second is a payload of drugs and a nanoscale structure to which the fraction that directs and the last is the fraction of charge that is attached [134].
Nanotechnology grants that the release of the drug is minimally invasive since it provides specific devices at a nanometric scale, and this same quality allows them to cellular membranes and cross pores. NPs can alter the pharmacokinetic and safety aspects of parent drugs, enable targeted drug concentration at specific sites, and regulate drug release to maintain synergistic drug concentrations and enhance properties [103]. Another significant contribution that nanotechnology has made is the release of drugs since it increases the effectiveness of medications through the control of administering the required dose and the properties of the nanomaterial. When NPs are explicitly administered to damaged organs, tissues, or cells, they significantly reduce the toxicity associated with the drug. Another critical point is that, by giving a gradual administration of the drug according to cell damage, a decrease in adverse effects can occur because of the mechanisms of cell death reported for different systems or composite materials using carbon-based NPs, shown in Table 1. As can be seen, the mechanisms do not allow us to elucidate whether any of the NPs could be considered more appropriate to cause death by apoptosis or if, on the contrary, it leads to necrosis [162], because that mainly depends on the dosage employed.
Table 1
Cell death mechanism reported in studies with carbon-based nanoparticles. Figures created with Biorender.com.
| Carbon-based nanoparticle | Description | Cell death mechanism reported | Concentration | Source |
| Nanodiamond-based | NDs were used to construct gemcitabine treatment for cancer therapy for the pancreas | The cells in the apoptotic process in the section treated with ND were significantly higher than those treated solely with gemcitabine and PBS | 0.2–5 μg/mL | [135] |
| NDs deliver miR-34a, an important miRNA that impedes tumor development and advance in many types of cancer, including breast cancer | Adding miR-34a-ND significantly increased apoptotic cell death after 72 h. Apoptotic cells were analyzed using an Attune NxT flow cytometer (invitrogen) | [136] | ||
| Detonation nanodiamond with all-trans-retinoic acid (ATRA) | It increased the apoptotic rates of HL-60 cells, enhancing the pharmacodynamics of ATRA for the therapy of leukemia cells | 0.78–25 μg/mL | [137] | |
| Complex of nanodiamond and annonacin | The composite significantly enhances its anticancer activity. Cell apoptosis decreases the width of the mammary ductal epithelium | 200 μg/mL | [10] | |
| Graphene-based | Graphene nanosheets | Graphene nanosheets were evaluated using membrane vesicles and artificial membranes. Increased oxidative stress and cellular levels of ROS mitochondrial dysfunction induce apoptotic process | 5 μg/mL–100 μg/mL | [138] |
| Graphene-based photothermal therapy may enhance cellular uptake. The FA/GO/(H + K) siRNA system was manufactured, and the level of uptake and its distribution within tumor cells in vitro was observed | They showed that siRNA FA/GO/(H + K) could effectively inhibit gene expression within tumor cells, which could cause apoptosis | 12.5–100 μg/mL | [139] | |
| Curcumin–graphene | The material permits the conservation of membrane integrity, allowing apoptosis | 50–1000 μg/mL | [111] | |
| Graphene oxide-based | Commercial graphene oxide | This research evaluated the cytotoxicity of graphene oxide on a rat pheochromocytoma PC12 cell line. It observed apoptosis produced by activation of caspase 9 | 5–60 μg/mL | [140] |
| Graphene oxide | The research concludes that graphene oxide concentrates in the digestive tract, increasing the apoptosis and oxidative rates | 30 μg–50 μg | [141] | |
| Graphene oxide with cisplatin | Graphene oxide and cisplatin induce necrosis in the CT26 cells | 50 μg/mL | [63] | |
| Copper oxide-reduced graphene oxide nanocomposites | The substance produced apoptosis in normal kidney rat cells in the subG1 phase and NRK52E, generating ROS | 100 μg/mL | [61] | |
| Graphene oxide nanocomposites reduced with Copper oxide were produced using a hydrothermal method based on copper nitrate. They were then characterized and examined for crystallinity and purity by X-ray diffraction | Low toxicity was measured by trypan blue and MTT and phenotype. These nanocomposites induce apoptosis presented in rat kidney cells | 100 μg/mL | [61] | |
| The nanocomposite of chitosan, folic acid, and graphene oxide as a carrier of D-pinitol | They quantified the apoptosis-related proteins Bax, Bc12, and caspases. The apoptosis was shown in HepG-2 cells | 0.00–500 μg/mL | [142] | |
| Functionalized graphene dendrimeric system | It produced apoptosis using doxorubicin and melatonin due to downregulating the X-linked inhibition of apoptosis | 10–1280 μg/mL | [143] | |
| Magnetic graphene oxide nanoparticles with an average diameter of 15–20 nm were used to assess the biosafety of the particles in a medical treatment | Magnetic graphene oxide causes ferroptosis in adipose mesenchymal stem cells, but overexpressing GPX4 improved the cell’s survival rate | 10–50 μg/mL | [144] | |
| Iron single-atom graphene oxide was evaluated to measure its ability to be a therapeutic agent for liver cancer treatment | The composite inhibits cell proliferation, induces reactive oxygen species, and promotes apoptosis, pyroptosis, and ferroptosis | [145] | ||
| Graphene oxide was functionalized to improve its cytocompatibility and allow the release of curcumin and doxorubicin in a pH-sensitive manner for cancer treatment | It converts infrared radiation into heat, allowing cancer cells to be selectively heated and destroyed. Heating induced by functionalized graphene during hyperthermia therapy can cause necrosis and apoptosis | 0.5 mg/mL | [146] | |
| Fullerenes-based | Engineered fullerenes | This research examined three different types of fullerenes. Its results show that the carboxylate derivatization of the carbon molecule is a key factor in apoptosis induction | 25–100 μg/mL | [147] |
| Fullerene C60 nanoparticles | Fullerenes suppress ferrous ion accumulation and renal lipid peroxidation that is related to ferroptosis | 200 μg/mL | [148] | |
| Fullerenol C60(OH)24 | Their results indicate that fullerenes adversely affect the endothelium due to proinflammatory and proapoptotic effects on endothelial cells | 1–100 μg/mL | [149] | |
| Quantum dots-based | It assessed the risk of intranasal administration of amino group-functionalized graphene quantum dots | They found that the nanoparticle triggered ferroptosis through augmentation of levels of ferrous iron and lipid peroxides | [150] | |
| Quantitative proteomics and lipidomics were combined to investigate the modifications caused by graphene quantum dots in macrophages | Graphene quantum dots exposure provokes ferroptosis in RAW264.7 macrophages | 25–100 μg/mL | [151] | |
| Fe-Salophen and FeSalen complexes serve as ligands on the exterior of graphene quantum dots | The complexes caused apoptosis in MCF6 cancer cells produced by nuclear fragmentation | 15.62–250 μg/mL | [152] | |
| Carbon dot nanoparticles were used as a gemcitabine nanocarrier for their excellent surface properties and noncytotoxicity | In high concentrations or prolonged exposure, they can damage cells directly, rupture the membrane, and release intracellular contents, leading to cell necrosis. They can also induce apoptosis by activating intracellular signaling pathways that lead to DNA fragmentation and controlled cell death | 0–1.0 mg/mL | [153] | |
| Single-walled carbon nanotubes-based | The SWCNT was grafted with metronidazole (MTZ) onto the surface and was added silver nanoparticles to produce an antibacterial material | Depending on the dose, the MTZ/SWCNTs/AgNPS induced apoptosis in gastric cancer cells | 0.97–500 μg/mL | [154] |
| SWCNTs with the carboxylic acid group were analyzed to test their toxicity in the lungs | Induced autophagic cell death in lung adenocarcinoma A549 cells | 5 mg/mL | [155] | |
| Amine-functionalized single-walled carbon nanotubes | The amine-functionalized carbon nanotube affects oxidative stress, resulting in inflammation and apoptosis | 20 mg/mL | [156] | |
| Carbon nanotubes with flaxseed and chitosan | Carbon nanotube–chitosan nanoparticles with flaxseed extract produce an apoptotic process in the MDA-MB-231 cell line | 71.81 mg/mL | [157] | |
| Multiwalled carbon nanotubes-based | Taurine-functionalized and acid-treated multiwalled carbon nanotubes | The taurine functionalized, and acid-treated multiwalled carbon nanotubes showed toxicity and apoptosis on RAW 264.7 cells | 5–30 μg/mL | [158] |
| Oxidized multiwalled carbon nanotubes | The immunohistochemical analysis of a tumor treated with carbon nanotubes by hyperthermia revealed more cell necrosis than the untreated tumor | 80 μg/mL | [158] | |
| The carbon nanotubes were functionalized, and bromocriptine (BRC) was conjugated. SEM, Raman, and FT-IR tests were performed to characterize the conjugate drug | Bromocriptine conjugates (BRC) produce necrosis due to the direct damage caused, resulting in cellular membrane rupture and release of intracellular contents | 0–200 μg/mL | [159] | |
| The toxicity of MWCNT over Cyprinus carpio was evaluated | It was found that malondialdehyde content increased and diminished glutathione activities. The exposure to nanoparticles induced ferroptosis associated with iron overload | 2.5 mg/L | [160] | |
| Multiwalled carbon nanotubes with ZnO nanoparticles | MWCNT with ZnO was used to analyze the toxicity effect on the intestine of carp. The toxicity and apoptosis were dependent on the concentration ratio | 50 mg/L of ZnONPs and 2.5 mg/L of MWCNT | [161] | |
Some new cell death signaling pathways may guide the production and research of highly specialized and selective biomolecules for treating diseases like cancer. More studies are needed to show the precise path these molecules take to trigger a particular cell death mechanism and to determine the processes by which a drug switches from one cell death process to another. In the hope of eliminating malignancies, several cell death mechanisms can be used independently or together as a cancer treatment. Knowing this, one can efficiently target by combining drugs that cause a variety of cell death pathways [103, 163].
From this point of view, the question arises whether cell death mechanisms can be helpful in the modulation or treatment of a disease. More mechanisms of cell death have been widely studied, such as oxeiptosis, eryptosis, necroptosis, ferroptosis, parthenotos, parapoptosis, oncosis, pyroptosis, alkaliptosis, and podoptosis [1, 104], but it is not easy to identify in the literature if a carbon-based NP system is related to some of them. The authors of this manuscript cannot claim that they are unrelated. Still, we can identify only a few studies that report other types of cell death by identifying a carbon-based NP as their cause.
For example, iron has been identified as having antitumor properties, which is recognized as ferroptosis, a type of programmed cell death [164]. In 2012, Dixon identified ferroptosis as a subtype of programmed cell death [164]. Unique variations in organelles, morphology, and biomarkers differentiate ferroptosis and apoptosis. There are facts about how apoptosis can develop into ferroptosis, which increases cell susceptibility to apoptosis. Apoptosis-stimulating proteins activate the tumor suppressor p53, which in turn causes apoptosis in response to DNA damage [164].
It has been identified that doped nitrogen-GQPs can induce mitochondrial oxidative stress in microglia, which ultimately leads to ferroptosis [165]. Another study showed that ferroptosis is a mechanism underlying MWCNT-induced respiratory toxicity by complicating mitochondrial biogenesis [166]. In addition, the ferroptosis signaling pathway was shown to be associated with exposure to MWCNT in experiments with Cyprinus carpio [160].
On the other hand, copper and calcium, through the processes of cuproptosis and calcicoptosis, are also relevant in cancer treatment. Cuproptosis consists of the abnormal addition of lipoylated mitochondrial enzymes and the control of decreased expression of iron–sulfur group proteins. Calcicoptosis mainly uses the retention and accumulation of calcium ions in tumor cells, which hinders the metabolism and proliferation of tumor cells and cell death [167]. A study reported that naphthalimide NP-conjugated Ca2+−doped carbon dots were used as a potential cancer therapy. The results confirmed that the substance-induced apoptosis by calcicoptosis [168].
Whether and how the different cell death mechanisms connect has not been sufficiently explored. A key discovery that lies at the origin of the nonapoptotic cell death field highlights the potential importance of these connections: Inhibition of caspase activity in some cells can convert a pro-apoptotic stimulus into a pronecroptotic stimulus [104].
Immunogenic cell death can activate the adaptive immune response in the host with a normal immune system. Some synthetic chemotherapy drugs and natural compounds have shown promising results in cancer treatment by triggering the release of molecules associated with damage to trigger the immune response [169].
The primary application of these particles is in drug delivery and delivery systems, including bioactive substances and biosensors. The NPs can be guided to specific diseased, damaged, or altered cells; this contributes to the delivery and release of the drug being more optimal and specific instead of being distributed equally throughout the body as with conventional medications [170, 171].
A clear example of this is NDs; they are part of the numerous structural families of the so-called nanocarbinos, which include amorphous carbons that have a nanometric size, such as fullerenes, diamonds, tubes, onions, horns, rods, etc. These have aroused great interest worldwide because of their large-scale economic synthesis of carbon using explosives, which are small primary particles around 4–5 nm. In addition, they have an easy functionalization on their surface, as well as bioconjugation and biocompatibility [69]. It should be noted that an active target should be chosen to have a greater specificity of cancer and a greater efficiency in the administration of the drug. These target cells can be cancer cells and/or the tumor microenvironment. In addition, NPs must be coated with biological components with a high affinity for the target cells of interest, so they can bind and accumulate [15, 172]. This leads to an interest in targeted therapy, which allows direct administration of chemotherapeutic drugs conjugated with carriers of a nanometric size, such as NDs, on target cells.
In addition to having the properties provided by diamonds, such as high thermal conductivity, hardness, and chemical inertia, they have an electrochemical potential in aqueous and nonaqueous media and extreme electrochemical stability [173]. NDs are commonly described as crystalline diamond cores with combinations of sp2 and sps3 bonds and an octahedral shape. These NPs have excellent compatibility against a variety of biological environments, which were chemically modified as a supportive treatment against cancer [174].
It has been suggested that chemotherapeutic substances molecules are coupled to the surface of NDs through hydrogen interactions with drug molecules and the functionalization of hydroxyl and carboxyl groups, which lie on the exterior face of NDs during synthesis [10, 15, 175]. On the other hand, we have CNTs. These nanotubes are also a potential carrier for medication delivery due to their large internal volume and capacity to penetrate cell membranes. Their unique needle shape allows the drug to be delivered into the cytoplasm of the target cell. Moreover, they possess a large surface area, which can be utilized for coupling many active ligands. However, it is crucial to note that we currently have limited information about the effect of CNTs on normal, tumoral, or embryonic human cells. Therefore, further research is necessary to comprehend the interaction mechanism between nanotubes and human cells [78].
In a study, ZrO2-NP in diamond-like carbon films is used to analyze their bactericidal effects [176]. They found changes in cell geometric forms associated with the apoptosis process. Also, Chow et al. [177] analyzed the biological response of NDs at high dosages (500 μg), establishing that ND does not affect liver function or produce significant changes in multiple tissues. On the other hand, Selvam et al. [166] used Fe-doped NDs in concentrations of 5–100 μg/mL, causing a change in the mitochondrial membrane as an early indicator of apoptosis in hypoxic and normoxic conditions. Horie et al. [75] 1, 0.1, and 0.01 mg/mL of NDs were used to expose A549 and HaCaT cells to evaluate the intracellular reactive oxygen level, mitochondrial activity, lipid peroxidation, and apoptosis. Their results suggest slight apoptosis was produced in HaCaT cells at 1.0 mg/mL concentration. On the other hand, these particles did not interfere with cell viability, membrane injury, or intracellular oxidative stress.
According to the literature, carbon dots with dimensions less than 10 nm report low toxicity in a dose-dependent way. For instance, carbon dots with surface passivation (PET and amines) used with amounts of 100–1000 μg/mL present low toxicity, and the mechanism of cell death is apoptosis [178]. On the contrary, GQPs hydroxylated and carboxylated present minimal toxicity produced by autophagy and apoptosis using 1–200 μg/mL [179]. In the same way, Li et al. [178] reported that carbon QDs with PEG surface passivation present minimal toxicity and cell death by apoptosis using high doses (50–500 μg/mL).
Sun et al. [180] show that nitrogen-doped carbon dots generate a high concentration of reactive oxygen species, inducing apoptosis in the mitochondrial pathway. On the other hand, Karami et al. show that a nanocarrier containing curcumin, chitosan, and carbon QDs with alumina can induce apoptosis. The system was examined in the breast cancer cell line. The results indicated that the interactions between CUR and the nanocarrier caused the sustained release over time and the programmed cell death. Based on these findings, this system is promising as a nanosystem for tumor treatment at a CQD concentration of 0.8 mg/mL [181]. Lee et al. [182] use concentrations from 50 to 500 μg/mL of alendronate-conjugated QDs to obtain imaging via fluorescence signals without necrotic cells in skin tissues. Bravikatti et al. [183] used carbon dots obtained from ginger through a green synthesis, observing areas of inhibition against periodontal pathogens at 500 μg/mL. They observed less antimicrobial activity than standard antibiotics but concluded that the treatment could generate ROS, causing oxidative stress. This damage could result in cell death through necrotic or apoptotic pathways.
Graphene is not used in its extraction form; it must be subjected to a series of processes that grant it virtues that make it biocompatible. The process consists of converting it to PEGylated graphene oxide (adding a layer of polyethylene glycol to graphene oxide). This new structure has a broad selectivity for these cells, making it easier for them to adhere [184].
To obtain graphene oxide, graphite is subjected to an oxidation process to break the van der Waals forces, thanks to the union of functional groups (hydroxyls, ethers, and epoxides) in the aromatic domains [185]. The most used method for synthesizing graphite oxide was reported in 1958 and is called the Hummers method. In this, highly oxidizing agents such as concentrated sulfuric acid, sodium nitrate, and potassium permanganate are used. In the elaboration of this, functional groups highly rich in oxygen of four types are introduced into the material: epoxides (-O-), hydroxyls (-OH), carbonyls (-C = O), and carboxyls (-COOH). The epoxides and hydroxyls are attached to carbon atoms with sp3 hybridizations in the basal plane. In contrast, the carbonyl and carboxyl groups are located on the edges connected to carbon atoms with sp2-type hybridizations according to the Lerf–Klinowsk model. Finally, the complete exfoliation of graphite oxide in polar solvents, like water, is achieved through the application of ultrasound or prolonged agitation, consequently resulting in sheets of one-layer graphite oxide, called graphene oxide sheets [61, 183–188].
The search for a method that can target a specific area of the body without harming others could be found in graphene. Several studies have shown that combining graphene with various drugs makes it possible to increase the load of drug that reaches cancer cells, thus increasing the chances of treatment success. On the other hand, it is feasible to create molecules with a high affinity for this type of cell in which graphene would become part of its components [41, 142, 184–190].
Graphene oxide with polyethylene glycol arms has sparked a promising revolution in cancer treatment. Due to its exceptional absorption of the near-infrared spectrum, its application in photothermal therapy triggers oxidative stress, caspase activation, and mitochondrial depolarization, leading to cell death. This groundbreaking discovery has been demonstrated in mice with carcinoma. Chemical and photothermal therapies were employed to enhance therapeutic efficacy further. Specifically, functionalized GO with six arms of polyethylene glycol was utilized as a carrier for porphyrin (which has a strong absorption band for photothermal therapy) and anticancer drugs (for chemical treatment) [184, 191].
Moreover, graphene oxide has shown the potential to inhibit the formation of tumor spheres and differentiate nonmalignant cells. This dual functionality of graphene oxide, as both a carrier and a direct therapy against breast cancer cells, instills confidence in its effectiveness [184, 192]. Nevertheless, recently, it was found that a low dose of graphene oxide, specifically low doses, can induce significant structural and morphological changes in the cellular membrane. While enhancing lung metastasis models, these changes also increase caution about the possible adverse effects of using graphene oxide in cancer treatment [193].
In another study, creating a polyethylene glycol complex coupled to graphene oxide was possible. This complex combines graphene oxide and polyethylene glycol, enhancing both substances’ properties. The study showed that PEG–graphene oxide affects mitochondrial oxidative phosphorylation (OXPHOS) in malignant mammary cells. This alteration in OXPHOS is an essential step in the energy production process of cancer cell mechanisms. By disrupting this process, PEG–GO reduces gene expression in energy metabolism, inhibiting ATP synthesis of cancer cell lines. This fact is consistent with studies by Zhou et al. [12]. They highlight that the autoinhibitory behavior of PEG–graphene oxide on cancer cell migration could be elevated when coupled with drugs against cancer, opening the possibility of this being used as an antimetastatic agent for cancer therapy [194]. This shows that graphene oxide not only works as a treatment for breast cancer but can also prevent this cancer from metastasizing by invading nearby tissues. Graphene oxide induces mitochondrion-related cascades that control cell survival and functionality [195]. Slekiene and Snitka support this since they suggest that graphene oxide, when combined with folic acid, is not only relevant, but it has been shown that the combination of graphene oxide coupled with the drug doxorubicin raises the reactive species of intracellular oxygen, contributing to increasing the toxic effect in the cell, generating apoptosis and subsequently its disintegration [11].
Concerning graphene, Dai et al. used concentrations from 7.5 to 60 μg/mL to evaluate the cells’ induced apoptotic cell death. They found that the cell apoptotic rate depended on time. On the other hand, Al-Ani et al. [111] analyzed curcumin–graphene on intracellular process and redox-activated apoptosis (at concentrations of 107.8 ± 8.9, 91.7 ± 8.0, and 59.1 ± 8.0 μg/mL). The apoptosis was evident with morphological features observed in micrographs, revealing time depending on redox parameters. The substance produced apoptotic bodies in colorectal malignant cell types. Pandey et al. [196] used graphene oxide NPs with doxorubicin and cisplatin-producing ER stress-mediated apoptosis in HeLa cells. They found evidence of early apoptotic cells and the autophagy inhibitor to induce late apoptosis. Cebadero-Dominguez et al. [197] analyzed the effects of graphene oxide in monocytes and T cells from humans. They did not find changes in apoptosis- or necrosis-related gene expression using a concentration of 1.95–250 μg/mL). Nevertheless, Rodrigues Siqueira et al. found that time and concentration correlated to the toxicity of graphene oxide and reduced graphene oxide. The concentrations that they used were 1–100 μg/mL. According to their results, graphene oxide did not stop cell replication, but they found evidence of higher concentrations of apoptotic and necrotic cells with different mechanisms of toxicity.
The different types of fullerenes are gaining great recognition due to their ability to deliver drugs, being implemented as carriers or “carriers.” Fullerene is transferred to cancer cells by UV/vis light irradiation, triggering biological damage through photodynamic therapy and ROS production. In malignant cells, a fullerene complex linked to polyethylene glycol PEG–C60 can be used, inhibiting DNA translation in cancer cells. Since the discovery of these, biomedical applications have continued to increase since they can generate reactive oxygen species [198].
C60 fullerenes have the remarkable quality of trapping free radicals to protect biological organisms against cellular injury and tissue malformation. Their double bonds are competent and highly effective in interacting with free radicals. Moreover, these can be introduced into the interior of the cells, inhibiting the productivity of free radicals. Similarly, it has been recorded that C60 fullerenes and some soluble derivatives have antioxidant activity, preventing lipid peroxidation and decomposition of the cell membrane [199].
The discovery of fullerols, derivatives of fullerenes with enhanced water solubility, is a significant advancement in the medical and biological fields. With their covalently joined hydroxyl groups, these compounds present unique properties that could revolutionize various applications [200]. In a cytotoxicity model for human breast cancer, the potential of fullerenes to protect against the effects of doxorubicin was tested. The results were promising, with the location of fullerene near the mitochondria, its ability to sequester free radicals, and its role as an artificial electron acceptor that inhibits monooxygenase. This research implies significant improvements in cancer treatment [201].
Concerning fullerene, Sumi et al. analyzed the effect of a bis-pyridinium fullerene derivative in BCR-ABL-positive leukemia cells. Their results demonstrated that the substance-induced apoptosis through ROS generation in a dose-related manner [202]. Funakoshi-Tago et al. [202, 203] found a similar result in cells transformed by the JAK2 V617F mutant, a gene that causes human myeloproliferative neoplasms. They found that the change of pyrrolidinium fullerene with an alkyl group enhances the apoptotic effect.
Finally, CNTs can also be functionalized with drugs, proteins, nucleic acids, and bioactive peptides. This process involves modifying the surface of the CNTs to enhance their biological properties, such as low toxicity and improved immunogenicity. This makes them ideal systems for the controlled release of drugs [204]. Furthermore, CNTs can internalize into cells, crossing cell membranes without causing deformation or altering cell composition. This property allows for the targeted and controlled transport of drugs, making them a promising tool in drug delivery [205].
In addition, CNTs can act as excipients in pharmaceutical formulations, which has garnered significant interest due to their capacity to react with macromolecules such as proteins and DNA. However, their toxicity is still not well understood. CNTs offer several methods for coupling drugs. The first method involves capturing the active ingredients inside the nanotube mesh, while the second method consists of functionalizing the walls of the nanotubes with the compounds of interest [206].
Within tumors, irregular structures lack oxygen and nutrients; however, nanotubes and graphene offer a promising solution with their unique properties (Table 2). Cancer cells in their tumor environment have a tolerance to heat negligible compared to healthy cells in the body. This has led to the exciting possibility of causing apoptosis in cancer cells due to a direct application of heat above the temperature threshold. In producing the denaturation and coagulation of cellular proteins, damage is also made in the membrane to produce death. At the same time, healthy tissues can disperse heat and maintain an average temperature, thus reducing damage [212].
Table 2
Comparison of the application of carbon-based nanoparticles in cancer breast treatments.
| Nanopartícles | Function | References |
| Nanodiamonds | • Carrier | [173] |
| • The nanodiamonds are used for selective tumor targets | ||
| Carbon nanotubes | • These can absorb radiation to get heat, which is why they have been selected as an alternative in thermal therapy against cancer | [50, 207, 208] |
| • Carbon nanotubes are transporters as they cross the plasma membrane and are distributed in different cell compartments | ||
| • Drug delivery | ||
| Fullerenes | • Carrier | [209, 210] |
| • Photodynamic therapy and ROS production | ||
| • Fullerene is biocompatible and can interact with the modulation of protein conformation onto the protein surface | ||
| • The use of fullerenes in photodynamic therapy is limited due to the nanoparticles’ low permeability across cell membranes, so their modification is necessary to improve their efficacy | ||
| • Fullerene with a carboxyl group can release modulated doxorubicin and paclitaxel in cancerous tissues | ||
| Graphene | • It has carrying properties | [211] |
| • It directs the treatment against a specific area of the body without causing harm to others. Various studies have found that combining this material with various chemotherapeutic agents makes it possible to increase the load of medication that reaches the site of action, increasing the chances of successful treatment | ||
The mechanism of action by which nanotubes emit heat when irradiated with CRI is due to the excitation of energy levels that occur in nanotubes and their subsequent relaxation. This relaxation process, known as phonon relaxation, involves an increase in the frequency of the vibrational modes located in the network of carbon atoms, resulting in the heating of the solution. This process is crucial in understanding how nanotubes can induce localized hyperthermia in cancer cells [213]. Other authors have cited that antibodies coupled to nanotubes used in targeted heat therapy are intensely attracted to proteins manufactured by breast cancer tumors, causing the nanotubes to clump together in the tumor. This precise targeting ensures that healthy tissues are not affected. When irradiated by infrared light, these nanotubes absorb this light-producing heat, incinerating the tumor. This highly effective method holds hopeful promise for cancer treatment [214].
Other research points to the use of antibodies coupled to nanotubes. CNTs functionalized with antibodies are captured intensely to proteins produced by breast cancer cells, causing the NP to accumulate in the tumor. Once these accumulate, the area is irradiated with infrared light, which is absorbed by the NPs, causing heat to be generated that incinerates the cancer [215].
Unfortunately, CNTs could be toxic. So, to be used as drug carriers, studies have been done about the factors involved in toxicity and how they can be modulated. The factors essential in determining their toxicity are impurities, structures, length, and surface [216]. When NPs are used in radiotherapy or by thermal ablation, when the cells are heated above a temperature threshold, typically 50°C, inducing apoptosis, this localized thermal effect is generated thanks to the interaction of NPs with IR or radiofrequency radiation [217].
Ghosh et al. [218] analyze the autophagy–apoptotic-related pathways produced by multiwalled and single-walled CNTs in human bronchial epithelial cells. MWCNT indices autophagic response and downregulation of caspase-3/7. Also, SWCNT shows apoptotic processes through proteomic analysis. Also, Wang et al. [158] show that taurine-functionalized MCWCNTs induce pulmonary toxicity in mice. Also, Cheng et al. [219] use 200 μg/mL of SWCNT to induce apoptosis in the same pathway.
A study compared the toxicity of carboxylated multiwall CNTs (MWCNT-COOH) and pristine nanotubes (p-MWCNT) in human liver cells. The p-MWCNTs showed more significant toxicity, inducing apoptosis, oxidative stress, cell damage, and cell cycle arrest, while the MWCNT-COOH, thanks to their functionalization with carboxylic groups, presented less severe effects. The mitochondrial apoptotic pathway was involved in both cases but less activated in MWCNT-COOH, suggesting greater safety for in vivo applications, although more studies are needed to confirm its biocompatibility [220].
Gutierrez-Hernandez et al. [221] identify the apoptosis pathway produced in a scaffold of cellulose/MWCNT. The concentration of MWCNT was from 0.25 to 0.5 mg/mL. The apoptotic process is promoted by the expression of TP53, which is involved in the genome reparation of the osteoblasts. On the other hand, Rezaei et al. [222] identify that MWCNT concentrations of 15 and 20 mg/L caused apoptotic and necrotic cells in liver tissues.
Apoptosis and necrosis could be reported for some systems that include carbon-based NPs, as shown in Table 3.
Table 3
Cell death induced by carbon-based nanoparticles.
| Carbon-based nanoparticle | Cell death mechanism | References |
| Nanodiamonds | • Apoptosis | [75, 137, 177, 223–225] |
| • Necrosis | ||
| Carbon nanotube | • Apoptosis | [64, 75, 137, 152, 154, 157, 160, 223, 224, 226] |
| • Necrosis | ||
| Graphene | • Apoptosis | [11, 63, 142, 152, 227–229] |
| • Necrosis | ||
| Fullerene | • Apoptosis | [147, 202, 203, 230–235] |
| • Necrosis | ||
5. Conclusion
It was determined that the four types of carbon-based nanopolymorphisms can produce cell death. Carbon-based NPs, such as graphene, CNTs, NDs, and fullerene, can exhibit various mechanisms leading to cell death, which depend on their shape, size, surface functionalization, and interactions with biological medium. Cell death induced by NPs includes membrane and DNA damage, mitochondrial dysfunction, and oxidative stress.
Furthermore, carbon NPs may directly interact with cell membranes, causing physical damage and perturbing membrane integrity. This disruption can lead to cell death through ferroptosis, necrosis, or apoptosis. Defining a prevalent mechanism for each NP depends on a dose-responsive manner. The concentrations at which the effect generated by the different carbon-based NPs have been seen are very variable; however, most of the studies carried out reveal that the cytotoxic effect analyzed is in the concentration range between 100 and 500 μg/mL. In several analyzed studies, it only was possible to find that NDs were shown not to be cytotoxic.
In summary, carbon-based NPs can induce cell death through multiple mechanisms. Understanding these pathways via mechanisms is crucial for safely designing and applying carbon NPs in various biomedical applications, such as cancer treatments.
Funding
This work was supported and sponsored by Juarez City Autonomous University.
Acknowledgments
The authors express their gratitude to Miss Andrea Sofía Rangel Martel for her assistance with language editing, as well as to the editors and anonymous reviewers for their valuable feedback and insightful suggestions. All figures in this manuscript were generated using Biorender.com.
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Abstract
Using carbon-based nanoparticles, such as diamond, graphite, fullerene, and nanotubes, has increased their research as possible strategies for drug delivery to control diseases, especially cancer. However, because these materials, when interacting with the living environment, release substances that are capable of inducing cell death by themselves, it is of vital importance to analyze the type of cell death that the particle can induce. Although there are different efforts to describe the kind of nanoparticles used to treat diseases such as cancer, no paper explains the mechanisms of cell death induced by different nanoparticle systems. Therefore, this paper attempts to gain cutting-edge information on using carbon-based nanopolymorphisms and the mechanism of cell death that the particles produce. In conclusion, carbon nanoparticles can interact directly with cell membranes, causing physical damage and disturbing the integrity of the membrane. This alteration can mainly lead to cell death by necrosis or apoptosis. The definition of a predominant mechanism for each nanoparticle depends on a dose-dependent manner. Primarily, the concentrations used to analyze cytotoxicity were 100–500 μg/mL. In several studies analyzed, it was only possible to find that the nanodiamonds proved not to be cytotoxic.
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Details
; Vargas-Requena, Claudia-Lucía 2
; Sifuentes-Chavarría, Josue-Itan 2
; Yepes-Mendoza, Maileth-Yoelis 3
; Daniel-Santiago Palacio-Castillo 4
; Jimenez-Vega, Florinda 2
; Olivas-Armendáriz, Imelda 5
1 Architecture, Design, and Art Institute Department of Design Juarez City Autonomous University Av. Del Charro 450 Norte, C.P., 32310 Ciudad Juárez Chih., Mexico
2 Biomedical Sciences Institute Department of Chemical and Biological Science Juarez City Autonomous University Av. Benjamín Franklin No. 4650, Zona Pronaf Condominio La Plata, 32310 Ciudad Juárez Chih., Mexico
3 Engineering Faculty Simón Bolivar University Cra. 59 #59-65, Nte. Centro Historico, Barranquilla Atlántico, Colombia
4 Engineering Faculty Antigua Estación del Ferrocarril Manizales Autonomous University Manizales Caldas, Colombia
5 Department of Physics and Mathematics Engineering and Technology Institute Juarez City Autonomous University Av. Del Charro 450 Norte, Ciudad Juárez C.P., 32310 Chih., Mexico