Carbon dots (CDs), which are also popularly known as carbon quantum dots (CQDs) or graphene quantum dots (GQDs), are small, zero-dimensional carbon nanomaterials that are extensively applied in biomedicine. These nanomaterials possess exceptional chemical, optical, electrochemical, and photoelectric properties. This article focuses on the key properties of CDs and their application in biomedical research.
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Carbon Dots: A Brief Overview
CDs are bright photoluminescent quasi-spherical nanoparticles composed of either amorphous or nanocrystal core, with sp2 or sp3 carbon hybridization. Typically, the size of CDs is below 10 nm. CDs were accidentally discovered by scientists while separating and purifying single-walled carbon nanotubes (SWCNTs). Later, they observed the fluorescence characteristics of CDs, which is extremely beneficial for biomedicine research.
There are two approaches to synthesizing CDs, namely, top-down and bottom-up methods. The top-down method involves the conversion of carbonaceous macromolecules into nano-sized CDs via dispersion or destruction by chemical, physical, or electrochemical methods. In the bottom-up process, the carbonaceous molecules undergo a series of polymerization and carbonization reactions via chemical processes to generate CDs.
CDs contain unique isotropic shapes with ultrafine dimensions with tuneable surface functionalities. For instance, the oxygen content of oxidized CDs varies between 5 and 50% by weight, and also contains many carboxyl and hydroxyl groups on their surface, making them more soluble in an aqueous medium. Incorporating several organic, inorganic, polymeric, or biological entities modifies their physical properties.
Key advantages of the application of CDs in clinical studies are its photobleaching resistance, low toxicity, hydrophilic surface, easy passivation, good cellular compatibility, and chemical stability. In contrast, semiconductor quantum dots are synthesized using heavy metals, making them less suitable for medical applications.
Properties of Carbon Dots
Scientists have studied CDs extensively, owing to their light-emitting capabilities. CDs can absorb a broad spectrum of light, i.e., from the UV region to the visible range. As CDs are photon-harvesting agents, maximum absorbance occurs at a short wavelength. The absorbance property of CDs can be modified via surface passivation. Scientists have developed red, green, and blue luminescent CDs using three isomers of phenylenediamines via the hydrothermal method.
One of the most important properties of CDs is its tunable photoluminescence, which is responsible for the high-intensity emission peaks from the ultraviolet to the visible to the NIR region. The phenomenon of getting excited via chemical reaction (chemical luminescence), electrochemical reaction (electrochemical luminescence), and absorption of photons (photoluminescence) are useful in clinical studies.
Based on various cytotoxic assays, researchers have stated CDs are non-toxic. Studies have reported that CDs passivated with polyethylene glycol (PEG) remained non-toxic up to a high concentration. No cytotoxicity was observed when these were injected into mice for up to twenty-eight days. Another study showed that when passivated with polyetherimide (PEI) and introduced to HT-29 cells, CQDs exhibited no cytotoxicity.
Carbon Dots and Biomedicine Innovations
CDs are luminescent carbonaceous nanoparticles, applied in many biomedical innovations due to their low cytotoxicity, high aqueous solubility, chemical inertness, and facile synthesis. These are used in bioimaging, biosensing, drug/gene delivery, pharmaceutical formulations, and photothermal therapy. Some of the biomedical innovations associated with the application of CDs are discussed below:
CDs present immense opportunities for bioimaging and bio labeling studies because of their inherent luminance properties, low cytotoxicity, and biocompatibility. Several in vitro and in vivo bioimaging studies have used QDs. QDs are often preferred over fluorophores and organic dyes because of their stability, high fluorescence, and ability to resist metabolic degradation. The fluorescence property of CDs helps differentiate between the living and apoptotic cancer cells.
QDs can penetrate cells via endocytosis but cannot reach the nucleus. However, to overcome this shortcoming, scientists coupled CQDs with TAT, a human immune deficiency virus-derived protein, which enabled CQDs to accumulate in cells and reach the nucleus.
Scientists revealed that emission at NIR spectral region is extremely important for in vivo nanotechnology-based studies, which require body tissue transparency in the NIR spectrum. Researchers have incubated breast cancer cells with CDs whose size was less than 5 nm for bioimaging.
CD-based biosensors are used to monitor glucose, phosphate, cellular iron, potassium iron, and pH. Researchers use CDs for fluorescent assay to detect nucleic acids via selective single-base mismatch. Several studies have indicated that Reactive oxygen species (ROS) are important biomarkers of various diseases, e.g., cancer, inflammation, arthritis, DNA damage, infection, etc. Scientists have developed ROS sensors using encapsulated CQDs in hydrogel made of ascorbic acid.
Using an electrochemical method, scientists have synthesized CDs to develop a two-photon fluorescent probe that can detect changes in pH levels from 6 to 8.5 with high sensitivity and specificity. This probe has been used for biosensing and bioimaging to monitor pH changes in living cells and tissues, especially malignant lung cells. As CDs possess high surface functionalization, considerable stability, and good electrical conductivity, they are applied to develop electrochemical biosensors to detect biomolecules, e.g., dopamine, glucose, DNA, cholesterol, ascorbic acid, hemoglobin, human carcinoembryonic antigen, etc.
Drug and Gene Delivery
Treatment of several diseases requires a precise drug delivery platform. CDs offer dual functions, i.e., they act as a nanocarrier for specific bioactive compounds and promote bioimaging. CDs conjugated with theranostic doxorubicin (DOX) revealed targeted drug release in tumor cells in a pH-dependent manner. Additionally, the fluorescence property of CDs promotes image-guided drug delivery.
Scientists stated that these are excellent gene delivery carriers that have been used in the treatment of lung cancer. In this application, CDs encapsulating siRNAs were efficiently released to the targeted sites.
Studies have indicated that photothermal therapy, which is also referred to as photodynamic therapy, plays an important role in the treatment of cancers. Two of the main advantages associated with photothermal therapy are fewer adverse effects and non-invasiveness. Scientists have reported that SWCNT-PEG-Fe3O4-CQD nanocarriers are effective against cervical cancer.
References and Future Reading
Phan, T.M.L. and Cho, S. (2022) In Vivo and In Vitro Biochemical Behaviors of Bioinorganic Materials for Advanced Medical and Pharmaceutical Technology. Bioinorganic Chemistry and Applications. 9303703, pp. 32. https://doi.org/10.1155/2022/9303703
Azam, (2021) Carbon Quantum Dots for Biomedical Applications: Review and Analysis. Frontiers in Materials,8. https://doi.org/10.3389/fmats.2021.700403
Koutsogiannis, P. et al. (2020) Advances in fluorescent carbon dots for biomedical applications. Advances in Physics: X, 5(1). DOI: 10.1080/23746149.2020.1758592
Ross, S. et al. (2020) The analytical and biomedical applications of carbon dots and their future theranostic potential: A review. Journal of Food And Drug Analysis, 28(4). https://doi.org/10.38212/2224-6614.1154
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