Carbon quantum dots and their biomedical and therapeutic applications: a review

Abstract

In recent years, nano carbon quantum dots (CQDs) have received increasing attention due to their properties such as small size, fluorescence emission, chemical stability, water solubility, easy synthesis, and the possibility of functionalization. CQDs are fluorescent 0D carbon nanostructures with sizes below 10 nm. The fluorescence in CQDs originates from two sources, the fluorescence emission from bandgap transitions of conjugated π-domains and fluorescence from surface defects. The CQDs can emit fluorescence in the near-infrared (NIR) spectral region which makes them appropriate for biomedical applications. The fluorescence in these structures can be tuned with respect to the excitation wavelength. The CQDs have found applications in different areas such as biomedicine, photocatalysis, photosensors, solar energy conversion, light emitting diodes (LEDs), etc. The biomedical applications of CQDs include bioimaging, drug delivery, gene delivery, and cancer therapy. The fluorescent CQDs have low toxicity and other exceptional physicochemical properties in comparison to heavy metals semiconductor quantum dots (QDs) which make them superior candidates for biomedical applications. In this review, the synthesis routes and optical properties of the CQDs are clarified and recent advances in CQDs biomedical applications in bioimaging (in vivo and in vitro), drug delivery, cancer therapy, their potential to pass blood-brain barrier (BBB), and gene delivery are discussed.

Fig. 1. (a) Synthesis route of CQDs from carbon source of carrots through hydrothermal method, reprinted with permission from ref. 78, copyright 2018 Elsevier Ltd., (b) synthesis of CQDs from the pyrolytic residue by chemical oxidation, when the Cu²⁺ ions are present in the solution, the fluorescence quenches, reprinted with permission from ref. 79, copyright 2018 Elsevier Ltd., (c) synthesis of CQDs from carbonization of polyacrylamide chains by formation a microemulsion. Reprinted with permission from ref. 80, copyright 2013 American Chemical Society.

Fig. 2. (a) Synthesis of CQDs through CVD method using C₂H₂ as the carbon source, reprinted with permission from ref. 47, copyright 2016 Elsevier Ltd., (b) synthesis of the CQDs through the hydrothermal method using alanine and ethylenediamine, reprinted with permission from ref. 66, copyright 2015 Elsevier Ltd., (c) microwave-assisted pyrolysis synthesis of magnetofluorescent CQDs from crab shell, reprinted with permission from ref. 81, copyright 2017 American Chemical Society.

Fig. 3. Fluorescence images of CQDs (top) and CdSe/ZnS commercial QDs (bottom) in the infinite dilution conditions derived from numerous QDs in several images and their relative fluorescence intensity with excitation at 458 nm (middle left); the two-photon fluorescence intensity image by excitation at 880 nm (middle right), reprinted with permission from ref. 114, copyright 2009 American Chemical Society.

Fig. 4. Excitation and emission spectra of the CQDs that were synthesized via heating of the ascorbic acid aqueous solution; (a) emission spectra at excitations ranging from 290 nm to 500 nm, (b) upconversion seen in the emission spectra of the CQDs, the PL emission spectra for excitations from 805 nm to 1035 nm, reprinted with permission from ref. 152, copyright 2012 Royal Society of Chemistry.

Fig. 5. (a) Synthesis method of CQDs from phenylenediamine isomers, oPD, mPD and pPD that results in o-CQDs, m-CQDs, and p-CQDs, respectively. (b) Photographs of the ethanol solutions of o-CQDs, m-CQDs, and p-CQDs in daylight (left) and under UV excitation with the wavelength of λ = 365 nm (right), (c) the m-CQDs, o-CQDs, p-CQDs mixtures in PVA films under excitation with a wavelength of λ = 365 nm: (I) m-CQDs; (II) o-CQDs; (III) p-CQDs; (IV) o-CQDs/m-CQDs/p-CQDs = 2 : 4 : 1 (w/w/w); (i–iv) o-CQDs/m-CQDs = 1 : 8, 1 : 4, 1 : 2, and 1 : 1; (v–viii) o-CQDs/p-CQDs = 4 : 1, 2 : 1, 1 : 1, and 1 : 2; (ix–xii) m-CQDs/p-CQDs = 1 : 4, 1 : 2, 1 : 1, and 4 : 1 (all ratios are w/w), (d) the normalized PL spectra of the PVA films with m-CQDs, o-CQDs, and p-CQDs (UV excitation of λ = 365 nm), (e) confocal fluorescence microscopy of m-CQDs, o-CQDs and p-CQDs of MCF-7 cells at a constant laser excitation wavelength of 405 nm, reprinted with permission from ref. 154, copyright 2015 John Wiley and Sons.

Fig. 6. Different CQDs synthesized through different controlled carbohydrate carbonization methods, the solution containing CQDs and regarding absorption (solid line), excitation (dashed line) and emission (colored line) spectra; the emission spectra are recorded by excitation at 370 nm for blue CQDs, at 400 nm for green CQDs, at 425 nm for yellow CQDs, and at 385 nm for red CQDs, reprinted with permission from ref. 155, copyright 2013 Springer Nature.

Fig. 7. (a) The in vivo fluorescence images of CQDs that are injected into a nude mouse; the excitation wavelengths are indicated above each image. The fluorescence signal and tissue autofluorescence can be seen in red and green emissions, respectively. (b) Signal-to-background separation of the image taken under 704 nm excitation, reprinted with permission from ref. 148, copyright 2011 John Wiley and Sons.

Fig. 8. (A) The in vivo images of the different organs of Kunming mice which are injected with CQDs at different post-injection periods (absorption wavelength of 405 nm and an emission wavelength of 500 nm), (B) the CQDs inside and around single neuron under CLSM; the arrow shows nucleus, reprinted with permission from ref. 163, copyright 2012 Springer Nature.

Fig. 9. Comparison of CQDs (top) and C–ZnS dots (bottom) after subcutaneous injection (a) bright field, (b and d) as-detected fluorescence, (c and e) color-coded images (the excitation/emission wavelength are indicated on the images), reprinted with permission from ref. 165, copyright 2009 American Chemical Society.

Fig. 10. The in vivo fluorescence imaging and PA imaging of the mice injected with CQDs, (a) the real-time red fluorescence images of the mice after i.v. injection of CQDs at different post-injection times, (b) the fluorescence intensities of different areas 24 h after the CQDs injection, (c) the variation of average fluorescence intensity emitted from tumor during time, (d) the PA imaging of the tumor (in mice) after 0, 2, 4, 6, 8 and 24 h post-injection, (e) mean intensity of the tumor as a region of interest (ROI) up to 24 h post-injection, reprinted with permission from ref. 149, copyright 2015 John Wiley and Sons.

Fig. 11. In vivo and ex vivo imaging of glioma-bearing mice administered with polymer-coated nitrogen-doped CQDs (5–15 nm) intravenously, (A–E) imaging after different post-injection periods, (F) ex vivo imaging of brain, heart, liver, spleen, lung, and kidney 90 m after CQDs administration, (G) brain coronal imaging 90 min after CQDs administration, reprinted with permission from ref. 191, copyright 2015 John Wiley and Sons.

Mohammad Jafar Molaei