INTRODUCTION:

Quantum dots (QDs) are semiconductor nanocrystals that show unique electronic and optical properties.¹ The size range of quantum dots is 1.5-10nm². QDs were first discovered by Russian physicist Alexei Ekimov In 1980.Quantum Dots are composed of groups II-VI or III–V elements of the periodic table³. There are various uses of QDs across the world due to their adaptable properties like, photostability, adjustable emission spectrum, and large quantum yield Quantum dots are nanomaterials with inherent electrical characteristics QD can be used as drug carrier vehicle and as a diagnostic in the field of nanomedicine⁴.

Very recently the application of nano-materials is seen in the areas of diagnosis as well as treatment of various diseases like, cardiovascular ailments, diabetes, neuro-muscular diseases and cancer⁵.

Today QDs are being used in different areas of science such as bio-labelling, LED technology, lasers, and solar cells⁶. Quantum dots are commonly known as Semiconducting nanoparticles possess unique size and shape, they have attracted much attention in biomedical imaging to enable diagnostics⁷. Lot of study has been done on graphene-family nanomaterials like graphene oxide and reduced graphene. Result of all these studies is satisfactory which resulted in evolution of graphene products into the GQDs in 2008 by Ponomarenko and Geim. This study made a breakthrough in the biomedical applications⁸. Further study generated interest of scientists in exploring more about GQDs, in this study researchers found that, biological applications of GQDs are more than that of any other quantum dots⁹. Graphene Quantum Dots are carbon-based zero-dimensional fluorescent nanomaterials which has a graphene lattice inside. Solubility of GQDs is more than carbon nanotubes. These are nanostructured materials whose size ranges usually less than 20nm while they can be of maximum size of 60nm, these size properties make them easily penetrate biological membrane¹⁰. Stability wise suspension of GQDs can remain very stable even in high electrolyte concentration and lower pH. The luminescence characteristics of GQDs are well considered, and the fluorescence is the reason for many of their biological applications like biosensing and bioimaging¹¹. These extraordinary properties make GQDs a hopeful candidate for disease diagnosis, bioimaging and carriers for the drug in the biomedical field over conventional QDs¹². Because of the nanosized fragments, GQDs initiate quantum effect and excitation confinement. They exibit excellent electro-optic properties like luminescence on excitation, high surface area and nonzero band gap¹³.

Luminescence properties is an elementary difference between GQDs and graphene. An atomic monolayer marks pure graphene a zero band semiconductor which have an infinite exciton Bohr diameter. Whereas the excellent physicochemical properties are offered by the heterogeneity of GQDs¹⁴. In recent studies it’s seen that due to presence of a polar group like oxygen in the structure the oxidised GQDs showed the improved polarity and peak emission wavelength properties. As in case of carbon nanotubes, due to the greater mechanical and thermal properties of graphene, many researchers have inspired and they considered GQDs for application in their respective research areas. Considering this background of study, there properties are having a least interest as they don’t play any vital role in properties of GQDs¹⁵. Poor dispersion in solvent and the aggregation are some of the major limitations of the graphene¹⁶. The methods for synthesizing Graphene Quantum Dots (GQDs) can be categorized into two main classes, first is top-down method and second is bottom-up method. In Top-down approach there is an involvement of straight cutting of carbon materials to get nanoscale GQDs. For this purpose different techniques like electron beam lithography techniques and liquid exfoliation technique can be used¹⁷. Top-down approach has the advantages of plentiful raw materials. They usually produce functional groups containing oxygen at the advantage, this results in their increased solubility and maximizing functionalization. On the other hand, non-controllable shape and size, low yield, large quantity of defects are the disadvantages of this approach¹⁸. Whereas the bottom-up approach is grounded on the growth of suitable molecular precursors which may be either polymers or small molecules, into nano-sized GQDs. For this purpose approaches like metal catalysed methods, soft-template, hydrothermal and microwave-assisted hydrothermal methods can be used. Low defects controllable size, shape and morphology are some advantages of this method over top down method. Conversely, the bottom-up technique has handful of disadvantages also like smaller dot size, aggregation issue and poor solubility. In further part let’s see about these approaches one by one¹⁹. Properties of the GQDs can be affected due to the technique used for their preparation. Primarily their properties depends in the heterogeneity behaviours¹⁵. When it comes to the applications, GQDs have a wide range of applications in different biomedical areas. GQDs can be active as a nanocarrier in the targeted drug delivery, bio imaging and sensing agent and furthermore they contains a wide variety of biological activities¹¹. Different types of the nanoparticle have been used in biomedical applications, but GQDs have a superior position among all those nanoparticles. Different types of in-vivo and in-vitro studies conducted on the toxicity profile of GQDs resulted in conclusion that they are having more biocompatibility and the also are non-toxic in nature¹³. Blood Brain Barrier (BBB) permeability is one of the chief features of GQDs. For crossing the BBB a molecule must have good lipid solubility and must have a size less than 40Da. Passive diffusion or the glucose transporter are the main mechanisms involved in the transport of the GQDs across BBB²⁰. Small size of GQDs and surface functionalization allows easy permeation across Blood Brain Barrier which helps in the targeted drug delivery to the brain. If BBB permeable precursors are used in the preparation of the GQDs then they can easily cross the BBB¹¹. In this particular review we are focusing on the different synthesis methods, characterization and applications of the GQDs.

2. Syntheses of Graphene Quantum Dots:

The methods for synthesizing Graphene Quantum Dots (GQDs) can be categorized into two main classes, first is top-down method and second is bottom-up method. In Top-down approach there is an involvement of straight cutting of carbon materials to get nanoscale GQDs. For this purpose different techniques like electron beam lithography techniques and liquid exfoliation technique can be used¹⁷. Top-down approach has the advantages of plentiful raw materials. They usually produce functional groups containing oxygen at the advantage, this results in their increased solubility and maximizing functionalization. On the other hand, non-controllable shape and size, low yield, large quantity of defects are the disadvantages of this approach¹⁸. Whereas the bottom-up approach is grounded on the growth of suitable molecular precursors which may be either polymers or small molecules, into nano-sized GQDs. For this purpose approaches like metal catalysed methods, soft-template, hydrothermal and microwave-assisted hydrothermal methods can be used. Low defects controllable size, shape and morphology are some advantages of this method over top down method. Conversely, the bottom-up technique has handful of disadvantages also like smaller dot size, aggregation issue and poor solubility. In further part let’s see about these approaches one by one¹⁹.

2.1. Bottom-up methods:

As previously mentioned bottom-up approach is grounded on the growth of suitable molecular precursors which may be either polymers or small molecules, into nano-sized GQDs. However, this approach includes different techniques like hydrothermal method, microwave-assisted hydrothermal method, soft-template method and metal-catalyzed method^18,19.

2.1.1. Hydrothermal method:

In this technique, the precursors are transformed into GQDs by strong oxidation with suitable chemicals under conditions liken high temperature and pressure¹⁷. GQDs with diverse size distribution with tuneable fluorescence can be synthesized by this technique¹¹. In hydrothermal crystallization of substances is done with the help of different methods from high vapour pressure to high temperature aqueous solutions. Many researchers developed single crystalline GQD by hydrothermal method. In the first step Hummers method is used to convert natural graphite powder to GO sheets by oxidation. In the second step, with the use of tube furnace GO sheets are reduced thermally to obtain Graphene sheets (GSs) in nitrogen atmosphere. In next step, cocn H2SO4 and HNO3 are utilised to oxidise the GSs under ultra-sonication, then dilution of this mixture is done with the help of deionized water. In order to remove acids this solution is filtered with the help of microporous membrane. Further for hydrothermal treatment the previously oxidised and purified GSs are made dispersion in deionized water, NaOH is added to maintain pH at 8. Heating of this suspension is carried out in Teflon lined autoclace. The brown filter solution is obtained by filtration of black suspension obtained from previous step, after cooling of the autoclave. Dialysis of colloidal dispersion is carried out using a dialysis bag yielding a strong fluorescent graphene nanoparticles^{21,22, 23,24}.

2.1.2. Soft-template method:

For environmental friendly synthesis of GQDs a new method was developed. The soft-template method is low cost and simplistic. This process does not include complicated processes for purification and separation. This method for production of GQDs is now gaining attention and being used for mass production^17,25.

2.1.3. Microwave-assisted hydrothermal method:

Hydrothermal method for development of GQDs is a time consuming method. For the replacement of this method a fast and effective method was developed which incorporates use of microwave so the method named Microwave assisted hydrothermal method. Hydrothermal method used to take couple of hours for getting the yield, due to this reason for industrial mass production of GQDs it was not a best fit method. Breakthrough was made as microwave can reduced this time to the few minutes to several seconds. In this method microwave assisted irradiation of natural graphite powder is done for synthesizing GQDs. Firstly using H2SO4 as medium graphite powder is sonicated, then slowly addition of KMnO4 is done. Throughout the process temperature is kept below 25^oC. Further this mixture is heated and with the help of MAS-II microwave it is refluxed, the power of microwave is kept 600W for 1 hr. After cooling this transparent suspension, dilution with deionized water is done. In an ice bath the neutralization with the help of NaOH to the pH 7 is done. Further to obtain brown filtrate and separating large sized graphene nanoparticles the filtration of diluted suspension is done with the help of 200nm nano-porous membrane. Dialysis of colloidal dispersion is carried out for 7 days using a dialysis bag yielding a strong fluorescent graphene nanoparticles^{23,24, 26,27,28}.

2.1.4. Nanolithography:

Scientists have found that ultra- high-resolution electron beam can be incorporated for the cleaving of graphene to optimum desired size. Although precision of this method is very high the yield obtained from this technique is very less and it requires specialized equipment. Lee et al. described on the size-controlled production of even GQDs using self-assembled block copolymers (BCP) as an engrave mask on graphene films developed by chemical vapour deposition (CVD). Even though this technique caused in a low yield, it give rise to very uniformly sized particles for penetrating effects of size and functionalization^29,30,31,32.

2.2. Top down Methods:

Top-down method is completely opposite of bottom up method considering precursor and product relationship. For preparing GQDs by using top-down method bulk materials are broken down to smaller nano-sized materials by either chemical or physical means. This method was used for preparation of first GQDs. This method is has numerous applications in discovery of novel materials and researching their structure and properties. In this approach various methods like liquid extrafolation, electron beam lithography, by means of hydrothermal, electrochemical, oxidation and ultrasonic are includes, let us see about the briefly^18,19.

2.2.1. Oxidative cleavage:

The principle involved in the oxidative cleavage is the cleaving of C-C linkage existing in precursors like carbon nanotubes, graphene and graphene oxide with the help of acid treatment. The acids used in the acid treatment process include nitric acid, sulphuric acid and other oxidative agents. Recent studies shown that GQDs can be obtained by treating graphene oxide sheets with nitric acid to form small cleaved pieces. Further for surface passivation this is treated with polyethylene glycol followed by hydrazine hydrate to get nanosized GQDs. Oxygenated groups like carbonyl (−(CHO)−), carboxyl (−COOH), epoxy (eOe), hydroxyl (−OH) and ether (−OCH3) can be removed by treating with oxygen, resulting in increased surface properties, solubility and optoelectronic properties^{11,33,34,35,36}.

2.2.2. Electrochemical Cutting:

The GQDs of size 3-5nm can be obtained by electrochemical method. This method involves cleaving of oxygen plasma treated graphene film. The oxygen plasma treating in this step increases hydrophilicity of product. With conversion efficacy of 1.28% these quantum dots were incorporated in solar cells. The stability of this product in water is observed to be several months. Another research group successfully synthesized GQSs having great water solubility, high yield and good size uniformity. The method used for production includes exfoliating graphite electrochemically then instead of high temperature but at room temperature the resulting nano-sized GQDs are reduced with the help of hydrazine^37,38,39,40.

2.2.3. Liquid exfoliation method:

In these days preparation of GQDs can be done by using liquid-phase exfoliation method. In this technique strong oxidizing agents can be used for intercalation of graphite. Then by using thermal or chemical methods expansion of graphite layers can be carried out. This approach for synthesizing GQDs has gain attention of many research groups. In preparation of GQDs for cutting of graphene acid is usually required. The GQDs prepared from this method shows a distinct blue luminescence. It yields product of uniform size and bulk carbon materials can be incorporated in synthesis^{18,41,42,
43,44}.

3. Characterisation of Graphene Quantum Dots:

To understand morphology, composition and structure of nanomaterials characterization is an essential step. GQDs contain unique characteristics like physical, chemical and optical features. Different characterization techniques can be used for the measurement of these different properties. Techniques used for characterization of GQDs are UV–Vis spectroscopy, X-ray Diffraction (XRD), atomic force microscopy (AFM), transmission electron microscopy (TEM), transmission electron microscopy (TEM), X-ray photoelectron spectroscopy (XPS), Raman spectroscopy, PL, atomic force microscopy (AFM) and Fourier transform infrared spectroscopy (FT-IR). These techniques are used to analyse electron state, functional group composition, crystal structure, surface morphology, fluorescence property, surface morphology, and vibrational patterns^{45, 46}.

3.1. X-ray diffraction (XRD):

For the identification of crystalline or amorphous phase XRD is a very important technique. It is used to understand particle size distribution and for understanding the extent of crystallinity. By determining the accurate atom arrangement, we can gather valuable information about dimensions of unit cell. When a surface of crystal gets hit by incident X-ray, the plane of crystal diffracts the incident ray in a specific direction. The intensity of the diffraction signal is plotted against the angle of the detector. The important information like disorder and chemical bonding can be obtained along with the 3-D electron density picture within the crystal can be obtained. Though this technique has such advantages it is still having some limitations like 1) XRD of large molecule appear less resolved in comparison with micro molecules. 2) This technique does not detect materials which have mixture of crystallinities below 5%. 3) There seems a broadening of XRD pattern in case of smaller particles, though particle remain their original crystal structure it has impression as amorphous structure. At around 20-25a broad peak is observed in case of GQDs which corresponds to XRD plane of graphite. Depending upon the inter-planar distance of graphene layers the shifting of peak value is observed^47,48,49.

3.2. Raman spectroscopy:

With the help of Raman spectroscopy one can gain information related to the molecular vibrations. On a sample a beam of monochromatic light is illuminated and detection of scattered light is done, here most of scattered light is having the same energy that of excitation source, this phenomenon is known as Rayleigh or elastic scattering. On the other hand from the laser frequency shifting of very small amount of scattered light takes place due to the interaction between vibrational levels of molecules and incident light. The plot of shifted light intensity vs shifted is plotted known as Raman shift in Raman spectrum. It is diversely used in the analysis of materials especially in case of nanomaterials based on graphene. It provides information about the electronic structure, material lattice vibration and crystal structure^50,51.

3.3. Ultraviolet-visible spectroscopy (UV–VIS):

For the quantitative analysis of different analyses UV-vis spectroscopy is elementary tool. Analysis of the optically active quantum dots and the highly conjugated organic compounds can be done with the help of this technique. Two types of peaks can be seen in the analysis of GQDs, first is at below 300nm which is due C=C aromatic structure and is attributed to the π→π ^*.The second one is attributed to n→π ^*and appears at range of 300-390nm and is due to oxygen containing groups on surface of GQDs. Shifts in the wavelength can be observed due to the change in functional groups on surface of GQDs or the change in structure. The excitation range of GQDs can be determined with the help of UV-vis spectrum analysis, which made possible to identify optoelectronic applications. The calibration is done with the help of blank solvent and desired solvent choice is made for sample preparation of the solution^52,53,54.

3.4. Fluorescence spectroscopy:

The analysis of fluorescence or PL from specimen can be done with the help of Fluorescence spectroscopy. It is an opposite phenomenon that of UV-vis spectroscopy, here the emission of light takes place due excitation of electron due to UV light, in molecules of certain compounds. Desired solvent is used for the preparation of sample and primarily it is associated with the vibrational and electronic state. In respect to the strong fluorescent properties of GQDs measurement of PL spectrum become very important. The GQD sample is excited for a characteristic measurement with a convinced excitation wavelength, this results in emission of consistent emission peak^55,56.

3.5. Fourier transform infrared spectroscopy (FT-IR):

When it comes to the qualitative analysis of functional groups of the materials and the surface properties FT-IR is a key technique for the characterization. For the analysis purpose, the small pellets are used made of sample materials, some of the IR radiation gets absorbed due to the molecular vibrations when sample is exposed to the IR radiation, while some of them get transmitted to the sample. The mode of molecular vibrations is detected and in the particular fingerprint region, the particular signal is created for each molecule. This phenomenon can be helpful in the identification of functional groups on the GQDs. As we have an emphasis on the optical properties of the GQDs, functional group identification has an important role. In the range of 3400 for O–H, 1600 C = C stretching and 1350 C = O of carboxy cm-1, IR signals for the FT-IR of GQDs can be seen. However, these functional groups may differ according to the applications, synthesis methods, and use of precursors^57,58,59.

4. Applications:

4.1. As a therapeutic agent:

Some exceptional features and activities of GQDs are being utilized in pharmaceutical applications⁶⁰. We already know that the GQDs along with other nanostructures have adrug-carrying capacity. Along with their drug carrying capacity, GQDs can be used as a therapeutic agent in some disease conditions. Due to their great biocompatibility and less cytotoxicity, they are suitable for biomedical applications. This unlocks the new doors in the field of therapeutics and drug delivery where GQDs can act both as therapeutic agent and carrier for drug¹⁸.

Sr. No.	Activity	Mechanism	Reference
1.	Anti-Alzheimer’s	It is reported that GQDs can avoid the aggregation of amyloid β peptides and they can protect from the cytotoxicity of peptides.	61, 62
2.	Anti-Diabetic	Fluorinated GQDs can inhibit the peptide aggregation by converting long fibril hIAPP aggregates into short thin fibrils	63
3.	In Hepatitis	GQDs are eliminated through liver, an intravenous injection of large GQDs is effective against immune-mediated fulminant hepatitis	64, 65
4.	Wound healing	GQDs facilitate fast wound closure and they can easily enter into the cell nucleus and induce cell proliferation	66
5.	Antimicrobial	Through the generation of reactive oxygen species (ROS) followed by oxidative stress.	67, 68

4.2. Biological imaging:

Application of GQDs in biological imaging has made great breakthrough detection of cancerous cells. With the help of these drug locating within the cells and tracking down the drug in case of targeted drug delivery can be possible⁶⁹. Biological imaging can be possible due the strong photoluminescence spectra of the GQDs. For extremely selective detection scientists have modified GQDs as very efficient fluorescent probes⁷⁰. For this purpose amine modification of GQDs which were exposed from the graphene oxide is done. Fe3O4 nanoparticles were conjugated with anti-human IgG antibodies to identify casts in urine⁷¹. The surface or the anti IgG functionalized Fe3CO4 nanoparticles linked with modified GQDs. Lastly, addition of fluorescent Fe3SO4/GQDs into the sample is done for detection of casts by fluorescent imaging. With the help of microscopy and fluorescent imaging assay, a series of pre quantitative cast was analysed for comparing the efficiency of fluorescent probe using GQDs and Fe3O4/GQDs. Results have shown that the amounts of fluorescent imaging assay from Fe3O4/GQDs were almost 10 times greater than that of microscopy¹⁸.

4.3. Drug Delivery:

Nanosystems for compact drug delivery with multifunctional features are currently being used in the cancer therapy. Popularity of these systems is due to their efficacy and more dose tolerance. A variety of functional groups like carboxyl, hydroxyl, carbonyl and epoxy groups, sp2 carbons and rich in p electrons are some of the interesting properties of GQDs which make them ideal candidates for the drug delivery applications. In addition to this, they have reduced size and have different chemical reactivity compared to the other materials based on graphene. Easy functionalization through the functional groups containing oxygen and the p-p interactions make GQDs ideal candidate for the purpose of drug delivery. A single atomic layer with small lateral size and oxygen rich surface are some of the special characteristics of GQDs which increases the drug loading of molecules and increases stability. In case of cancer the fluorescence can act as a medium for tracing drug delivery in cancer cells. Considering all these advantages GQDs has made its place in past few decades for the drug delivery applications for various diseases^{18, 60,72,73}.

4.4. In cancer therapy:

In the modern cancer therapy, modern therapies like photodynamic therapy, radiotherapy and photothermal therapy are being used along with the conventional chemotherapy⁷⁴. For the rapid relief combination of these therapies is used for getting the synergistic effect. In cancer therapy, GQDs have an inexorable part and they pack a potential a prospect for oncology researchers ⁷⁵.

4.4.1. Photodynamic therapy:

Photodynamic therapy (PDT) is also known as photo-chemotherapy. It is a form of phototherapy which involves the application of light and a photosensitizing chemical substance, applied in combination to provoke cell death by molecular oxygen (phototoxicity). A stimulating phenomenon that GQDs can produce the reactive oxygen species (ROS) in tumour cells was experiential. In addition, the up adaptation distinguishing of GQDs can transform low energy NIR light to UV-visible light, which has been widely inspected for biological submissions. Therefore, GQDs can be well-thought-out and outstanding resources for photodynamic therapy. Xing and co-workers elucidated the mechanism of PDT. Furthermore, photo-induced cytotoxicity and oxidative stress of GQDs were also studied by Yin et al. Their conclusions proposed GQDs as anti-oxidants and pro-oxidants upon irradiation because they have the potential to become potent anti-oxidants for controlling ROS induced cell damage^18,76,77,78.

4.4.2. Photothermal therapy:

Apart from the above-mentioned PDT, the additional therapeutic method has been accomplished using GQDs. Photothermal therapy (PTT) denotes the usage of electromagnetic radiation (e.g. often in infrared wavelengths) for the management of numerous medical conditions, such as cancer. This approach is an extension of photodynamic therapy, in which a photosensitizer is excited with an exact band of light. This activation transports the sensitizer to an excited state where it then discharges vibrational energy in the form of heat that kills the targeted cells. PTT requires oxygen to react with the targeted cells or tissues but this is not the case in PDT. Current studies on PTT are examining the use of longer wavelength light, which is less energetic, and so less injurious to nearby cells and tissues. For instance, Zhu and co-workers fabricated DOX-MMSN/GQDs which were used as a multifunctional platform for controlled drug delivery, magnetic hyperthermia, and photothermal therapy^18,79,80,81.

REFERENCES:

1. Chan WC, Maxwell DJ, Gao X, Bailey RE, Han M, Nie S. Luminescent quantum dots for multiplexed biological detection and imaging. Current opinion in biotechnology. 2002 Feb 1; 13(1):40-6.

2. Liang JG, Ai XP, He ZK, Pang DW. Functionalized CdSe quantum dots as selective silver ion chemodosimeter. Analyst. 2004; 129(7):619-22.

3. Li J, Zhu JJ. Quantum dots for fluorescent biosensing and bio-imaging applications. Analyst. 2013; 138(9):2506-15.

4. Ladd TD, Jelezko F, Laflamme R, Nakamura Y, Monroe C, O’Brien JL. Quantum computers. nature. 2010 Mar;464(7285):45-53.

5. Harman TL, Tittel FK, Graf JC, Bakhirkin Y. Development of Quantum-Cascade Laser based biosensor technology. Y2003 Annual Report. 2004:59.

6. Cheng X, Lowe SB, Reece PJ, Gooding JJ. Colloidal silicon quantum dots: from preparation to the modification of self-assembled monolayers (SAMs) for bio-applications. Chemical Society Reviews. 2014;43(8):2680-700.¬¬

7. Wagner AM, Knipe JM, Orive G, Peppas NA. Quantum dots in biomedical applications. Acta biomaterialia. 2019 Aug 1;94:44-63.

8. Le XH, Pham NT, Dao NT, Laverdant J, Nguyen HY, Phan NH, Pham TN. Colloidal nitrogen-doped graphene quantum dots: Raman spectra, photoluminescence maps and radiative lifetimes. InSymposium venue (p. 88).

9. Shen J, Zhu Y, Yang X, Li C. Graphene quantum dots: emergent nanolights for bioimaging, sensors, catalysis and photovoltaic devices. Chemical communications. 2012;48(31):3686-99.

10. Fan Z, Li S, Yuan F, Fan L. Fluorescent graphene quantum dots for biosensing and bioimaging. Rsc Advances. 2015;5(25):19773-89.

11. Henna TK, Pramod K. Graphene quantum dots redefine nanobiomedicine. Materials Science and Engineering: C. 2020 May 1;110:110651.

12. Volkov Y. Quantum dots in nanomedicine: recent trends, advances and unresolved issues. Biochemical and biophysical research communications. 2015 Dec 18;468(3):419-27.

13. Biswas MC, Islam MT, Nandy PK, Hossain MM. Graphene quantum dots (GQDs) for bioimaging and drug delivery applications: a review. ACS Materials Letters. 2021 May 26;3(6):889-911.

14. Das P, Ganguly S, Banerjee S, Das NC. Graphene based emergent nanolights: a short review on the synthesis, properties and application. Research on Chemical Intermediates. 2019 Jul;45(7):3823-53.

15. Mei Q, Liu B, Han G, Liu R, Han MY, Zhang Z. Graphene oxide: from tunable structures to diverse luminescence behaviors. Advanced science. 2019 Jul;6(14):1900855.

16. Khan U, O'Neill A, Lotya M, De S, Coleman JN. High‐concentration solvent exfoliation of graphene. small. 2010 Apr 9;6(7):864-71.

17. Bacon M, Bradley SJ, Nann T. Graphene quantum dots. Particle & Particle Systems Characterization. 2014 Apr;31(4):415-28.

18. Tian P, Tang L, Teng KS, Lau SP. Graphene quantum dots from chemistry to applications. Materials today chemistry. 2018 Dec 1;10:221-58.

19. Yan Y, Gong J, Chen J, Zeng Z, Huang W, Pu K, Liu J, Chen P. Recent advances on graphene quantum dots: from chemistry and physics to applications. Advanced Materials. 2019 May;31(21):1808283.

20. Perini G, Palmieri V, Ciasca G, De Spirito M, Papi M. Unravelling the potential of graphene quantum dots in biomedicine and neuroscience. International journal of molecular sciences. 2020 Jan;21(10):3712.

21. Shen J, Zhu Y, Yang X, Zong J, Zhang J, Li C. One-pot hydrothermal synthesis of graphene quantum dots surface-passivated by polyethylene glycol and their photoelectric conversion under near-infrared light. New Journal of Chemistry. 2012;36(1):97-101.

22. Luo P, Guan X, Yu Y, Li X, Yan F. Hydrothermal synthesis of graphene quantum dots supported on three-dimensional graphene for supercapacitors. Nanomaterials. 2019 Feb;9(2):201.

23. Hoang TT, Pham HP, Tran QT. A facile microwave-assisted hydrothermal synthesis of graphene quantum dots for organic solar cell efficiency improvement. Journal of Nanomaterials. 2020 Feb 11;2020.

24. Kundu S, Pillai VK. Synthesis and characterization of graphene quantum dots. Physical Sciences Reviews. 2020 Apr 1;5(4).

25. Tang L, Ji R, Li X, Teng KS, Lau SP. Size‐dependent structural and optical characteristics of glucose‐derived graphene quantum dots. Particle & Particle Systems Characterization. 2013 Jun;30(6):523-31.

26. Luo Z, Qi G, Chen K, Zou M, Yuwen L, Zhang X, Huang W, Wang L. Microwave‐assisted preparation of white fluorescent graphene quantum dots as a novel phosphor for enhanced white‐light‐emitting diodes. Advanced Functional Materials. 2016 Apr;26(16):2739-44.

27. Hou X, Li Y, Zhao C. Microwave-assisted synthesis of nitrogen-doped multi-layer graphene quantum dots with oxygen-rich functional groups. Australian Journal of Chemistry. 2015 Sep 22;69(3):357-60.

28. Yoshinaga T, Iso Y, Isobe T. Optimizing the microwave-assisted hydrothermal synthesis of blue-emitting L-cysteine-derived carbon dots. Journal of Luminescence. 2019 Sep 1;213:6-14.

29. Puddy RK, Chua CJ, Buitelaar MR. Transport spectroscopy of a graphene quantum dot fabricated by atomic force microscope nanolithography. Applied Physics Letters. 2013 Oct 28;103(18):183117.

30. Peng J, Gao W, Gupta BK, Liu Z, Romero-Aburto R, Ge L, Song L, Alemany LB, Zhan X, Gao G, Vithayathil SA. Graphene quantum dots derived from carbon fibers. Nano letters. 2012 Feb 8;12(2):844-9.

31. Sun H, Wu L, Wei W, Qu X. Recent advances in graphene quantum dots for sensing. Materials today. 2013 Nov 1;16(11):433-42.

32. Shaari N, Kamarudin SK, Bahru R. Carbon and graphene quantum dots in fuel cell application: An overview. International Journal of Energy Research. 2021 Feb;45(2):1396-424.

33. Chen W, Lv G, Hu W, Li D, Chen S, Dai Z. Synthesis and applications of graphene quantum dots: a review. Nanotechnology Reviews. 2018 Apr 1;7(2):157-85.

34. Su J, Zhang X, Tong X, Wang X, Yang P, Yao F, Guo R, Yuan C. Preparation of graphene quantum dots with high quantum yield by a facile one-step method and applications for cell imaging. Materials Letters. 2020 Jul 15;271:127806.

35. Wang CC, Lu SY. Carbon black-derived graphene quantum dots composited with carbon aerogel as a highly efficient and stable reduction catalyst for the iodide/tri-iodide couple. Nanoscale. 2015;7(3):1209-15.

36. Madni A, Noreen S, Maqbool I, Rehman F, Batool A, Kashif PM, Rehman M, Tahir N, Khan MI. Graphene-based nanocomposites: synthesis and their theranostic applications. Journal of Drug Targeting. 2018 Nov 26;26(10):858-83.

37. Ananthanarayanan A, Wang X, Routh P, Sana B, Lim S, Kim DH, Lim KH, Li J, Chen P. Facile synthesis of graphene quantum dots from 3D graphene and their application for Fe3+ sensing. Advanced Functional Materials. 2014 May;24(20):3021-6.

38. Wang L, Zhu SJ, Wang HY, Qu SN, Zhang YL, Zhang JH, Chen QD, Xu HL, Han W, Yang B, Sun HB. Common origin of green luminescence in carbon nanodots and graphene quantum dots. ACS nano. 2014 Mar 25;8(3):2541-7.

39. Huang H, Yang S, Li Q, Yang Y, Wang G, You X, Mao B, Wang H, Ma Y, He P, Liu Z. Electrochemical cutting in weak aqueous electrolytes: the strategy for efficient and controllable preparation of graphene quantum dots. Langmuir. 2018 Jan 9;34(1):250-8.

40. Zhang Z, Zhang J, Chen N, Qu L. Graphene quantum dots: an emerging material for energy-related applications and beyond. Energy & Environmental Science. 2012;5(10):8869-90.

41. Lu L, Zhu Y, Shi C, Pei YT. Large-scale synthesis of defect-selective graphene quantum dots by ultrasonic-assisted liquid-phase exfoliation. Carbon. 2016 Nov 1;109:373-83.

42. Zdrazil L, Zahradnicek R, Mohan R, Sedlacek P, Nejdl L, Schmiedova V, Pospisil J, Horak M, Weiter M, Zmeskal O, Hubalek J. Preparation of graphene quantum dots through liquid phase exfoliation method. Journal of Luminescence. 2018 Dec 1;204:203-8.

43. Ciesielski A, Haar S, Aliprandi A, El Garah M, Tregnago G, Cotella GF, El Gemayel M, Richard F, Sun H, Cacialli F, Bonaccorso F. Modifying the size of ultrasound-induced liquid-phase exfoliated graphene: from nanosheets to nanodots. ACS nano. 2016 Dec 27;10(12):10768-77.

44. Zhang YM, Zhang J, Zhu ZQ, Liu QJ. Low-cost preparation of graphene quantum dots by liquid-phase exfoliation of carbon fibers. InMaterials Science Forum 2016 (Vol. 852, pp. 489-495). Trans Tech Publications Ltd.

45. Facure MH, Schneider R, Mercante LA, Correa DS. A review on graphene quantum dots and their nanocomposites: from laboratory synthesis towards agricultural and environmental applications. Environmental Science: Nano. 2020;7(12):3710-34.

46. Shinde DB, Pillai VK. Electrochemical preparation of luminescent graphene quantum dots from multiwalled carbon nanotubes. Chemistry–A European Journal. 2012 Sep 24;18(39):12522-8.

47. Ramachandran S, Sathishkumar M, Kothurkar NK, Senthilkumar R. Synthesis and characterization of graphene quantum dots/cobalt ferrite nanocomposite. InIOP Conference Series: Materials Science and Engineering 2018 Feb 1 (Vol. 310, No. 1, p. 012139). IOP Publishing.

48. Samuei S, Fakkar J, Rezvani Z, Shomali A, Habibi B. Synthesis and characterization of graphene quantum dots/CoNiAl-layered double-hydroxide nanocomposite: Application as a glucose sensor. Analytical biochemistry. 2017 Mar 15;521:31-9.

49. Safardoust-Hojaghan H, Salavati-Niasari M. Degradation of methylene blue as a pollutant with N-doped graphene quantum dot/titanium dioxide nanocomposite. Journal of Cleaner Production. 2017 Apr 1;148:31-6.

50. Wu J, Wang P, Wang F, Fang Y. Investigation of the microstructures of graphene quantum dots (GQDs) by surface-enhanced Raman spectroscopy. Nanomaterials. 2018 Oct;8(10):864.

51. Rajender G, Giri PK. Formation mechanism of graphene quantum dots and their edge state conversion probed by photoluminescence and Raman spectroscopy. Journal of Materials Chemistry C. 2016;4(46):10852-65.

52. More MP, Lohar PH, Patil AG, Patil PO, Deshmukh PK. Controlled synthesis of blue luminescent graphene quantum dots from carbonized citric acid: Assessment of methodology, stability, and fluorescence in an aqueous environment. Materials Chemistry and Physics. 2018 Dec 1;220:11-22.

53. Liu X, Han J, Hou X, Altincicek F, Oncel N, Pierce D, Wu X, Zhao JX. One-pot synthesis of graphene quantum dots using humic acid and its application for copper (II) ion detection. Journal of Materials Science. 2021 Mar;56(8):4991-5005.

54. Zhang Z, Fang C, Bing X, Lei Y. Graphene quantum dots-ZnS nanocomposites with improved photoelectric performances. Materials. 2018 Apr;11(4):512.

55. Röding M, Bradley SJ, Nydén M, Nann T. Fluorescence lifetime analysis of graphene quantum dots. The Journal of Physical Chemistry C. 2014 Dec 26;118(51):30282-90.

56. Ju J, Chen W. Synthesis of highly fluorescent nitrogen-doped graphene quantum dots for sensitive, label-free detection of Fe (III) in aqueous media. Biosensors and bioelectronics. 2014 Aug 15;58:219-25.

57. Baweja H, Jeet K. Economical and green synthesis of graphene and carbon quantum dots from agricultural waste. Materials Research Express. 2019 Jun 19;6(8):0850g8.

58. Zhang W, Liu Y, Meng X, Ding T, Xu Y, Xu H, Ren Y, Liu B, Huang J, Yang J, Fang X. Graphenol defects induced blue emission enhancement in chemically reduced graphene quantum dots. Physical Chemistry Chemical Physics. 2015;17(34):22361-6.

59. Luo Q, Zhong Z, Zheng Y, Gao D, Xia Z, Wang L. Preparation and evaluation of a poly (N-isopropylacrylamide) derived graphene quantum dots based hydrophilic interaction and reversed-phase mixed-mode stationary phase for complex sample analysis. Talanta. 2021 Mar 1;224:121869.

60. Tajik S, Dourandish Z, Zhang K, Beitollahi H, Van Le Q, Jang HW, Shokouhimehr M. Carbon and graphene quantum dots: A review on syntheses, characterization, biological and sensing applications for neurotransmitter determination. RSC Advances. 2020;10(26):15406-29.

61. Liu Y, Xu LP, Wang Q, Yang B, Zhang X. Synergistic inhibitory effect of GQDs–tramiprosate covalent binding on amyloid aggregation. ACS Chemical Neuroscience. 2017 Dec 15;9(4):817-23.

62. Kim D, Yoo JM, Hwang H, Lee J, Lee SH, Yun SP, Park MJ, Lee M, Choi S, Kwon SH, Lee S. Graphene quantum dots prevent α-synucleinopathy in Parkinson’s disease. Nature nanotechnology. 2018 Sep;13(9):812-8.

63. Guo JL, Lee VM. Neurofibrillary tangle-like tau pathology induced by synthetic tau fibrils in primary neurons over-expressing mutant tau. FEBS letters. 2013 Mar 18;587(6):717-23.

64. Volarevic V, Paunovic V, Markovic Z, Simovic Markovic B, Misirkic-Marjanovic M, Todorovic-Markovic B, Bojic S, Vucicevic L, Jovanovic S, Arsenijevic N, Holclajtner-Antunovic I. Large graphene quantum dots alleviate immune-mediated liver damage. Acs Nano. 2014 Dec 23;8(12):12098-109.

65. Wang X, Ning Q. Immune mediated liver failure. EXCLI journal. 2014;13:1131.

66. Kumawat MK, Thakur M, Gurung RB, Srivastava R. Graphene quantum dots for cell proliferation, nucleus imaging, and photoluminescent sensing applications. Scientific reports. 2017 Nov 20;7(1):1-6.

67. Liu J, Rojas-Andrade MD, Chata G, Peng Y, Roseman G, Lu JE, Millhauser GL, Saltikov C, Chen S. Photo-enhanced antibacterial activity of ZnO/graphene quantum dot nanocomposites. Nanoscale. 2018;10(1):158-66.

68. Ristic BZ, Milenkovic MM, Dakic IR, Todorovic-Markovic BM, Milosavljevic MS, Budimir MD, Paunovic VG, Dramicanin MD, Markovic ZM, Trajkovic VS. Photodynamic antibacterial effect of graphene quantum dots. Biomaterials. 2014 May 1;35(15):4428-35.

69. George D, Suri A, Dutta K, Nayak S. Targeted Drug Delivery Using Graphene Quantum Dots: Approaches, Limitations and Future Perspectives. ECS Transactions. 2022 Apr 24;107(1):16081.

70. Abbas A, Tabish TA, Bull SJ, Lim TM, Phan AN. High yield synthesis of graphene quantum dots from biomass waste as a highly selective probe for Fe3+ sensing. Scientific reports. 2020 Dec 4;10(1):1-6.

71. Lu H, Li W, Dong H, Wei M. Graphene quantum dots for optical bioimaging. Small. 2019 Sep;15(36):1902136.

72. Iannazzo D, Pistone A, Salamò M, Galvagno S, Romeo R, Giofré SV, Branca C, Visalli G, Di Pietro A. Graphene quantum dots for cancer targeted drug delivery. International journal of pharmaceutics. 2017 Feb 25;518(1-2):185-92.

73. Wang X, Sun X, Lao J, He H, Cheng T, Wang M, Wang S, Huang F. Multifunctional graphene quantum dots for simultaneous targeted cellular imaging and drug delivery. Colloids and Surfaces B: Biointerfaces. 2014 Oct 1;122:638-44.

74. Alsaab HO, Alghamdi MS, Alotaibi AS, Alzhrani R, Alwuthaynani F, Althobaiti YS, Almalki AH, Sau S, Iyer AK. Progress in clinical trials of photodynamic therapy for solid tumors and the role of nanomedicine. Cancers. 2020 Oct;12(10):2793.

75. Fan HY, Yu XH, Wang K, Yin YJ, Tang YJ, Tang YL, Liang XH. Graphene quantum dots (GQDs)-based nanomaterials for improving photodynamic therapy in cancer treatment. European journal of medicinal chemistry. 2019 Nov 15;182:111620.

76. Dougherty TJ, Gomer CJ, Henderson BW, Jori G, Kessel D, Korbelik M, Moan J, Peng Q. Photodynamic therapy. JNCI: Journal of the national cancer institute. 1998 Jun 17;90(12):889-905.

77. McCaughan JS. Photodynamic therapy. Drugs & aging. 1999 Jul;15(1):49-68.

78. Dolmans DE, Fukumura D, Jain RK. Photodynamic therapy for cancer. Nature reviews cancer. 2003 May;3(5):380-7.

79. Liu H, Li C, Qian Y, Hu L, Fang J, Tong W, Nie R, Chen Q, Wang H. Magnetic-induced graphene quantum dots for imaging-guided photothermal therapy in the second near-infrared window. Biomaterials. 2020 Feb 1;232:119700.

80. Yao X, Niu X, Ma K, Huang P, Grothe J, Kaskel S, Zhu Y. Graphene quantum dots‐capped magnetic mesoporous silica nanoparticles as a multifunctional platform for controlled drug delivery, magnetic hyperthermia, and photothermal therapy. Small. 2017 Jan;13(2):1602225.

81. Wang H, Mu Q, Wang K, Revia RA, Yen C, Gu X, Tian B, Liu J, Zhang M. Nitrogen and boron dual-doped graphene quantum dots for near-infrared second window imaging and photothermal therapy. Applied materials today. 2019 Mar 1;14:108-17.

82. Indranil Singh. A Review on in-Vivo Imaging of Cancer Cells by Bioconjugated Quantum Dots. Asian J. Pharm. Res. 2018; 8(4): 243-248.

83. Anita S. Godase, Nayana V. Pimpodkar, Yogita R. Indalkar. An Overview on A Pyrazole: Promising Moiety. Asian J. Pharm. Tech. 2015; Vol. 5(4) 201-213.

84. Sanket Rathod, Ketaki Shinde, Namdeo Shinde, Nagesh Aloorkar. Cosmeceuticals and Nanotechnology in Beauty Care Products. Research Journal of Topical and Cosmetic Sciences. 2021; 12(2):93-1.

85. Vaidiyanathan. R, B. Anand. Opto chemical Transducers of GaInN Quantum glowing structure of Biosensor and Chemical Sensors for Health Care System. Research J. Pharm. and Tech 2017; 10(12): 4362-4364.

86. Dipti Bhave, Snehal Deshpande, Upendra Dabholkar. Surfactants as Quantum Dots used in Bio-Imaging.Research J. Science and Tech. 2018; 10(3):188-196.

87. Sanket Rathod, Sneha Mali, Namdeo Shinde, Nagesh Aloorkar. Cosmeceuticals and Beauty Care Products: Current trends with future prospects. Research J. Topical and Cosmetic Sci. 2020; 11(1):45-51.

Received on 31.05.2022 Modified on 03.07.2022

Asian J. Pharm. Res. 2022; 12(4):341-348.

DOI: 10.52711/2231-5691.2022.00054