Carbon-based nanomaterials as an emerging platform for theranostics

Kapil D. Patel ab, Rajendra K. Singh ab and Hae-Won Kim *abcd
aInstitute of Tissue Regeneration Engineering (ITREN), Dankook University, Cheonan 31116, South Korea. E-mail: kimhw@dku.edu; Fax: +82 41 550 3085; Tel: +82 41 550 3081
bDepartment of Nanobiomedical Science & BK21 PLUS NBM Global Research Center for Regenerative Medicine, Dankook University, Cheonan 31116, South Korea
cDepartment of Biomaterials Science, College of Dentistry, Dankook University, Cheonan 31116, South Korea
dUCL Eastman-Korea Dental Medicine Innovation Centre, Dankook University, Cheonan 31116, South Korea

Received 13th August 2018 , Accepted 21st December 2018

First published on 21st December 2018


Carbon-based nanomaterials include fullerenes, carbon nanotubes, graphene and its derivatives, graphene oxide, nanodiamonds, and carbon-based quantum dots. Due to their unique structural dimensions and excellent mechanical, electrical, thermal, optical and chemical properties, these materials have attracted significant interest in diverse areas, including biomedical applications. Among them, there has been recent focus on the imaging of cells and tissues and the delivery of therapeutic molecules for disease treatment and tissue repair. The broad-range one-photon property of carbon based-nanomaterials together with their biocompatibility and ease of functionalization has made them candidate imaging agents for tumor diagnosis. In particular, the intrinsic two-photon fluorescence property of carbon based-nanomaterials in the long wavelength region (near-infrared II) allows deep-tissue optical imaging. This review highlights the recent development on carbon based-nanomaterials in the field of one-photon and two-photon imaging and discusses their possible and promising diagnostic and therapeutic applications for the treatment of various diseases including cancer.


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Kapil D. Patel

Kapil D. Patel received his PhD in Nanobiomedical Science from Dankook University, South Korea (2015). Currently, he is a Research Fellow at the Institute of Tissue Regeneration Engineering (ITREN), Dankook University. His research interests include the development of functional nano-biomaterials for tissue repair and regeneration.

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Rajendra K. Singh

Rajendra K. Singh received his PhD in Physics from the Indian Institute of Technology (IIT), India (2009). He continued his postdoctoral research (2010–2013) at the Institute of Tissue Regeneration Engineering (ITREN), Dankook University. Currently, he is a Research Professor at Dankook University. His research topics include bioactive glasses, magnetic nanoparticles, and imaging nanomaterials for tissue regeneration and cancer theranostics.

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Hae-Won Kim

Hae-Won Kim is a professor of Nanobiomedical Science with a joint appointment in the Dental College at Dankook University. He received BS (1997) and PhD (2002) from Seoul National University, and worked at the National Institute of Standards and Technology (NIST, 2002) and University College London (2003–2004). He is currently the director of the Institute of Tissue Regeneration Engineering (ITREN), and leads the team of the BK21 NBM Global Research Center. His research focuses on nano-biomaterials, cell–biomaterial interactions, and cell engineering for musculoskeletal, dental and neural tissues. He is the co-editor-in-chief of the Journal of Tissue Engineering.


1. Introduction

In the last few decades, carbon-based nanomaterials (CBN) have shown tremendous impact in the biomedical field with their ability to deliver therapeutic molecules and allow visualization of cells and tissues, which are necessary for the cure and treatment of diseased and damaged tissues. CBN, as members of the carbon family, include fullerenes, carbon nanotubes (CNTs), graphene (G) and its derivatives (graphene oxide (GO)), nanodiamonds (NDs), and carbon-based quantum dots (CQDs). The possible biomedical applications of CBN, as depicted in Fig. 1, include bioimaging,1–3 fluorescence labelling of cells,4 stem cell engineering,5–7 biosensing,8–10 drug/gene delivery,11–15 and photothermal7,16 and photodynamic therapy.17–19 The unique optical properties of CBN, i.e., intrinsic fluorescence, tunable narrow emission spectrum, and high photostability, allow their potential use in the imaging and diagnosis of cells and tissues. Furthermore, modification of their surfaces with functional groups (carboxylic acid, hydroxyl, and epoxy) allows the opportunity to optimize their properties. Besides excellent optical properties, CBN possess high surface areas and mechanical and electrical properties, which make them one of the most desirable and qualified candidates for theranostic applications. Above all, the biological safety of CBN, which is related to their aqueous stability and interactions with cells and tissues, is one of the fundamental issues for their practical biomedical application.20
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Fig. 1 Carbon-based nanomaterials (CBNs) and their diverse applications in theranostics. Optical imaging; reproduced with permission from the American Chemical Society from ref. 34. Raman imaging; reproduced with permission from the American Chemical Society from ref. 29. Photodynamic photothermal therapy; reproduced with permission from the John Wiley and Sons from ref. 35.

Some recent studies have spurred their potential utility in anticancer and anti-inflammatory treatments. For example, CBN stimulate reactive oxygen species (ROS) when taken up by cancer cells, leading to lipid and DNA damage, and cell death.21 Also, graphene materials affect the metabolic activity of macrophages, increasing the ROS levels and damaging the mitochondrial membrane, which cause cell death by apoptosis.22,23 On the other hand, when CBN are biofunctionalized, they enhance the delivery efficacy through reduced clearance and improved retention in the body.

Among their properties, the optical properties of CBN have recently enabled significant progress in their applications for one-photon and two-photon imaging. Specifically, Raman imaging, photoacoustic (PA) imaging, up-conversion near infrared (NIR) imaging, and other optical (even non-optical imaging) modalities have recently been extensively studied.24–30 It is now acknowledged that CBN are multifunctional, multimodal, high-performance one-photon and two-photon imaging agents,4,26,31,32 and thus hold great promise for applications in cell labelling and diagnosis for tissue repair and disease treatment. Accordingly, some groups have recently reviewed the synthesis of CBN and their emerging applications;33 however, there was no focus on their theranostic applications.

In this review, we highlight the aspects of CBN for theranostics applications, while covering their related features in detail including optical properties, biocompatibility, and in vivo applications. Initially, we explain the mechanism of the origin of the various imaging properties of CBN, then emphasize their promising roles as diagnostic and therapeutic nanomaterials for the treatment of cancer and many other diseases, and finally discuss the challenges and opportunities for the development of future realistic theranostic platforms.

2. Carbon-based nanomaterials

Although carbon-based molecules such as fullerenes (C60, C70, and C84) were discovered in 1985,36 the existence of C60 was predicted in 1970.37 Most fullerenes (e.g., C60) are spheroid in shape, although oblong shapes like a rugby ball also exist (e.g. C70). Later, the discovery of the carbon nanotube (CNT) in 199138 boosted the research in the field of carbon related nanomaterials. Structurally, CNT is a one-atom-thick sheet of graphite rolled into a tube with a diameter of one nanometer, which exhibits different properties depending solely on how the nanotubes are rolled.39,40 The properties of CNTs include high tensile strength and modulus, making them very stiff.41 Also, due to their one-dimensional nanotubular structure, their electrical and thermal conductivity greatly increase and even surpass that of conductive metals.42 Recently, the discovery of a one atom layer thick atomic carbon sheet, i.e. graphene, has placed CBN at the forefront in the materials science world. Some of the notable characteristics of graphene are its high intrinsic carrier mobility (200[thin space (1/6-em)]000 cm2 V−1 s−1),43,44 thermal conductivity (∼5000 W m−1 K−1),45 Young's modulus (∼1.0 TPa),46 and optical transmittance (∼97.7%).47 CBN have been explored in various fields, including the electronics and semiconductor industry,48,49 data storage devices,50 sensors51 and bioelectronics,52,53 composite materials,54 energy research,55 catalysis,56,57 and most recently biomedicine58,59 and theranostics.60–62 Some of the key studies on CBN (and their composites/hybrids) developed thus far particularly for therapeutic and diagnostic applications are summarized in Table 1.
Table 1 Some representative CBN and their composites/hybrids developed for therapeutic and diagnostic applications with key references
CBN (or hybrid) Synthesis Key features Applications Ref.
C80 With carboxyl-Gd3N@C80, HyC-3-Gd3N@C80 One-step reaction/functionalization Antioxidative, anti-inflammatory, specific targeting, multimodal contrast agents Raw264.7 cells, ROS and RNS scavenging, MRI, delivery, cancer theranostics 63
C80 With Gd3N@C80(OH)x(NH2)y One-step reaction IL-13 amino coated particles, targeting GBM, IL-13 peptide conjugation U-251 GBM cell, targeted MRI detection, orthotopic mouse model for cancer therapy 64
C80 With PDA, Gd3N@C80 One-step and self-polymerization Multimodal imaging, combined chemo-PTT U87MG cells, MR, PA, PET multimodal imaging guided combinatory PTT therapy 65
C60–G, CNT and rGO With PDA Modified Hummers method Photoacoustic imaging, synergistic PDT and PTT, single light induced PTT and PDT, MRI 4T1 breast subcutaneous and orthotopic mice model, MRI and PA imaging, 66–68
CNT (SWCNT) With PDA–PEG Chemical process Radionuclide labeling, multimodal imaging 4T1 in vivo tumor, T1 and T2-MRI imaging, PTT, NIR-triggered PTT and radioisotope therapy 69
CNT (SWCNT) With EB Simple chemistry Long circulating, in vivo stability, ROS generation, fluorescence imaging, PDT/PTT combined therapy SCC-7 cells, image-guided PTT/PDT, fluorescence and photoacoustic imaging 70
CNT (SWCNT) With PL–PEG–NH2 Ultra-short pulse microwave Convert ultra-short microwave energy into TA shock, mitochondria targeting Thermoacoustic (TA) tumor therapy deep-seated tumor models, cancer therapy 71
G Core–shell (SiO2@G) Modified Hummers’ and Stöber method 140–180 nm, targeted drug delivery, pH-responsive, light-triggered drug release, combined chemo-PTT HeLa cells, combined chemo-PTT therapy, in vitro and in vivo cancer therapy 72
GO With AuNP Sol–gel Enhanced PTT via strong plasmon coupling GO and AuNPs Tumor-tropic mesenchymal stem cell, in vivo tumor ablation, cancer therapy 7
GO With Cy5 Quenching method Fluorescence imaging, enhanced single molecular quenching Detection of microRNA-21, MRNA imaging 73
GO With chitosan–DMMA Self-assembly 84 nm, pH-sensitive intracellular drug delivery Efficient intracellular delivery, surface charge-responsive, long term blood circulation 74
GO With PEG–folate Modified Hummers method Wavelength-dependent PL in the visible and NIR region, low laser power intensity B16F0 melanoma tumors, multicolor fluorescence imaging, bimodal PDT and PTT destruction of tumors 75
rGO With PEG-g-PDMA, P-g-P, and HA Solvothermal pH responsive fluorescence emission, NIR irradiation MDAMB-231, A549, and MDCK cells, NIR-PTT in vitro and in vivo 76
GQD Capped MSN Sol–gel 50–60 nm, pH/temperature-responsive drug delivery, synergistic chemo-PPT 4T1 cells, breast cancer, fluorescence imaging and monitoring of drug release, targeted cancer therapy 77 and 78
GQD With PEG-P Strong acid exfoliation and solvothermal 5 nm, intrinsic fluorescence, intracellular cancer-related mRNA detection MCF-7, HDF, A549 cells, PTT and PDT cancer therapy 79
GQD N-Doped Modified Hummers method and heat treatment 5 nm, ROS for PDT, N-doped GQD as photosensitizer, N for PDT, high photostability and dual modality E. coli, PDT, antibacterial, bioimaging, for multidrug resistant bacteria, bioimaging 80
CQD With FeN, folic acid and riboflavin Hydrothermal 5 ± 3 nm, 120 ± 10 nm, magneto-fluorescence-CD, light triggered simultaneous PTT and PDT HeLa, HepG2 cells, NIR-PTT combined chemotherapy, PDT, fluorescence imaging, in vivo cancer therapy 81
CQD Gd-Doped Hydrothermal 18 nm, PL, QY = 13.4%, T1 contrast agents and radiosensitizers HepG2, VSMC, 4T1, and A549 cells, T1-MRI, radiotherapy, cancer therapy 82
CQD Hydrophobic cyanine dye and PEG800 One pot solvothermal 3 nm, high photothermal and photostability, in vivo imaging and sensing HpG2 cells, NIR-fluorescence imaging, in vitro/in vivo imaging, PTT cancer therapy 83
ND Starch and tris–acetate–EDTA (TAE) as carbon source Microwave-assisted hydrothermal method Reproducible green synthesis, fluorescence, tunable QY, PLQY 28%, bioimaging Photoluminescence, bioimaging, reducing agent and photocatalyst 84
ND Air oxidation 4–25 nm, surface defects, in vivo stability, in situ hyperpolarization MR imaging, cellular tracking, cancer therapy 85
ND With glucose (GI) Sonochemical process Surface functionality of the ND regulates fluorescence NIR-fluorescence, sensor, nanoscale tracer, and drug delivery 86


2.1. Fullerenes

Buckminsterfullerene (C60), which was discovered in 1985, has received significant attention due to its unique photophysical and photochemical properties.87,88 Buckminsterfullerene falls into the category of spherical fullerenes. The key feature of fullerenes is their ability to act as sensitizers for the photoproduction of singlet oxygen (1O2) ROS, and thus are utilized for blood sterilization and photodynamic cancer therapy.89–93 However, the dispersibility of fullerenes is a major issue for their use in nanomedicine. Their low solubility in many solvents, especially in water, where singlet oxygen has a long lifetime, is the main problem. Thus, several methods have been developed to functionalize fullerenes with hydrophilic groups to enhance their water solubility.94,95 Consequently, the developed fullerenes have found potential use as antimicrobial, antiviral, and antioxidant agents.96,97

The antioxidant role of fullerenes, i.e., scavenging free radicals including ROS and reactive nitrogen species (RNS), has spurred their biomedical applications.98,99 Glutathione C60 derivatives help protect cells from nitric oxide-mediated apoptotic death.99 When pre-incubated with C60 the IgE-dependent mediator released in human mast cells (hMCs) and peripheral blood basophils was significantly inhibited, demonstrating the role of fullerenes as a negative regulator of allergic response.100

Fullerenes are also potential photosensitizers. They can absorb photons in the ultraviolet and visible electromagnetic spectrum to produce photo-excited fullerene species in the triplet state and lead to the generation of singlet oxygen or ROS depending on the polarity of the medium. Furthermore, light-harvesting antennae can be attached to fullerenes to increase the quantum yield of ROS production. Therefore, fullerenes can be used in photodynamic therapy (PDT) for treating cancer and killing microorganisms.

The nanoscale cage-like structure of fullerenes allows the construction of molecular or particulate entities, where one or more functional groups are covalently attached to the fullerene cage surface in a geometrically controlled manner. This is applicable for the targeted delivery of drugs across biological membranes and receptor ligands for agonizing or antagonizing cellular and enzymatic processes. Liposome formulation provides an alternative route to prepare fullerenes for pharmaceutical applications with enhanced distribution, absorption and delivery efficiency. Substantial scientific knowledge on fullerene medicine has been gained; however, the progress in clinical studies is lacking due to the concerns regarding long-term safety and toxicity of fullerenes. In contrast, fullerene-based cosmetic products have been clinically tested and used in human skincare for many years, suggesting that at least the topical application of fullerenes is safe.101,102

Additionally, the stable cage-like structure of fullerenes provides an abundant room for the encapsulation of atoms, molecules, and ions. For example, water-soluble gadolinium metallofullerenes (gadofullerenes) are very promising magnetic resonance imaging (MRI) contrast agents due to their high relaxivity. The fullerene cage has strong affinity to Gd3+ ions, encapsulating them inside stably, thus offering reduced long-term safety concerns associated with Gd3+ ions by preventing their release in the biological environment.103

Fullerenes can self-assemble into vesicles called fullerosomes, which can act as multivalent drug delivery vehicles with the possibility of different targeting properties.104

2.2. Carbon nanotubes

Carbon nanotubes (CNTs) are rolled up seamless cylinders of graphene sheets with unique intrinsic properties. Based on the number of graphene layers in the cylindrical tubes, CNTs are classified as single wall carbon nanotubes (SWCNTs) and multiwall carbon nanotubes (MWCNTs). The diameter of SWCNTs and MWCNTs varies from 0.4 to 2.5 nm and a few nanometres to 100 nm, respectively. Each layer in MWCNTs interacts through van der Waals forces105,106 and a variety of combinations of 2D crystals with different electrical, optical and mechanical properties is possible to constitute multi-layered CNTs to provide different physical phenomena and device functionality.107

However, the poor dispersibility of CNTs is one of the biggest barriers for their use in nanomedicine. Thus, several functionalization routes have been developed to disperse them and consequently improve their biocompatibility.108,109 Covalent functionalization is possible through the defective carbon atoms on the sidewall or at the end, where carboxylic acid groups or carboxylated fractions are generated through oxidization, which are then chemically modified via amination or esterification.110,111 Recently, several polymers,110,112 metals,113,114 and biological molecules115–117 have been used to graft to the surface of carboxylated CNTs. Nevertheless, concerns for the biocompatibility (cell and tissue toxicity) of CNTs have been raised as a practical issue, and many in-depth studies are still ongoing, although it is generally accepted that when the surface of CNTs is properly functionalized (modified), their cell and tissue compatibility can be improved significantly.118,119

Functionalized CNTs have offered great opportunities in many biomedical applications, including biosensing, disease diagnosis and treatment.120 They are used to detect various biological targets, allow biomedical imaging,121–123 and deliver therapeutic molecules including drugs and genes.124–127 Their intrinsic spectroscopic properties, including Raman scattering and photoluminescence, can provide valuable means for tracking, detecting and imaging diseases. They can also help monitor in vivo therapy status, pharmacodynamical behavior and drug delivery efficiency.

2.3. Graphene and its derivatives

Graphene is a single or few-layered two-dimensional sp2-bonded carbon sheet, which is another class of sp2 nanocarbon materials and exhibits many outstanding properties in physics and chemistry. Since its discovery in 2004, graphene has been extensively studied in many different fields. Utilizing the interesting optical, electrical, and chemical properties of graphene, various graphene-based biosensors have been fabricated to detect biomolecules with high sensitivities.53,128–131 Graphene has a poly-aromatic surface structure with an ultrahigh surface area, which is available for the efficient loading of aromatic drug molecules via π–π stacking for applications in drug delivery.132 Its thermal conductivity and mechanical stiffness are as high as 3000 W m−1 K−1 and 1060 GPa, respectively.133 Recent studies have shown that individual graphene sheets have extraordinary electronic transport properties.134,135 One possible route to harnessing these properties for biomedical applications is incorporating graphene sheets in a nanocomposite material.

Although pristine graphene has excellent electrical conductivity, it has poor aqueous solubility; thus, various derivatives such as graphene oxide (GO), reduced graphene oxide (rGO), few-layer graphene oxide (FLGO) and chemically changed graphene (CCG) have been developed. GO and rGO are much more suitable for sol–gel chemistry and effective candidates for the synthesis of biocompatible nanocomposites. GO sheets, i.e., the oxygenated counterparts of one-atom thick graphene sheets, can be produced as a high surface single layer by the Hummers method.136 GO has been applied in several biotechnologies such as biosensors,137–139 cellular imaging,51,140 nanoprobes,140,141 drug delivery,59,142 and others.143 The functional groups present on the surface and at the edges of GO collectively act to inhibit electron transfer.144 This is why GO has low electrical conductivity; whereas, its reduced form (rGO) exhibits higher electrical conductivity.

Recently, GO-based nanocarriers have gained significant attention for anticancer drug delivery and imaging due to their high drug loading and effective delivery capacity.145 Their specific surface area reaches approximately 2600 m2 g−1, which is more than double that of most nanomaterials.146,147 Moreover, unlike pristine graphene, GO exhibits high water dispersibility and endows pH-dependent negative surface charge to maintain high colloidal stability.148 However, GO can be aggregated in salt media such as protein-rich cell culture media and phosphate buffered saline.148 Another interesting property of GO is physisorption via π–π stacking, which is effective for loading many aromatic drug molecules such as doxorubicin, a potent anticancer drug.149,150 Thus, owing to its small size, intrinsic optical properties, large specific surface area, low cost, and useful non-covalent interactions, GO is a promising material for biomedical applications. Furthermore, GO has the ability to release drug molecules upon stimuli such as NIR light,151,152 potentiating its use as a delivery carrier. However, to date, the in vivo behaviors of GO, such as its blood circulation, inflammation responses, and clearance mechanism, are not fully understood, which require future intensive studies.

2.4. Carbon quantum dots

Carbon quantum dots (CQDs) are small carbon nanoparticles with sizes less than 10 nm. The first report on quantum-sized bright and colourful photoluminescence CQDs, published in 2007 by Sun et al., used laser ablation of a carbon target and a surface passivation method.153 Recently, CQDs have been extensively studied to gain high fluorescence quantum yield (QY) with facile synthesis methods.4 CQDs have generally been synthesized from organic materials, including natural polymers (e.g., chitosan,154 gelatin,155 and other sources156). Amino acids,157 apple juice,158 grape peel,159 and vegetables160,161 have also been used to produce CQDs. Furthermore, various simple and low cost-effective methods have been developed for the synthesis of CQD, including laser ablation,153 electrochemical oxidation,162 combustion/thermal microwave heating,152,163,164 supported synthesis,165 chemical oxidation,50 hydrothermal carbonization,166 and pyrolysis.167 Furthermore, uniform nitrogen-doped CQDs were synthesized via a one-step solvothermal process using nitrogen rich solvents, such as N-methyl-2-pyrrolidone (NMP) and dimethyl-imidazolidinone (DMEU).168 A facile chemical method was recently developed to synthesize –C(O)OH-modified CQDs, which is considered an innovative route for acid attack on CNTs.169 Moreover, the introduction of surface defects, tailoring their size and chemical modifications have been used to tune the fluorescence properties of the CQDs.

2.5. Nanodiamonds

NDs are nanocrystals that consist of tetrahedrally bonded carbon atoms in the form of a three-dimensional (3D) cubic lattice; thus, this structure imparts the properties of a diamond and an onion-shaped carbon shell containing a coating of functional groups on its surface.2,170–176 The sp2/sp3 bonds in NDs are quite flexible, endowing them with the ability to assume two geometrical forms, i.e., the stretched face of diamond can behave as a graphene plane and the puckered graphene may become a diamond surface. The intrinsic properties of NDs are of great interest, and the smaller the size of NDs, the superior their properties.177–179 For NDs with a size smaller than 2 nm, theoretical works predict quantum confinement effects due to an increase in their band gap.180 The size and properties of NDs depend on their synthetic method, as previously reported.178,181

NDs can be easily functionalized with different ligand molecules, which are used as platforms for the conjugation of various biological molecules, chemical compounds and drugs.182–184 Due to their high surface area and ease of functionalization and doping, NDs have been studied as theranostic agents.185,186 The optical properties of NDs are due to the presence of nitrogen-vacancy (NV) defect centers, a nitrogen atom next to a vacancy, which allow their use as photoluminescent probes.174 NV centers are created by irradiating NDs with high energy particles such as electron, proton, and helium ions, followed by vacuum annealing at 600–800 °C,187,188 which both form vacancies that migrate and get trapped by the nitrogen atoms present in the diamonds. Furthermore, the NV centers emit bright fluorescence at 550–800 nm. This excellent emission property together with their low cytotoxicity make NDs a promising fluorescent probe for single-particle tracking in heterogeneous environments.187,189,190 When functionalized, their biocompatibility is known to be superior to single-walled and multi-walled CNTs and carbon black.149

3. Rationale for imaging and delivery

Recently, CBN have emerged as promising platforms for one-/two-photon imaging and therapeutic applications. Compared to QDs and traditional fluorescence dyes, CBNs have significant advantages, such as robust chemical inertness, easy functionalization, high resistance to photobleaching, biocompatibility, large surface area, and high two-photon absorption cross-section,191 which are particularly beneficial for use as theranostic nanoparticles.

Among their optical modalities, two-photon fluorescence microscopy (TPFM) is a powerful technique for biomedical applications due to its various advantages, including deep tissue penetration, low tissue autofluorescence/phototoxicity, reduced photobleaching/photodamage, and high 3D spatial resolution, over normal fluorescence imaging systems.192,193 Two-photon fluorophore nanomaterials are key to the success of TPFM, and should possess a large two-photon absorption cross-section, high fluorescence quantum yield, low photodecomposition quantum yield, low toxicity, and low photoleaching.194,195 In the last few decades, significant effort has been made to design and synthesize two-photon fluorophores with different compositions, such as organic dyes, quantum dots, gold nanoparticles, and carbon-based materials.94,196–199 Among them, CBN are emerging potential nanoplatforms for two-photon imaging and therapies.200 Accordingly, the origin of the photo-reactive nature of CBN and the various ways to tune their optical properties to find optimal bioimaging and diagnostic applications are discussed below.

3.1. Origin of the optical properties in carbon based-nanomaterials

The intrinsic fluorescence properties of CBN have enabled their potential applications in imaging and cell labeling. Upon photo-excitation, CBN exhibit fluorescence properties. Many studies have shown the structural-dependent fluorescence imaging properties of CNTs in the NIR-II region.201,202 The conversion of oxide defects to carboxylic acid groups through chemical treatment generates NIR photoluminescence properties in SWCNT.203 The remarkable stable and size-tunable NIR fluorescence from SWCNT is of special merit for fluorescence-based bioimaging and sensing.204–207 In fact, the fluorescence properties of SWCNTs were first discovered upon ultrasonic exfoliation of the nanotube bundles that wrapped the individual SWCNT with surfactant molecules.208 Recently, chemical doping through oxygen209 or sp3 defects210 and surface modification through oxygen-excluding surface organization211 resulted in a significantly increased fluorescence QY of 20%. Moreover, DNA-wrapped SWCNTs with reducing agents, including dithiothreitol (DTT), trolox, and β-mercaptoethanol in aqueous media, enhanced the fluorescence QY to over 30%.212 Although high quality samples with almost completely pure SWCNT exhibited improved fluorescence QY through the addition of reducing agents, which increased the irradiative rates at quenching sites213,214 and passivated the defect sites,212 still the intrinsic fluorescence QY remains poor.201,215 Furthermore, the defect-induced fluorescence QY distribution depends on the SWCNT growth method and processing technique. The surfactant used to coat the surface of SWCNTs may lower their average fluorescence and reduce their sensitivity to extrinsic quenching defects.216

To address the low intrinsic fluorescence QY issue in CBN, researchers have developed several extrinsic quenching and surface functionalization methods.217–219 Metals (e.g., gold and silver) are well established materials for surface-enhanced Raman scattering (SERS)220,221 and surface-enhanced fluorescence164,222 due to their localized surface plasmon resonance (SPR) property. Single-stranded DNA (ssDNA)-wrapped SWCNTs modified by Au APs produced enhanced photoluminescence by forming an Au–DNA–SWCNT nanohybrid, in which ssDNA acts as excellent molecular spacers that protect the SWCNTs from direct contact with NPs to prevent PL quenching, and also the Au NPs next to the SWCNTs enhance PL.223 Using this nanohybrid, the bioimaging of HeLa cells was successfully carried out. The quenching of SWCNTs by dissolved oxygen generates a simple, facile and nondestructive method for wrapping ssDNA on the surface of SWCNTs.218 In another example of metal-enhanced fluorescence of Au-coated SWCNT, the fluorescence factor was suggested to depend on the NP–SWCNT distance and SPR of the Au substrate.50

Graphene-based materials have also attracted great attention in the field of biosensing and imaging. Generally, graphene is a nonfluorescent material, but GO is fluorescent due to various reasons including its structure defects. The fluorescence by GO produced ranges in the ultraviolet, visible, and NIR wavelengths with approximately 7% fluorescence QY.224–226 Nano-sized GO showed strong photoluminescence properties under both one-photon (OP) excitation (continuous wave laser) and two-photon excitation (ultrafast pulsed laser) in the visible and NIR regions, enabling dye-free labeling of cells for diagnosis.227–229 The photoluminescent properties in graphene-based nanomaterials originate from (i) the introduction of an energy band gap by converting G into finite small sizes or creating sp2 islands in GO and (ii) creation of structural defects through exhaustive chemical oxidation and reduction.

The excitation-dependent photoluminescence properties of CBN have numerous merits. It is interesting to note that the fluorescent carbon nanomaterials prepared by several methods generate almost the same excitation-dependent photoluminescence properties.153,230,231 It was also reported that the emitted light wavelength becomes red-shifted as the excitation wavelength increases and the emission can cover the full visible range.153,232 Recently, several experiments have been carried out to understand the origin of the photoluminescence properties in CBN.29,233,234 In most studies, the excitation-dependent photoluminescence and corresponding emission spectra of CBN showed a decrease in intensity at long wavelengths,235,236 although in some cases, the emission spectra showed an intensity increase first and then decrease.237–239 There are two fixed bands in the emission spectra of CBN, which correspond to π–π* transitions and δ–π* transitions.240–242 This excitation-dependent photoluminescence phenomenon is frequently observed in CBN.155,243–247

The origin of the photoluminescence in multicolor fluorescent hollow carbon spheres has been explained based on the quantum confinement effect. Their indirect energy band gap is 2.5 eV, which ensures the quantum confinement effect.248–251 The quantum confinement effect also endows energy band gap properties in graphene quantum dots (G-QDs), which is different to the case in the semi-metallic graphene sheets. Thus, tailoring the size of energy band gap through the charge transfer effect of the functional groups in G-QDs is an effective way to control their photoluminescence properties.252

The quantum confinement effect is also termed the size effect phenomenon, which is a well-accepted photoluminescence mechanism.253–257 In a recent study, Yeh et al. reported the quantum confinement effect of GO–QDs under ambient conditions with the observation of excitation-independent photoluminescence properties. Furthermore, they also suggested that the mechanism involves electron transitions from the antibonding π (π*) to oxygen nonbonding (n-state) orbitals. The observed quantum confinement is ascribed to the size change in the sp2 domains, which leads to a change in the π*–π gap, where the n-state levels remain unaffected by the size change.258 The schematic energy level diagrams for GO–QD specimens are shown in Fig. 2.


image file: c8mh00966j-f2.tif
Fig. 2 Mechanisms of optical imaging with CBN. (A) Schematic representation of the density of electronic states for a single carbon nanotube structure illustrating the mechanism of the origin of fluorescence in SWCNT. Reproduced with permission from Science Publishing Group from ref. 259. (B) Schematic energy level diagram for GOQD specimens. A schematic of the energy levels associated with the size-dependent PL emissions from GOQDs. The energy levels were determined based on ultraviolet photoelectron spectroscopy (UPS) and photoluminescent excitations (PLE) analysis. The level of the n-states is not disturbed by a change in the particle size, whereas the levels of the π, π*, and σ* orbitals vary considerably with particle size. The π* → n recombination, which involves phonon scattering and an electron transition, is responsible for the excitation wavelength-independent PL in the GOQD specimens. The relaxation of electrons from the σ* orbital to the π* orbital is essential for PL emissions induced by short-wavelength excitation. The PL color varies from orange-red (for QD79) to blue (for QD10). Quantum confinement effects (QCE) and surface/edge states in GQDs. Reproduced with permission from the American Chemical Society from ref. 258. (C) Energy level structures to explain the optical behaviors of the photoexcited electrons in GQDs, including their radiative recombination from discrete sp2-related states and continuous defect states, thermally activated decay into non-radiative traps, and non-radiative relaxation from higher to lower defect states. Reproduced with permission from the American Chemical Society from ref. 260. (D) Schematic illustration of one/two-photon excitation-induced PDT through type I and type II mechanisms. Reproduced with permission from the Royal Society of Chemistry from ref. 200.

3.2. Surface defect and doping effects

There are several methods to create surface/structural defects that can cause florescence in CBN.152,252,261 The chemical functional groups such as COOH, OH, C–O–C, C–N present on the surface of CBN, collectively act as surface defects. Also, damaged chemical bonds on their uppermost surface cannot be neglected. There are sp2- and sp3-hybridized carbons on graphene-based nanosheets, and any change in the surface molecular arrangement in any site can be surface defects. The functional groups on the surface are continuous defects responsible for emission,261–264 and different defect states are emitters corresponding to different wavelengths.260

The origin of the fluorescence properties of CQDs is correlated with surface passivation153,252,265 and their fluorescence emission ranging from the visible to NIR region is related to photogenerated electrons and holes trapped at diverse surface sites and their associated radiative recombination,265 while the optical absorption of CQDs is ascribed to the π-plasmon transitions in the carbon nanoparticle core of the dot.252 Besides, CQDs have been found to be highly photochemically stable, without showing any photobleaching effect.153

Doping is another way to create photoluminescence properties in CBN.266–271 Doping CBN with heteroatoms can effectively tune the intrinsic photoluminescence property of graphene. Recently, various heteroatom-doped CBN have been produced. Boron-doped GQD (B-GQD) was prepared via the electrolysis of graphite rods in an aqueous borax solution.272 Doping of dual heteroatoms endowed better optical properties to carbon nanodots.273 The emissive properties of both doped and undoped GQDs with sizes in the range of 3–11 nm analyzed at the single particle level revealed green, red, and NIR fluorescence upon excitation at 488, 561, and 640 nm, respectively. Nitrogen-doped GQD (N-GQD) with diameters in the range of 3.4–5.2 nm showed a larger proportion of particles with NIR emission compared to the undoped particles.226

3.3. Important aspects of carbon-based nanomaterials for imaging and delivery

Although the optical properties of CBN are essential for imaging purposes, their applications as theranostic platforms require some of important considerations. A high loading capacity for cargo molecules is an advantage for nanocarriers. Accordingly, decreasing the particle size (to below tens of nm, thus increasing their surface area) and functionalizing their surface with proper chemical groups can significantly enhance their loading capacity. In fact, the intrinsic chemical interactions of CBN with drugs and proteins, such as π–π interactions, hydrogen-bonding and hydrophobic interactions, are beneficial properties for effective biomolecular loading.274–277 Also, the abundant reactive oxygen functional groups present on the basal planes and at the edge of the GO/rGO sheets endow great opportunity to covalently link biomolecules.59,274,278,279

Along with the loading, the controlled (e.g., timely, sustained and on-demand) release of molecules should improve the therapeutic effects. Accordingly, stimuli-responsive materials are often functionalized with CBN to allow the light-, pH-, enzyme-, or temperature-dependent release of therapeutic molecules. Furthermore, the surface functionalization strategies extend to target specific cells (e.g., cancer cells, inflammatory cells, and stem cells) and intracellular components (e.g., mitochondria and nuclei) or to prolong blood circulation (using polyethylene glycol) to avoid nonspecific cellular uptake, all of which can significantly enhance their therapeutic efficacy while reducing systematic side effects such as fetal organ toxicity.

The body distribution and tissue/organ toxicity of CBN should be critically considered, although the proposed clearance mechanisms are not fully understood. Control of the particle size and proper functionalization of the surface of CBN has been shown to improve their colloidal stability and body clearance, alleviating some of the related concerns. Since CBN have low-dimensional (0D, 1D and 2D) properties, their shape- and size-related cellular interactions that can affect the cellular delivery efficiency of therapeutics and cause specific organ accumulation should be carefully considered.

Without using therapeutic molecules, photo-therapies (e.g., PTT and PDT) are also possible with CBN, where their photo-therapeutic ability depends on their opto-thermal properties.280,281 ROS is a major contributor to PDT besides photosensitizers. Nitrogen-doped graphene showed a significantly higher amount of ROS than nitrogen-free GQD in PDT upon NIR exposure. Therefore, the size and shape of NPs, surface functionality, dispersibility, doping of nitrogen atoms and optical properties at selected wavelength light and energy are key in PDT and PTT therapy.282 Fluorinated ruthenium(II) complexes (Ru1–Ru5) possessing excellent two-photon properties and single oxygen quantum yield were used in the PDT process.283 Thus, surface functionalization, N-doping, particle shape and size, and ROS activity have been shown to influence the photothermal and photodynamic properties of CBN284–286 and are thus carefully considered in designing CBN to combine their therapeutic potential through PTT or PDT together with the chemotherapy of delivered drugs.

Their differing cellular interactions and resultant accumulation and existence can also influence the diagnostic applicability of CBN. As mentioned before, surface defects and doped atoms enable different photoluminescence properties, which offer significant opportunity to tune the optical properties of CBN.287–289 Furthermore, a dimensional change in CBN, e.g., conversion of 2D graphene sheets into 0D chemically stable G-QD, can them endow novel photoluminescence and suitable physiological properties due to the strong quantum confinement and edge effects.289–292

A schematic of CBN as a promising theranostic platform integrating the capacity of therapeutics delivery, optical imaging and photo-therapies is shown in Fig. 3.


image file: c8mh00966j-f3.tif
Fig. 3 CBNs as multifunctional theranostic platforms. Integrated ability of therapeutic molecule delivery, optical imaging and photo-therapies is depicted.

4. Potential imaging platforms

Optical-based imaging techniques mainly rely on the capability of optical probes. Although two-photon excitation uses a high intensity laser power beam, usually by a femtosecond laser, one-photon excitation requires continuous wavelength low laser power. CBN have become a new type of high performance one-photon and two-photon fluorescence agent for imaging cells.

4.1. One-photon imaging

4.1.1. Fluorescence imaging. One-photon (down-conversion fluorescence) is a common type of fluorescence that is measurable by photoluminescence spectroscopy. The different colors in CBN are attributed to doping elements (N and O) and crystal defects.293,294 In fact, bioorganic dyes and metal dots have been broadly used for one-photon cell labelling, imaging and microsurgery, but they emit low power fluorescence photons after the absorption of high energy excitation photons. However, the use of high energy photons has some drawbacks in clinical applications, such as low penetration depth, cell damage, and autofluorescence of samples.

Recently, CQDs prepared via an electrochemical method were reported to have tunable peak emission wavelengths upon excitation by white light and full visible spectrum under proper synthetic conditions.295 The results demonstrated that the CQDs had more oxygen and nitrogen bonding with carbon, and were capable of sensitive detection and cell imaging.294 Lin et al.296 prepared CQDs with a size of 6.8 nm and a non-crystalline structure via autoclaving in citric acid formamide solution (Fig. 4A-i and ii). Depending on the excitation wavelengths from 330 to 600 nm, the color emission pattern was different (Fig. 4A-iii). MCF-7 cells incubated with the CQDs were optically visualized under a confocal microscope at excitation wavelengths of 405, 488, and 543 nm (Fig. 4A-iv). CQDs have also been incorporated into different types of NPs, such as gadolinium,82 gold,7,297,298 silver,299,300 manganese,301 cobalt,302 copper,303 iron oxide,304 and silica.77,78,305,306 For example, when incorporated into organosilica NPs, CQDs could highlight cells in tissue under fluorescence imaging with multi-colors (Fig. 4B).34


image file: c8mh00966j-f4.tif
Fig. 4 C-Dots developed for fluorescence imaging. (A) Preparation and excitation-dependent fluorescence imaging potential of C-dots: (i) schematic illustration showing the production of multi-color C-dots, (ii) TEM image of the C-dots, (iii) fluorescence emission images in the range of 330 nm to 600 nm, and (iv) confocal images of the C-dots in MCF-7 cells under bright field, 405, 488, and 543 nm excitation, and merged images (from left to right). Reproduced with permission from John Wiley and Sons from ref. 296. (B) Excitation-dependent in vivo optical imaging of C-dots in bioactive glass nanoparticles (C-BON100): as-prepared samples (left) and in vivo optical images at two different excitation wavelengths (right) after injection (100 μL, 2 mg mL−1). Reproduced with permission from the American Chemical Society from ref. 34.
4.1.2. Raman imaging. Cell and deep tissue imaging is a vital technique used to explore biological events, e.g., existence and processes in cells, and tracking of delivered drugs with NPs. The Raman imaging technique has high spatial resolution, photostability, high sensitivity and multiplexing capability. The Raman technique characterizes the structural bonds of many CBN because they have characteristic Raman fingerprint spectra.307–309 The Raman technique is based on the unique inelastic vibrational mode of photons, and thus the Raman spectroscopy signals have higher photo-stability, signal-to-noise ratio, and resolution compared with fluorescent probe signals. Therefore, Raman has rapidly emerged as a potential substitute to investigate CBN and their imaging of cells.310,311

GO has been widely used for Raman imaging, and NPs such as gold and silver are often combined with GO to improve its imaging intensity. GO decorated with Au NPs was used for the Raman imaging of cancer cells,96,312 where the HeLa cells labelled with Au/GO showed much stronger Raman scattering signals than that with GO. GO–Ag NPs synthesized via an in situ reduction method using PVP28 exhibited Raman scattering with an enhancement factor as high as 48.4. Results suggest that GO-based NPs are potential optical probes with high spatial resolution for cancer cell imaging through Raman spectroscopy.

For example, Tan et al.29 reported alkyne-PEG-functionalized AgCu@graphene (ACG) NPs fabricated using chemical vapor deposition (Fig. 5A). The ACG NPs were utilized for cell imaging by surface-enhanced Raman spectroscopy (SERS), where the functionalization of ACG with the alkyne molecule diphenylacetylene helped the localization of the NPs in cells. The functionalized ACG NPs were well visualized in the cytoplasm of MCF-7 cells under three Raman modes (D, G, and alkyne).


image file: c8mh00966j-f5.tif
Fig. 5 CBN used for Raman imaging. (A) AgCu@graphene nanoparticles for Raman imaging: (i) preparation of alkyne-PEG, (ii) schematic of the alkyne-PEG functionalization of ACGs, (iii) Raman spectra of alkyne-PEG without and with ACGs, and (iv) Raman imaging of MCF-7 cells incorporated with alkyne-PEG-modified ACGs in different modes. Reproduced with permission from the American Chemical Society from ref. 29. (B) CNT/silica on Au nanoparticles for the Raman-based detection of biomolecules inside living cells: (i) schematic illustration of the gold functionalization of CNTs, (ii) SEM images of the microspheres with CNT, deposited gold nanoparticles, and growth on the gold nanoparticles (from left to right, respectively), and Raman imaging of fibroblast cell with particles in (iii) bright field, (iv) Raman confocal image with three different colors (green: cytoplasm, blue: nucleus, and red: CNT), and (v) 3D image (green: cytoplasm and red: CNT (G-band)) distribution. Reproduced with permission from John Wiley and Sons from ref. 313.

CNTs were also used for intracellular mapping with the SERS technique. For example, silica-coated CNTs were used for Raman microscopy imaging after decoration with gold NPs313 (Fig. 5B). Raman mapping revealed three colors, which showed the spatial distribution of the nanoprobes (in red) in the cytosol. Gogotsi et al.307 also reported a similar work using Au-coated CNTs for in situ intracellular signaling using the SERS technique. Kern et al.314 further developed CNTs electrodeposited with Au NPs for both fluorescence imaging and Raman mapping.

4.1.3. Phosphorescence imaging. CBN are used as phosphors that can be excited by UV light. Room temperature phosphorescence (RTP) materials such as CBN,315,316 metal based-nanomaterials,317 and organic phosphorescence materials318,319 have been developed for application in optical chips, bio-imaging, sensing, photocatalysis, and security systems. The phosphorescence of CBN originates from its carbonyl and C–N groups.320 Recently, Yang et al.301 prepared carbon-based phosphorescent nanomaterials with N-doping (N-CQD) via a one-pot heat treatment from urea D. Their phosphorescence properties were shown to originate from the C[double bond, length as m-dash]N bonds on the surface of N-CQD, and the NPs exhibited a long lifetime (1.06 s) under 280 nm excitation. Lin et al.315 also developed phosphorescent CD materials using poly(vinyl alcohol) (PVA) and m-phenylenediamine (‘m-CDs–PVA’), which also exhibited photo-fluorescence and up-conversion properties. A composite film of m-CDs–PVA was transparent and excited under UV light and a femtosecond laser (NIR light) to create blue fluorescence and cyan up-conversion image, respectively. Notably, when the UV light was turned off a green glow color (phosphorescence property) was observed,315 and the room temperature phosphorescence spectra of the film exhibited an emission at about 506 nm under UV light (Fig. 6A).
image file: c8mh00966j-f6.tif
Fig. 6 Phosphorescent properties of CBN. (A) m-CDs–PVA composite film: systematic illustration showing multimode emission under excitation with UV light (365 nm, PL mode), after the light was turned off (RTP mode), and under excitation with a femtosecond laser (800 nm). Reproduced with permission from the Royal Society of Chemistry from ref. 315. (B) Nucleic acid-functionalized phosphorescent C-dots and GO, illustrating the actions of RTP logic gates. Reproduced with permission from the Royal Society of Chemistry from ref. 322.

In a similar approach, C-dots were dispersed in a PVA matrix.316 Their phosphorescence was observed under UV lamp at room temperature, and their emission peak was centered at 500 nm with a lifetime of 380 ms. The phosphorescence properties of the C-dots were shown to originate from the C[double bond, length as m-dash]O bonds on their surface and long lifetime.316 Xu et al.321 reported the observation of phosphorescence and fluorescence properties in triphenylamine-functionalized GO nanosheets. Under a 400 nm excitation wavelength, the phosphorescence emission peak was centered at 485 nm with a lifetime of 6.95 ms. The phosphorescence properties were shown to originate from the aromatic hydrocarbons-carboxylic bond in the GO nanosheets.321

Recently, room temperature phosphorescence logic gates were reported using single-strand nucleic acid (ssDNA)-functionalized GO and CD (Fig. 6B). Specifically, phosphorescence-based INHIBIT, OR, and OR-INHIBIT logic gates are operated by targeting ssDNA, Hg2+ and DOX.322 The cDNA-DD were loaded onto the surface of GO via π–π interactions. Similarly, Yue et al.323 reported amphiphilic CD (ACQD) with phosphorescence properties, which were synthesized via the hydrothermal treatment of oil-soluble N-doped CD. The ACQD NPs allowed not only exhibited phosphorescence but also two-photon and fluorescence for Fe3+ ions.323

4.2. Two-photon imaging

Two-photon excitation is a potential approach for the application of CBN in the NIR region (700–1100 nm). Upconversion NIR fluorescence probes have gained great interest for bioimaging and biosensing applications due to their high intense signal beam, low cytotoxicity, weak scattering of emission light, low photobleaching, low fluorescence background, and deep tissue penetration depth. Recently, CBN have shown as promising next-generation two-photon probes due to their unique properties such as non-blinking fluorescence emission, water solubility, high cell permeability and good biocompatibility. However, the exploration of CBN for two-photon imaging and sensing is still in its infancy.191,324

The two-photon luminescence intensity depends on the two-photon absorption cross-section and the emission quantum yield. The absolute value of two-photon absorption cross-sections of fluorescence materials depends on the wavelength in the range of 690 to 1200 nm. The measured two-photon fluorescence quantum yields of CBN such as N-GQD,325 nitrogen-rich CQDs,326 nGO,327 GQD,328 and peptide-decorated GQD,329 were 0.31, 0.63, 0.35, 0.35, and 0.64, respectively. Furthermore, CQDs were developed as two-photon fluorescent probes with high sensitivity and selectivity in a broad pH range (6.0–8.5).330 Recently, the two-photon emission quantum yield of aqueous GO modified with an aptamer was determined to be 0.34.331 This aptamer APT-modified GO-based two-photon fluorescence platform was used for the selective and multicolor imaging of methicillin-resistant Staphylococcus aureus (MRSA) in the first and second biological transparency NIR windows using the wavelength range of 760–1120 nm331 (Fig. 7A-i). In the presence of the aptamer-modified hybrid GO, MRSA was conjugated clearly inside the GO sheet (Fig. 7A-ii). The two-photon fluorescence experiments at 760, 880, 980 and 1120 nm excitation wavelengths suggested the efficacy of the GO in multicolor bio-imaging (Fig. 7A-iii–vi). This is due to the fact that the two-photon photoluminescence from GO was tuned just by varying the NIR excitation energy without changing its chemical composition and size. Furthermore, fluorescence image became brighter for a bigger circle due to the strong interaction between the hybrid GO and aggregated MRSA.


image file: c8mh00966j-f7.tif
Fig. 7 Two-photon cell and tissue imaging with CBN. (A) GO-based two-photon fluorescent imaging: (i) schematic representation of the system for selective biological sensing in the first and second biological transparency windows. (ii) TEM image of MRSA bacteria with aptamer-modified GO. (iii–vi) Multicolor two-photon fluorescent imaging of MRSA using aptamer-modified GO. MRSA position shown by circles. Reproduced with permission from the Nature Publishing Group from ref. 331. (B) FRET-C dot drug delivery system: (i) schematic illustration of the surface functionalization of FRET-C dots and the mechanism for drug delivery and (ii) 3D two-photon confocal fluorescence imaging under excitation at 810 nm. FRET-C dot-incubated glomerular tissues at different pH levels. Reproduced with permission from John Wiley and Sons from ref. 332.

In a recent study by Zhao et al.,332 they designed Förster resonance energy transfer (FRET)-based C-dots for two-photon imaging and drug release tracking in deep tumor tissues with a thickness in the range of 65–300 μm (Fig. 7B-i). Glomerular tissues were incubated with C-dot–DOX at solution various pH (pH 7.4, 6.5, and 5.5) for 30 min and then observed with a two-photon microscope (with 810 nm), where the C-dot fluorescence and FRET signal of DOX were simultaneously imaged with two different wavelength channels (C-dots at 475–525 nm and DOX at 575–625 nm) (Fig. 7B-ii).

4.3. Non-optical imaging

CBN have also been developed for non-optical imaging modalities, including photoacoustic, magnetic resonance, and computer tomographic imaging, which can compensate or improve the optical imaging capacity of CBN for better theranostic performances.
4.3.1. Photoacoustic imaging. Photoacoustic (PA) imaging is a non-invasive imaging modality based on the use of laser-generated ultrasound and combines the merits of both optical and ultrasonic properties.333 Recently, PA imaging has gained much attention as a promising imaging technique due to its versatility and cost-effectiveness, and its dependence on the absorption of low energy (visible and NIR laser light) to excite broadband ultrasound waves. The waves are encoded with the optical properties of the tissue and can be recorded and reconstructed in the form of 3D absorption-based images. During PA imaging, the translation of optical absorption into acoustic waves avoids the penetration depth or spatial resolution limitation of other optical imaging techniques, which generally arise from the strong scattering from tissue. This imaging technique has potential applications in the assessment of breast, skin and colon cancers as well as cardiovascular and dermatological diseases.

PA imaging is often combined with PTT to improve the cancer targeting and irradiation of tumors.334 A nano-rGO construct was used as a dual modality imaging and PTT platform with excellent PA contrast and PTT effects in living mice.335 Moreover, the therapeutic and imaging efficacy of the CBN was shown to be improved by the combination of PA imaging and PDT.228 PS-loaded nGO–PEG was utilized for multimodal imaging-guided PDT and for improving cancer cell killing efficiency. PA imaging results in the thermoacoustic (TA) effect, in which the photon absorbed is changed into heat energy. Thus, CBN were mostly designed to increase the photon absorption at a specific wavelength, and consequently to increase the PA or TA strength.336 However, photon absorption relies on multiple physical parameters such as heating, thermoelastic expansion and mechanical vibration. Thus, in several studies, CBN were coated with high absorption nanoparticles, which demonstrated improved thermal confinement to amplify the PA signal with effective light–sound conversion for improved PA imaging.337–339

PA imaging has also been combined with fluorescence imaging.67,340 CNTs were the first CBN used for in vivo PA imaging.341,342 The strong photon absorption of CNTs at 500–700 nm leads to the generation of acoustic waves upon excitation with laser light, which mainly depends on the concentration of CNTs (Fig. 8A).342 In addition to CNT, GO, GQDs, and G nanoribbons have also been reported as potential PA modality agents.334,335,343 Similarly to CNT, the low photon absorbance of GO was improved with the conjugation of ICG, which was used for PA imaging with HeLa cells.334 The nGO (size ∼70 nm) was also reduced and functionalized with BSA protein for higher stability and lower toxicity (Fig. 8B).335 Agarose gel filled with nGO showed weak PA intensity; whereas, that with nano-rGO exhibited a 3-times stronger PA signal in tumor tissue (Fig. 8B). Mandal et al.344 reported that P- and N-doped carbon QDs could produce dual wavelength emission of green and red with QY 30% and 78%, respectively. RAW cells were imaged with green and red colours under excitation at 461 and 566 nm, respectively, suggesting they are good candidates for fluorescence and PA imaging of tumors.344 Biodegradable, NIR-absorbing N-doped C-dots were also used for PA imaging and PTT using organic acid as a controllable nitrogen source.345 Wang et al.340 reported that red-emitting C-dots could absorb light ranging from 400 to 750 nm for PA imaging and PTT in living mice. C-Dots with a particle size of 10 nm were synthesized with good dispersibility at high pressure via an autoclave method (Fig. 8C). After injection in nude mice, in vivo fluorescence and PA imaging and the PTT effect were manifest in the tumor tissue.


image file: c8mh00966j-f8.tif
Fig. 8 PA imaging with CBN. (A) ICG-CNT: (i) PA signal vs. concentration and (ii) in vivo images showing ultrasound (gray) and PA (green) in mice subcutaneously injected with ICG-CNT at 0.82–200 nM. Vertical slices (dotted black line) sampled. Reproduced with permission from the American Chemical Society from ref. 342. (B) Nano-rGO conjugated BSA: (i) scheme showing the preparation of nano-rGO, (ii) PA signals and images of nano-rGO (0.05 μg mL−1), nano-GO (0.05 μg mL−1) and agarose gel, and (iii) PA signals in the tumor region as a function of the injection time. Reproduced with permission from Elsevier from ref. 335. (C) C-Dots: (i) synthesis, (ii) TEM images of the C-dots, and (iii) PA images of the tumors in the mice after intravenous injection with C-dots at different time points. Reproduced with permission from John Wiley and Sons from ref. 340.
4.3.2. X-ray computer tomography, magnetic resonance imaging, radionuclide imaging, and other imaging modalities. The combination of other potential imaging techniques such as MR or CT imaging with CBN offers a powerful set of harmonizing bioimaging outputs. However, the intrinsic properties of CBN cannot generate such imaging modalities; therefore, hybrid or nanocomposite forms of CBN through the incorporation of other imaging agent are needed.

Recently, the well-known MR imaging agent Gd3+ was conjugated with C-dots to form magnetic-fluorescent C-dots.346 The Gd3+-conjugated C-dots were prepared with a size of 47 nm via a one-pot hydrothermal process using a mixture of GdCl3, ethanediamine, and citric acid at 200 °C for 4 h (Fig. 9A). In vivo MR and fluorescence imaging revealed the distribution of the NPs in a mice in vivo model. Similarly, Gu et al.347 reported the synthesis of Gd-doped green luminescent C-dots via a microwave polyol method for multimodal imaging. The obtained Gd-doped C-dots showed a quantum efficiency of 5.4% and T1-weighted value of 11.35 mM−1 s−1. A dual response imaging system was also synthesized through the surface conjugation of amine-terminated C-dots with cDTPAA and further Gd3+ chelation.348 The C-dots–DTPA–Gd showed good solubility, strong fluorescence, high relaxivity and negligible cytotoxicity.348 Gd-Encapsulated C-dots were synthesized using Gd–DTPA (gadopentetic acid) at 300 °C. The produced Gd@C-dots showed strong fluorescence and T1-weighted MR imaging for dual-modality bioimaging applications.349 In another study, waste crab shells were used to prepare magneto-fluorescent C-dots via a microwave-assisted pyrolysis method.350 Three different transition metal ions (Gd3+, Mn2+, and Eu3+) were incorporated into the carbon matrix of C-dots, leading to strong T1, T2, and T2-weighted MR imaging, respectively.


image file: c8mh00966j-f9.tif
Fig. 9 MR/CT imaging modality combined with fluorescent nature of CBN. (A) Gd–C-dots for MR/fluorescence imaging: (i) schematic illustration of the synthesis of Gd–C-dots via the hydrothermal process and (ii) TEM image of Gd–C-dots and their size distribution (inset). (iii) In vivo MR imaging of mice before and after injection of Gd–C-dots. (iv) Fluorescence images of the liver slices of the control and Gd–C-dots. Reproduced with permission from the American Chemical Society from ref. 346. (B) GO–IONP–Au for MR/CT/fluorescence imaging: (i) schematic showing the GO–IONP–Au nanocomposites. (ii) MR imaging and (iii) CT imaging. Reproduced with permission from Elsevier from ref. 352.

Computed tomography (CT) is generally used for the diagnosis of cancer. CT can provide balanced anatomical information between tissues and NPs and measures the absorption of X-ray. CT attenuation contrast depends on higher atomic number elements such as Au, iodine, and Gd and the concentration of the NPs. Zhang et al.351 developed Ag-coated GO NPs for X-ray imaging together with chemo-photothermal therapy. Further, both iron oxide and gold NPs were decorated on GO for MR and CT bimodal imaging352 (Fig. 9B), demonstrating the potential of multifunctional graphene-based nanocomposites for multi-modal imaging in cancer theranostics.

Nuclear imaging with positron emission tomography (PET) and single photon emission computed tomography (SPECT) has the merit of high sensitivity. Molecules containing radioisotopes are generally used as nuclear agents, including 18F, 64Cu, 124I, and 68Ga for PET imaging and 99mTc for SPECT imaging. SPECT or PET is usually combined with other imaging modalities, such as CT and MRI327,353–361 to enhance both resolution and sensitivity. For example, Gd3+ and 64Cu2+ ions were both encapsulated in nanotubes (GNT) for integrated MR and PET imaging.353 The MR imaging displayed that the T1 relaxivity values for the 64Cu@GNT and GNT were similar (52.7 and 53.4 mM−1 s−1, respectively). The PET imaging of 64Cu@GNT revealed the localization of agents to specific organs, while the 64Cu@GNTs were localized mainly in the liver and lung without significant uptake in the gastrointestinal and kidney tract. Specifically, after 4 h injection, the free 64Cu2+ was localized primarily in the liver and slightly in the gastrointestinal tract. Recently, PET imaging was also combined with optical imaging. GO–PEG–NH2 was functionalized with fluorescein and 64Cu for the observation of targeting efficacy of the follicle-stimulating hormone receptor (FSHR) and its biodistribution through fluorescence and PET multi-modal imaging.359

Wang et al. developed 99mTc-radio-labeled and iron oxide nanoparticle-coated CNT hybrids for dual SPECT/MR imaging.354 The 99mTc radio-labeling on the surface of iron oxide nanoparticle-coated MWCNT was enabled through a dipicolylamine-alendronate linker. The hybrid nanoparticles enabled SPECT/CT imaging and γ-scintigraphy to quantitatively analyze their in vivo biodistribution, demonstrating the capacity of radio-labeled CNT hybrids as dual MRI and SPECT contrast agents for in vivo use. Similarly, SWCNTs conjugated with iron oxide nanoparticles and gallium-67 were used to investigate the targeting of breast cancer stem cells by dual-imaging with MR and SPECT.355 More recently, a chelator-free strategy based on ultra-small nano GO (usNGO) was reported for MR and SPECT/CT multimodal imaging.326 For SPECT and MR imaging, 99mTc and Gd3+ were linked to usNGO–PEG, respectively. The radio-labeled nanoparticles (99mTc–usNGO–PEG) injected subcutaneously into the left footpad of mice were clearly visualized up to 24 h via SPECT/CT imaging. With MR imaging, the signal of Gd from the nanoparticles was also intense after their injection up to 24 h, highlighting the multi-modal imaging capacity of the 99mTc- and Gd-linked ultra-small nanosized GO.

5. Light-mediated therapies and theranostic multifunctional platforms

Light-mediated or light-activated drug delivery and therapies are potential platforms in which light sources with wavelengths ranging from 300–1000 nm (UV, visible, and NIR) are used to produce thermal or biochemical energy for the treatment of diseases. There are three typical light-based therapy methods, photothermal therapy (PTT), photodynamic therapy (PDT) and light-mediated chemotherapy. PTT is a photothermal agent-based therapy, in which nanomaterials (with or without photosensitizing agent) can absorb light and convert optical energy into thermal energy to produce heat, leading to the photoablation of cancer cells/tumors. On the other hand, PDT uses nanomaterials that can produce reactive oxygen species (ROS) at specific wavelengths of light, which leads to apoptotic and necrotic cell death. Light-mediated chemotherapy is a method to treat cancerous cells, in which chemotherapeutics (anticancer drugs) are loaded into carriers and then released through the light-activating action of nanomaterials. Often, these light-based therapies are used in combination with each other, such as PTT–PDT, chemo-PTT, and chemo-PDT, which has more enhanced therapeutic efficacy than the individual therapies.362–364

These multimodal nanoplatforms can facilitate not only the delivery of drugs, but also provide imaging contrast. Nanoplatforms based on CBN can possibly tackle many of the limitations encountered in conventional treatment methods, such as poor solubility of therapeutic drugs, low accumulation of drugs at therapeutic sites, poor light-induced destruction of tumors and other unwanted side-effects. CBN have been shown to exhibit excellent optical properties with large excitation coefficients and band-to-band transitions in the NIR region and capacity for imaging and tracing of deep tissues for disease diagnosis and therapy.365,366 In the following section, we summarize the performance of light-mediated therapeutic and diagnostic platforms of CBN, with an emphasis on NIR light-mediated chemotherapy, PTT, PDT, and their combinations.

5.1. Light-mediated chemotherapy, photothermal therapy and photodynamic therapy

The light-mediated therapeutic strategy using UV, visible, or NIR light and nanocarriers is a promising tool to precisely control the delivery of therapeutic molecules and imaging probes in vitro and in vivo. Some considerations include limited tissue penetration depth, light absorption/scattering and possible light toxicity to healthy tissue. Among the light sources, NIR with wavelengths ranging from 700 to 1000 nm is considered to endow deeper tissue penetration and lower photo damage and autofluorescence, which are effective for light-mediated therapies.

CBN are used for light-mediated chemotherapy to treat cancers. In chemotherapy, drugs used to inhibit the growth of tumors are released by the stimuli-responsive action of CNB. In fact, different types of nanocarriers have been developed to be responsive to specific stimuli including pH, temperature, ultrasound, enzyme, reduction/oxidation, and light.367–369 Among them, pH responsiveness was used for CBN since the pathological condition of tumor tissue and intracellular endosome/lysosome has a lower local pH by 1–2.5 pH in comparison with that (pH 7.4) of blood and normal tissues. Furthermore, NIR light was utilized for effective chemotherapy with CBN.370,371 The exogenous activation with NIR light due to its merits of low energy absorption and deep penetration for human tissue was an excellent external stimulus to release drugs at a desirable site and time.

For light-mediated PTT, the nanocarriers accumulated near the tumor site generate heat under NIR-light irradiation with a laser and damage tumor cells. CBN provide excellent nanoplatforms for light-mediated PTT due to their broad-range optical properties, i.e. absorption extending from the UV to NIR region.153,372–375 For UV-mediated PTT, carbon-dots with folate-conjugated reducible PEI were developed and utilized for gene delivery. Due to its short wavelength (<400 nm), UV light can generate high energy that can damage other native tissues, which often raises concerns on the use of UV light-mediated therapy in-clinic. Thus, visible light-mediated therapeutic delivery has been studied. Recently, porphyrin conjugated-SWCNTs were applied for the inactivation of Staphylococcus Aureus via visible-light mediated therapy.376

On the other hand, the NIR light-mediated therapeutic delivery has been considered as an optimal way to treat cancer with high tissue penetration depth, low fluorescence background, and low cytotoxicity. For example, NIR photoluminescence CNTs coated with an amphiphilic and biocompatible polymer were shown to produce high quality of images of brown fat.377 Also, nano-rGO sheets with PEGylation increased the NIR absorbance by more than 6-fold, and their conjugation with peptide for cancer cell targeting and selective photoablation at low power increased the PTT efficiency significantly.378

Light-mediated PDT is another emerging therapeutic and imaging technique to treat tumors. The PDT method is based on the toxic ROS either self-generated from nanoparticles67,379 or through the photosensitizer (PS) used together with nanoparticles380,381 upon UV, visible or NIR irradiation. PDT is a non- or minimally-invasive anticancer theranostic method that has lower side effects and systemic toxicity and higher efficiency compared with traditional chemotherapy and radiation therapy.382–384 However, the limited tissue penetration depth (at UV or visible light), short lifetime of ROS, and the photostability and dispersibility issues of PS (such as Ce6 and ZnPc) can hinder the potential therapy of solid tumors in deep tissue sites.16,385 Thus, NIR is preferable to enable deep tissue penetration with fluorescence imaging.384,386

In the PDT technique, different ROS can be formed including OCl, ˙OH, H2O2, O2, 1O2.374,387,388 It is known that CBN have the capacity to generate different forms of ROS.379,389 For example, SWCNTs can generate light-independent ROS (superoxide anion, O2˙) via electron transfer from carboxylated groups,390 while GQD can generate light-dependent ROS (1O2) via a multistate sensitization process. Similarly, fullerene nanoparticles have been used for PDT.391 Photochemical ROS were reported to be generated by different water soluble fullerenes (C60), which induced toxicity in HaCaT keratinocytes.392 Also sugar-derived fullerene nanoparticles could kill cancer cells under 1270 nm visible light.393

In addition to single light-mediated therapy, multimodal therapies such as PTT/PDT, PTT/chemotherapy, and PDT/chemotherapy have been introduced to be more effective for cancer treatment. For example, a GO–fullerene C60 hybrid (GO–C60) showed simultaneous PDT and PTT triggered by 808 nm NIR light.394 Likewise, CNTs were effective in generating 1O2 under laser excitation,395–397 which were combined with PTT through functionalization (PEI and PVPk30).395 Recently, Chao et al. reported that an Ru(II) complex with CNTs showed photothermal and two-photon PDT effects on cancer therapeutics.398 Moreover, Murakami et al. found that semiconducting and metallic-enriched SWCNTs exhibited PTT and PDT effects with H2O.399 Nano-sized GO was also designed to generate ROS and exert a hyperthermia effect upon ultra-low doses of NIR excitation (980 nm, 250 mW cm−2).75 Furthermore, various multifunctional nanoparticles including MSN,400 up-conversion nanoparticles,401–403 gold nanoparticles402,404 and polymeric nanoparticles405 have been used with CBN for multimodal therapies for cancer treatment.

PTT or PDT has been widely used in combination with chemotherapy. In fact, PTT and PDT often fail to destroy tumor sites due to unwanted heat distribution and hypoxic conditions, and the surviving cancer cells can further result in local recurrence and distant metastasis.175,406 To overcome these issues, researchers have developed the combination of PTT/PDT-chemotherapy as an optimal strategy for the treatment of cancer. For combined PTT/PDT-chemotherapy, different materials are often combined with CBN to provide high drug loading efficiency and stimuli responsiveness. For example, ND complexes and mesoporous carbon nanospheres were combined to effectively load and release drugs in response to pH changes,407–409 and GO and SWCNTs functionalized with polymers were demonstrated to show controlled drug release under NIR-irradiation.410–413 Recently, the combined therapy of PTT with drug was investigated using multifunctional nGO, where the synergistic therapeutic effect was based on the photothermal property of nGO under NIR irradiation and the chemotherapeutic effect of DOX.414 Moreover, graphdiyne (GDY) nanosheet-based nanoplatforms were developed for combinatory PTT/chemotherapy in cancer treatment. The broad absorption of GDY across the entire visible light region makes it qualified for PTT in cancer treatment.415 Under NIR-irradiation, GDY/DOX exhibited a higher cancer inhibition rate compared to individual therapy both in vitro and in vivo.416 Similarly, several other CBN were also developed for the combined approach of PTT/chemotherapy to treat cancers.274,417–419

Photodynamic-chemo multimodal therapy has recently been used to reduce the side effects of chemotherapy, while improving the therapeutic efficiency. Zang et al. designed a pH-responsive drug delivery system composed of C60–PEI–DOX for both PDT and chemotherapy.391 Recently, Lin et al. developed a combined chemotherapy and PDT strategy using GO as the drug delivery system. In their study, 7-ethyl-10-hydroxycamptothecin (SN-38) was used as a chemotherapy drug and hypocrellin as a photosensitive anticancer drug. The combined PDT/chemotherapy showed a significant antiproliferative effect compared with PDT and chemotherapy alone.420 In fact, several studies have demonstrated that the combination of PDT with chemotherapy could overcome drug resistance by invoking multiple anticancer mechanisms.421–423

The aforementioned light-induced combined therapies based on CBN are summarized in Table 2.

Table 2 Summary of the light-induced multimodal therapies of cancer utilizing CBN and their composites/hybrids
Multimodal therapy CBN (composites/hybrids) Applications Mechanism Ref.
Chemo/PTT PEG–GO/CuS In vivo cervical cancer therapy PEG–GO/CuS-mediated photothermal ablation and light-triggered DOX release inhibited mouse cervical tumor growth. 424
Chemo/PTT Polydopamine–rGO–MSN In vivo antitumor therapy π–π stacking and pore absorption and/or van der Waals force for DOX loading, and pH and NIR-irradiation dependent cancer therapy. 425
Chemo/PTT GO@Ag Inhibition of tumor growth in vivo marine tumor model and X-ray imaging. DOX was loaded by ester bond to GO@Ag, which was functionalized with an NGR peptide motif for a tumor targeting ligand. 351
Chemo/PTT nGO–PEG–OCT Anti-tumor efficacy strategy via cancer cell specific targeting. Somatostatin receptor-mediated tumor specific targeting delivery. 426
Chemo/PTT FA–GdN@CQDs–MWCNTs Magnetofluorescence CNT for combined chemo/PTT therapy with fluorescence and MR imaging for cancer excision. pH and NIR-responsive intracellular drug delivery to kill cancer cells and PTT from CQD–CNT inhibited tumor growth in tumor-bearing mice model. 427
Chemo/PTT MWCNT@PVPy–S–PEG–FA pH-Responsive drug delivery and efficient chemo-photothermal therapeutic nanoagents to treat cancer. FA–PEG–SH for active targeting ability and to extend blood circulation time and PVPy to enhance photothermal effects of MWCNT and loading of targeting/drug molecules. 428
Chemo/PTT hCNs Chemotherapeutic drug and gene delivery for cancer therapy. Porous hallow CNs with tunable center-radial mesopore channels and crater-like inner surface for drug/gene loading. 429
Chemo/PDT PEG–nGO Ablation of tumor both in vivo and in vitro by combination of photothermal therapy and chemotherapy via nGO. NIR-irradiation with power 2 W cm−2 with spot size 6 × 8 mm for 5 min, DOX chemotherapeutic drug and nGO–PEG PDT agent. 430
Chemo/PDT C60–PEI C60–PEI was used for local chemotherapy with external PDT to improve the therapeutic efficacy of cancer treatment. DOX was covalently conjugated in to C60–PEI by pH-sensitive hydrazone linkage and further labelled with CdSe/ZnS QD. 391
PTT/PDT Au@GON Generation of localized SPR, Raman scattering, amphiphilic surface and photothermal conversion and Raman bioimaging. Au@GON exhibited properties such as LSPR, SERS and photothermal effects. 431
PTT/PDT Ce6–ND–PCM PDT and PTT combined approach for tumor therapy. The single oxygen generation from PCM nanoparticles conjugated with Ce6 utilized as PDT agent and selective laser exposure for PTT. 432
PTT/PDT C-Dot Red-light-triggered theranostic agent for imaging and PTT/PDT combined cancer therapy. C-Dot exhibited combined PTT and PDT effects under 635 nm laser irradiation with generation of singlet oxygen. 433
PTT/PDT/chemotherapy rGO–AuNCs Hydrogel-based NIR-responsive delivery and combined PTT/PDT/chemo therapy. AuNCs as photothermal agent and enhanced singlet oxygen agent, GO as drug delivery carrier via π–π stacking, hydrogen and hydrophobic bond, and fluorouracil and DOX as chemotherapeutic drug. 434


5.2. Light-mediated therapeutics–diagnostics combinatory approaches

Numerous therapeutic–diagnostic combined approaches have been developed for the treatment of diseases. Among them, light-mediated combined approaches have been potentially developed using CBN, where light-mediated PTT in combination with optical imaging is a typical example. Recently Ryu et al. developed folic acid (FA)-conjugated nanodiamond (ND) nanoclusters for selective PTT and imaging of tumor tissue.435 The surface of the ND nanoclusters with carboxylic groups was aminated using ethylenediamine and further conjugated with FA via carbodiimide chemistry (Fig. 10A). KB cell death was visualized well in vitro with the ND and FA-ND nanoclusters upon exposed to an NIR laser for 5 min (Fig. 10B). The temperature of the ND dispersion was shown to increase in vitro upon NIR laser exposure. This was also proven in vivo after intravenous injection in tumor tissue, and the in vivo imaging visualized the fluorescence signals clearly (Fig. 10C and D), suggesting the efficacy of the FA-ND nanoclusters in NIR-mediated PTT and imaging for cancer treatment.
image file: c8mh00966j-f10.tif
Fig. 10 NIR-mediated PTT and imaging of tumor tissue using nanodiamond-based nanoclusters. (A) Systemic illustration of the synthetic process. (B) Fluorescence in vitro images of KB cells under laser on and off conditions. KB cells were incubated with ND and FA-ND nanoclusters for 12 h and exposed to NIR irradiation (5 min, 2 W cm−2), followed by live/dead staining (left green fluorescence, middle: red fluorescence, and right: merged imaged). (C) In vivo thermographic images of tumor-bearing nude mice locally irradiated by NIR laser (2 W cm−2) for 5 min after 72 h post-intravenous injections of FA-ND nanoclusters (0.1 wt%). (D) In vivo non-invasive fluorescence images of tumor-bearing nude mice at 1 and 72 h. Reproduced with permission from John Wiley and Sons from ref. 435.

PDT-combined tissue imaging was also facilitated through CBN. The quantum yield of GQD was shown to be ∼1.3, a level reported to be the highest for PDT agents, which enabled the visible-light activated imaging and PDT treatment of tumor tissue (Fig. 11). Nitrogen-doped GQDs coupled with PS were prepared for PDT, which were based on the fluorescence resonance energy transfer (FRET) mechanism.436 In the FRET-based system, two-photon species and PS act as the energy donor and acceptor, respectively. This study confirmed the high photostability, biocompatibility and efficient theranostics (PDT plus optical imaging) of the PS-conjugated N-GQD nanoplatforms under NIR irradiation.


image file: c8mh00966j-f11.tif
Fig. 11 Visible-light mediated multistate sensitization mechanism, in vivo imaging and PDT with GQDs. (A) Schematic illustration of the 1O1 generation mechanism by conventional PDT agents (left) and GQDs (right). (B) Bright-field and red-fluorescence in vivo images after subcutaneous injection of GQDs in different areas. The excitation wavelength was 502–540 nm, and the collected fluorescence channel was 695–775 nm. (C) Photographs of the mice after various treatments on the 1st, 9th, 17th and 25th days. (PDT: GQDs + light irradiation, C1: GQDs only and C2: light irradiation only). Reproduced with permission from the Nature Publishing Group from ref. 67.

PTT/PDT combined with optical imaging has recently been enabled by CBN. Kalluru et al.437 showed that nGO exhibited single-photon excitation wavelength-dependent photoluminescence in the visible and NIR region and utilized it for in vivo multicolour fluorescence imaging. Furthermore, they confirmed that the formation of singlet oxygen can be combined with PTT for the destruction of tumors using ultralow doses (∼0.36 W cm−2) of NIR (980 nm) light. In their study, nGO was functionalized with PEG and further conjugated with FA to form tumor targeted nanoplatforms to exert simultaneous in vivo fluorescence imaging and PTT/PDT synergistic effects for cancer treatment. Zhang et al.438 also developed an rGO–Ru–PEG nanotheranostic platform, in which PS and phosphorescent Ru–PEG were attached to the PTT agent rGO surface via π–π stacking and hydrophobic interactions. The rerelease of Ru–PEG was pH dependent and the release rate increased considerably under NIR irradiation. The cancer cell killing mechanism involved the generation of ROS from the nanohybrid and cathepsin-initiated apoptotic signalling pathways under light excitation. Thus, the nanohybrid demonstrated high treatment efficacy in vivo when irradiated with 808 nm (PTT) and 450 nm (PDT) laser. Wang et al.35 reported that C-dots can be utilized as red-light-triggered theranostic agents for simultaneous single oxygen 1O2 photodynamic and photothermal therapy. C-Dots were synthesized using polythiophene benzoic acid with sizes in the range of 6 to 10 nm (Fig. 12A and B). The obtained C-dots showed light absorption and red-light emission with good dispersibility, biocompatibility and photo-stability. Also, the C-dots simultaneously generated single oxygen 1O2 and heat under laser irradiation due to their triple energy state (Fig. 12C). The cancer cells treated with the C-dots were clearly imaged at two excitation wavelengths and were damaged significantly due to the PDT/PTT effects under laser power (Fig. 12D). The in vivo real time images demonstrated fluorescence imaging and photothermal imaging with PDT/PTT (Fig. 12E). Similarly, Wang et al.439 reported self-assembled C-dots with PS via an ionic self-assembly method. Under laser irradiation, the obtained C-dots generated single oxygen 1O2 with a high quantum efficiency of 45.4%. In vitro and in vivo studies demonstrated that the C-dots were effective for the simultaneous NIR activation of PS, fluorescence imaging, and PDT therapy.


image file: c8mh00966j-f12.tif
Fig. 12 C-Dot-based combined PDT/PTT with bioimaging. (A) Fabrication of C-dots. (B) TEM image of C-dots. (C) Mechanism for the single oxygen 1O2 generation by C-dots. (D) In vitro imaging and PDT/PTT with cancer cells. (E) Fluorescence images of calcein AM/PI-stained cancer cells with laser irradiation; 635 nm laser at power densities of 0.1 W cm−2 (PDT) and 2 W cm−2 (PDT/PTT) for 10 min. (F) In vivo real-time fluorescence imaging and photothermal imaging with PDT/PTT. Reproduced with permission from John Wiley and Sons from ref. 35.

For PTT/chemotherapy with combined imaging, Chen et al.440 recently developed nanocarriers composed of rGO/carbon/MSN, which were biocompatible, photo-responsive, cell-penetrating, and large-payload, and showed NIR-triggered photo-chemothermal therapy with tissue imaging. While amorphous carbon and MSN are beneficial for molecular loading due to their high surface area and chemistry, rGO can produce photon-to-thermal energy transfer under NIR irradiation for PTT and chemotherapy (Fig. 13). The photon heating effect was analysed with NIR irradiation and the drug release was shown to be stepwise with a change in temperature, confirming the possibility of NIR-triggered photothermal chemotherapy. The in vivo treatment of mice bearing MDA-MB 231 tumor cells resulted in a significant decrease in tumor size within 14 days, which was accomplished via the optical probing of tissues.


image file: c8mh00966j-f13.tif
Fig. 13 NIR-induced combined PTT/chemotherapy and optical imaging with rGO-based nanocookies for tumor treatment. (A) Schematic illustration of chemo/photothermal therapy using rGO/carbon/mesoporous silica nanocookies under NIR light-control. (B) NIR-stimulated drug (CPT) release profiles from rGO and nanocookies: single 5 min NIR exposure initiated at time 0, multiple exposures repeated 5 times after 5 min waiting time following previous exposure. (C) Tumor volume change with PBS + NIR (control), CPT + NIR, nanocookie-CPT (no NIR), nanocookie + NIR, nanocookie-CPT + NIR. (D) Infrared thermal image of PBS + NIR (control), CPT + NIR, nanocookie-CPT (no NIR), nanocookie + NIR, and nanocookie-CPT + NIR treatment. Color bar on the right shows the temperature in degrees Celsius. (E) At day 4 after NIR irradiation (808 nm, 0.75 W cm−2, 5 min, 1 min interval for every min treatment). Tumor turned into a scab at the sites injected with nanocookie + NIR and nanocookie-CPT + NIR. Reproduced with permission from John Wiley and Sons from ref. 440.

Furthermore, combined PTT/PDT/chemotherapy with bioimaging was possible with CBN. Together with the innate imaging modalities of CBN such as fluorescence, photothermal and photoacoustic imaging, other imaging modalities (e.g., CT and MR imaging) have also been introduced by hybridizing CBN with other nanomaterials, such as iron oxide NPs, gadolinium NPs, cobalt NPs,441 and upconversion NPs. For example, hybrid nanoparticles of Fe3O4 with a porous carbon coating were synthesized via a one-pot solvothermal method.29 The MR imaging of Fe3O4 and the fluorescence imaging with the NIR photothermal effect of carbon nanoparticles were demonstrated simultaneously. Also, SiO2-coated hollow carbon nanospheres encapsulating Fe3O4 nanoparticles were used for ultrasound imaging, MR imaging, and NIR-activated PTT.442 Similarly, Zhang et al. designed iron oxide NP (IONPs)-coated fullerene with functionalized PEG (C60–IONP–PEG) for PDT, radiofrequency thermal therapy, and MR imaging.443,444 Recently, multifunctional nanoplatforms based on upconversion nanoparticles (GdOF:Ln@SiO2 mesoporous capsule) with C-dot incorporation, namely UCMCs, were developed as promising multifunctional nanoplatforms for cancer theranostics.385 The yolk-like UCMCs provided multifunctional theranostic platforms for therapy (PTT/PDT/chemotherapy) and imaging (PT, CT, and MR imaging) triggered by single NIR light, as demonstrated in Fig. 14. The release of DOX from UCMCs-DOX was shown to exert an anticancer effect under NIR-irradiation. Moreover, the PTT/PDT effects of inhibiting tumor growth were demonstrated in H22 tumor-bearing mice injected intratumorally with UCMCs-DOX. Finally, three different imaging modalities including photothermal imaging, CT imaging, and T1-weighted MR imaging were also well demonstrated.


image file: c8mh00966j-f14.tif
Fig. 14 Multifunctional theranostic nanoplatform showing combined PTT/PDT/chemotherapy with photothermal/CT/MR imaging. (A) Schematic illustration showing the synthesis of GdOF:Ln@SiO2–ZnPc–CDs microcapsule. (B) Fluorescence images of HeLa cells incubated with UCMCs-DOX and NIR irradiation (LIVE & DEAD stains, control included). (C) In vivo drug release under NIR irradiation after injection of UCMCs-DOX, illuminated by bright red UC emission. (D) Representative photographs of the mice after various intratumoral treatments. (E) PT imaging, CT imaging of tumor-bearing mouse before intratumor injection and after UCMCs injection, and in vitro T1-weighted MR imaging of UCMCs. Reproduced with permission from the American Chemical Society from ref. 385.

As previously mentioned, various modalities of imaging and therapeutic methods can be endowed in CBN-based nanoplatforms for disease treatment. Some representative studies of CBN-based combined theranostics are summarized in Table 3.

Table 3 CBN-based nanoplatforms for combined theranostic applications
CBN-based nanocarrier Type of material/therapeutics Imaging modality Comments Ref.
C60 IONP PDT, RTT MRI Cancer theranostic application 443
C60 Au DOX, PDT/RTT X-ray imaging Tumor-specific PDT-chemotherapy with X-ray imaging for theranostics. 445
CNT PTT/PDT Fluorescence, PA imaging Long circulating SWNT for imaging-guided cancer therapy. 70
CNT Gd PTT MRI Photothermal dissection of tumor metastasis. 446
CNT Fe3O4–MSN DOX MRI Drug delivery and MRI application. 114
GO IO DOX MRI Enhanced tumoricidal effect due to hyperthermia and specific DOX release with MRI performance. 447
GO Su PTT Photoacoustic imaging PTT and photoacoustic imaging for precise image-guided tumor treatment. 448
GO HA Anti-PNA21 Fluorescence imaging CD44 receptor-mediated endocytosis for breast cancer detection and inhibition of miR-21 oncogenic sensing. 449
GO MnOx/TiO2 PTT, SDT, ultrasound therapy MRI Nanosonosensitized sonocatalytic tumor eradication via photothermal, sonodynamic, and ultrasound therapy with MRI. 450
GO Au PTT/PDT Photothermal imaging In vivo imaging, bimodal photoablation, photo-controlled cancer theranostics. 82
GO Fe3O4 DOX MRI Folic acid-conjugated Fe3O4@nGO with DOX for tumor targeted therapy. 73
GQD Nuclear imaging Photoluminescence and pH sensing. Clathrin-mediated endocytosis for nuclear targeting. 451
GQD UNCP PDT Mitochondria-targeted cancer cell killing using NIR-irradiation PDT. 452
GQD FA DOX Fluorescence imaging Breast cancer therapy 453
CQD Gd Radiotherapy MRI Removal of solid tumor via MRI-mediated radiotherapy. 454
CQD siRNA Fluorescence imaging Theranostic nanoagents for gene delivery in lung cancer therapy. 455
CQD PDT Fluorescence imaging Nucleus targeting, nucleus imaging and enhanced cytosolic nuclear drug delivery for cancer therapy. 456
CQD PTT PT, PA, and FA imaging Hyperthermia-promoted cytosolic and nucleus delivery with multimodal imaging and PTT for cancer treatment. 457
CQD C-BON DOX, PTT Optical imaging Chemotherapy, photothermal therapy and optical imaging for theranostics. 34
CQD hMOS DOX Optical imaging Chemotherapy, in vivo imaging for cancer therapy. 458
ND MSN Dil Optical imaging Bioimaging and drug delivery for theranostic application. 459
ND Au Optical, electronic imaging Fluorescent nanodiamond for optical and electronic cell imaging. 460
ND PTX Fluorescence imaging Drug delivery with selective targeting, imaging and enhanced chemotherapeutic efficacy. 461
ND PEG DOX Fluorescence imaging Clathrin-/caveolae-mediated endocytosis, pH-responsive drug delivery, selective targeting, and imaging for cancer therapy. 462
ND miRNA Fluorescence imaging NIR fluorescence nanohybrid for synchronous tumor imaging and microRNA modulated therapy. 463


6. Biocompatibility issues of carbon-based nanomaterials

As demonstrated, CBN have been found to be promising theranostic platforms for biomedical applications. However, although CBN have shown excellent efficacy in various imaging modalities and therapies, their possible tissue toxicity should be carefully addressed for their clinical applications in the future. The biocompatibility issue of nanomaterials generally correlates with their in vivo degradation and organ distribution. Accumulation studies have demonstrated that carbon nanomaterials are degradable in vivo although their degradation rate is highly dependent on their type and physicochemical properties.464,465 In many cases CBN can exit the body through renal excretion without noticeable degradation.466,467 In principle, the degradation products of CBN are carbon. However, initial studies have reported that their toxicity originate from some toxic elements at the trace levels,466,468 which were incorporated or doped during their synthesis, and thus their potential toxicity can be significantly resolved by increasing their purity.33 The biocompatibility of CBN should also be considered in the context of their physicochemical properties (e.g., surface chemistry) since they determine their dispersibility and thus aggregation and accumulation in the body. Accordingly, most studies modified the surface of CBN with functional groups to enhance their dispersibility in aqueous media, and the increased dispersibility was demonstrated to enhance their biocompatibility significantly.469–471 Another point to consider is the difficulty in analysing the biodistribution of CBN. Although label-free mass spectrometry imaging was recently reported to detect the body distribution of CBN in mice based on the intrinsic carbon cluster fingerprint signal, this method could not determine if the nanomaterials were transformed in vivo.472 Therefore, in most cases, carbon nanomaterials are radio-labeled to detect their biodistribution.473 Considering these aspects, here the biocompatibility of CBN is addressed in the sequence of fullerenes, CNTs, G/GO/rGO, GQDs, and NDs.

Fullerenes are the first materials in the category of CBN that have hardly been less for biomedical applications. Polyhydroxylated gadolinium metallofullerene nanocrystals (GFNCs) were the first water-soluble modified gadofullerenes.474–476 Interestingly, the water-soluble and negative-charged GFNCs could be excreted from the body of mice within several days, suggesting their low toxicity.477 Subsequently, the long-term toxicity of GFNCs was evaluated with different concentrations and time points. After administration of the PEG-functionalized GFNCs in vivo, the evaluation of blood biochemistry and organ histology suggested relatively low long-term toxicity.478 Biodistribution studies have also been conducted with 14C-radiolabeled carboxylated fullerene derivative in rats.479 After intravenous administration, the nanomaterial was shown to rapidly spread to several organs with no significant signs of toxicity. However, interestingly, the intraperitoneal injection showed tissue toxicity. It was deduced that the fullerene may have induced severe inflammatory responses when administered to a confined site at high concentrations; whereas, its presence in the bloodstream at diluted concentrations could avoid this issue. However, fullerenes are highly lipophilic, which slows down their excretion kinetics and accumulation in specific organs, raising the concern of their possible long-term toxicity.480

CNTs, with their one-dimensional morphology, have gained much attention with regard to their cellular uptake and body distribution. Studies have demonstrated that CNTs can be enzymatically degraded by peroxidases481,482 in macrophages,389 eosinophils,483 neutrophils,484 and microglia485 and the extracellular space,486 thus minimizing the concerns for their toxic effect due to their accumulation in the body. In an early study, the pharmacokinetic behavior of water-soluble SWCNTs functionalized with the chelating molecule diethylentriaminepentaacetic (DTPA) was examined after labeling with 111In for imaging purposes.487 When intravenously administered to mice, the functionalized CNTs were not detected in the liver or spleen, being rapidly cleared from systemic blood circulation through the renal excretion route. A subsequent study showed that when the functionalization degree was high, the renal clearance was enhanced, but when the functionalization was low, reticuloendothelial system (RES) accumulation (i.e., liver and spleen) was observed.356 Also, the diameter of the functionalized MWCNTs was demonstrated to affect their organ biodistribution in mice.488 Furthermore, the chain length of the functionalized molecule PEG was proven to determine the biodistribution and circulation of the SWCNTs.489 One recent study disclosed the importance of the PEG conformation and its influence on the protein corona formation on the SWCNTs,490 suggesting that the original properties of CBN change in vivo due to biomolecular interactions.

Biocompatibility studies on graphene-based materials have recently been carried out. The in vivo fate of graphene-based materials most likely depends both on their lateral dimensions and thickness (i.e., layer number) and the degree of functionalization, which may play an important role in biological interactions in vivo, including corona formation.491 The body distribution of GO functionalized with PEG was investigated after 125I-labeling.492 The results demonstrated that the functionalized GO was mainly accumulated in the liver and spleen after intravenous administration. Substantial bone uptake was also noticed at early time points, possibly owing to macrophage uptake in the bone marrow. In another study, PEG-functionalized GO was proven to be gradually cleared (and/or degraded), without appreciable toxicity up to 3 months post-exposure.492 Also, radio-labeled and chemically-functionalized GO was accumulated predominantly in the liver and spleen, while renal excretion was also evidenced.493 Another study also reported the pharmacokinetics and the quantitative in vivo biodistribution of PEG-functionalized GQDs.494 The results revealed that after oral administration the functionalized GQDs were not adsorbed in any organ, but were excreted quickly. On the other hand, after injection intraperitoneally, the functionalized GQDs were engulfed by phagocytes and accumulated in the RES system, and their intake and accumulation rate were dependent on their shape and size.

C-Dots including GQDs are the most recently developed carbon materials. An early study investigated the in vivo kinetic behavior of C-dots after three different injection routes (intravenous, intramuscular, and subcutaneous).495 The results showed that the C-dots were efficiently and rapidly excreted from the body, and their clearance rate was ranked to be intravenous > intramuscular > subcutaneous. A recent study reported the in vivo toxicity of luminescent C-dots with sizes in the range of 5–8 m. When injected via the tail vein, the C-dots showed little sign of toxicity and were distributed mainly in the intestine and cleared from the body through faeces.495 GQDs with sizes in the range of 20–40 nm were also investigated for their in vivo toxicity.495 When injected intravenously, the GQDs revealed little obvious acute toxicity up to 30 days, although minor histopathological changes were noticed, particularly in the liver and lungs, which warrant long-term observation in the future.

Compared to other carbon nanomaterials, NDs were proposed to have a lower chance of inducing oxidative stress of cells.496 When injected into the blood stream of rats, the NDs could attach to the red blood cell membrane after 30 min, suggesting that they may remain in the blood circulation for several cycles without being excreted, and after 2 h, they were accumulated mostly in the liver and lung tissue.497,498 The pulmonary toxicity of the NDs was also studied through intratracheal administration in mice. The NDs were found to exist in the alveoli and bronchia at different time points, while exhibiting no noticeable adverse effect on the lung based on the histological and ultrastructural findings. Moreover, the result suggests that their engulfment by lung macrophages may be an important route to remove NDs.499 A recent study500 also reported no significant morphological changes in kidney and spleen tissue samples of rats and monkeys after ND administration of different doses. Furthermore, the respiratory toxicity of NDs was found to be much lower than that of CNTs and other carbon nanomaterials.501,502 However, a possibility of dose-dependent toxicity in lung, liver, kidney and blood still exists when intratracheally treated.503

As discussed, while many studies have been accumulated on the toxicity and body distribution of CBNs, they are not enough to draw a simple conclusion. We notice that the biocompatibility of CBNs depends largely on the physico-chemical properties of the original materials, such as size, shape, and surface chemistry (functional groups) as well as their biological interactions such as corona formation and aggregation in the. Therefore, more in vitro and in vivo studies are needed, such as long-term in vivo monitoring, modelling in large animals, and determination of the underlying mechanisms of their biological interactions, which may illuminate the advantages (theranostic performance) of CBNs for the development of future clinical applications.

7. Concluding remarks

Over the last two decades, extensive studies on CBN (fullerenes, CNTs, G and its derivatives, NDs, and CQDs) have demonstrated their potential applications in a variety of areas, including electronic devices, catalysis, biosensing, drug delivery and bioimaging. The unique structural dimensions, chemical stability, optical and electrical properties, and surface tunability of CBN are well suited for their diverse applications. Recent global health issues and the significant need to treat intractable diseases have empowered the development of CBN, particularly for the therapeutics and diagnostics applications. The optical properties of CBN including fluorescence, luminescence and phosphorescence endowed the possibility of multimodal imaging and light-mediated therapy and diagnosis. Besides, their low dimensionality, large surface-to-volume ratio, tunable surface chemistry, and acceptable biocompatibility are some of the key assets that position CBN as fascinating nanoplatforms for the combinatory approach of drug delivery and diagnosis in the treatment of diseases including cancer.

The quantum confinement effect, surface defects, and functionalized status are common mechanisms involved in the origin of the fluorescence or photoluminescence in CBN. Despite their high specific surface areas, the finely-tuned surface chemistry of CBNs with bio-functional peptides, polymers, and metallic materials is important to achieve a high loading capacity and sustained and controlled release of drugs as well as to achieve sensitive and high-resolution imaging contrast. Quantum confinement- and defect-based intrinsic strategies to generate imaging properties are one simple way of utilizing CBN for theranostics, which mainly adopt one-photon optical imaging, fluorescence, Raman and phosphorescence imaging modalities. Beyond one-photon imaging, two-photon up-conversion NIR-imaging and non-optical properties such as photoacoustic, photothermal, CT, MRI, and other diverse imaging modalities are potentially applicable for multifunctional theranostics. Accordingly, CBN can support diagnostic functions through chemical integration or synergy with therapeutics delivery for the theranostic treatment of diseases and traumas.

While the optical properties of CBN are essential for imaging, their applications as theranostic platforms require some important considerations. A high loading capacity of cargo molecules depends on the capacity of nanocarriers. Thus, decreasing the size (below tens of nm to increase surface area) and functionalizing the surface of CBN with proper chemical groups can significantly enhance their loading capacity. In fact, the intrinsic chemical interactions of CBN with drugs and proteins, such as π–π interactions, hydrogen-bonding and hydrophobic interactions, are advantageous for effective biomolecular loading. Also, the abundant reactive oxygen functional groups present on the basal planes and edge of the GO/rGO sheets endow great opportunity to covalently link biomolecules.

Together with the loading, the controlled (e.g., timely, sustained and on-demand) release of molecules should improve the therapeutic efficacy. Accordingly, stimuli-responsive materials are often functionalized with CBN to allow the light-, pH-, enzyme-, or temperature-dependent release of therapeutic molecules. The surface functionalization strategies extend to target specific cells (e.g., cancer cells, inflammatory cells, and stem cells) and even intracellular components (e.g., mitochondria and nuclei), and to prolong blood circulation (using polyethylene glycol) to avoid nonspecific cellular uptake, all of which can significantly enhance the therapeutic efficacy while reducing systematic side effects such as fetal organ toxicity. While targeted cells (mostly tumor cells) have been extensively studied with CBN, more specific targeting of intracellular components remains largely unexplored. Considering that the important intracellular mechanisms involved in many diseases and tissue repair processes are through the actions of cellular organelles, their targeting is a highly important area of research in the future.

Without the help of therapeutic molecules, light-induced therapies (e.g., PTT and PDT) are possible with CNB, which is considered a potential merit to avoid possible chemotherapy-associated tissue toxicity and side effects. The photo-therapeutic ability of CBN depends on their opto-thermal properties (PTT) and ability to generate ROS (PDT), which largely depend on their size, shape, surface chemistry, and nitrogen doping. Often, phototherapies are used in combination with chemotherapy to synergize the therapeutic efficacy through thermal increase or ROS generation together with controlled drug delivery.

The light-activated actions of CBN in both therapies and bioimaging have spurred the development of combined systems for theranostics, such as optimal imaging with PTT/PDT/chemotherapy. Furthermore, CBN composites and hybrids with other functional nanomaterials (e.g., iron oxide NP, gadolinium NP, cobalt NP, upconversion NP, MSN, and polymer) enable multifunctional theranostics with bi-/tri-modal imaging ability (MR-/CT-/photoacoustic-imaging) and improved drug loading and therapeutic efficacy.

Another important area to clarify is the possible tissue/organ toxicity of CBN and their interaction mechanisms with cells and tissue, particularly for their long-term use. As some in vivo studies and critical reviews have highlighted, the body distribution and in vivo toxicity of CBN are quite variable depending on their properties, such as size, shape and surface chemistry. Accordingly, control of their particle size/shape and proper functionalization of their surface have been shown to improve their colloidal stability and body clearance rate, relieving some these concerns. Since CBN have low-dimensional (0D, 1D and 2D) properties, their shape- and size-related cellular interactions and consequent cellular uptake efficiency of therapeutics and specific organ accumulation should be carefully considered. However, their clearance mechanisms are not fully understood, warranting future studies to particularly follow their long-term fate in large animal models.

As demonstrated, the excellent optical properties of CBN have enabled recent significant progress in the fields of theranostics through one-photon and two-photon imaging and therapeutics delivery. More specifically, Raman imaging, photoacoustic imaging, up-conversion NIR imaging, and other optical and even non-optical imaging modalities together with photothermal, photodynamic and chemo therapies have been extensively studied. Thus, it is anticipated that CBN may be promising nanoplatforms in the near future for clinical applications, and not limited to cancer treatment but extended to other intractable diseases and tissue repair processes when more preclinical studies are carried out.

Abbreviations

ACGAgCu@graphene
CBNCarbon-based nanomaterials
CCGOChemically change graphene oxide
CNTCarbon nanotube
CTComputed tomography
CQDCarbon-based quantum dot
CPT(S)-(+)-Camptothecin
CTComputer tomography
CVDChemical vapour deposition
DOXDoxorubicin
FLGOFew layer graphene oxide
GGraphene
GOGraphene oxide
GQDGraphene-based quantum dot
HCSHollow carbon spheres
hMCsHuman mast cells
IONPIron oxide nanoparticles
MWCNTMultiwall carbon nanotube
MRIMagnetic resonance imaging
NDNanodiamond
NIRNear infrared
NVNitrogen vacancy
OPOne-photon
PAPhotoacoustic
PATPhotoacoustic therapy
PLPhotoluminescence
PDTPhotodynamic therapy
PTTPhotothermal therapy
PSPhotosensitizer
QYQuantum yield
QCEQuantum confinement effects
rGOReduced graphene oxide
ROSReactive oxygen species
RTPRoom temperature phosphorescence
SPIOSuperparamagnetic iron oxide
SPRSurface plasmon resonance
SERSSurface-enhanced Raman scattering
SWCNTSingle wall carbon nanotube
TPTwo-photon
TPFMTwo-photon fluorescence microscopy

Conflicts of interest

There are no conflicts to declare.

Acknowledgements

This research was supported by the National Research Foundation of Korea (NRF), Republic of Korea (GRL Program 2015-0093829, NRF-2018R1D1A1B07048020, NRF-2017R1C1B1011387, NRF-2018R1A2B3003446, and NRF-2018K1A4A3A01064257).

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Footnote

Both authors contributed equally to this work.

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