Graphene Oxide Platform for Cancer Research

Version	Summary	Created by	Modification	Content Size	Created at	Operation
1		shaoshan Mai	--	5892	2024-01-26 15:46:25	\|
2	format	Jason Zhu	-97 word(s)	5795	2024-01-29 03:14:57	\|

This entry is adapted from the peer-reviewed paper 10.3390/ijms25021066

Pancreatic cancer, notorious for its grim 10% five-year survival rate, poses significant clinical challenges, largely due to late-stage diagnosis and limited therapeutic options.

graphene graphene oxide 3D culture organoids

1. Properties of Graphene Oxide

Graphene, a two-dimensional honeycomb lattice of carbon atoms, is typically synthesized via chemical vapor deposition or mechanical exfoliation of graphite, noted for its exceptional electrical, mechanical, and thermal properties ^[1]. GO created using the Hummers method introduces oxygen-containing functional groups to graphite, resulting in a material with a large surface area and functional versatility, albeit with reduced electrical conductivity compared with graphene ^[2]^[3]. Reduced graphene oxide (r-GO), obtained by removing these oxygen groups from GO, restores some of graphene’s electrical and structural features ^[4]. Graphene quantum dots (GQDs), small graphene fragments synthesized through top–down or bottom–up methods, exhibit unique optical and electronic properties due to quantum confinement and edge effects ^[5]. Both GO and r-GO, rich in functional groups, are adaptable for diverse modifications and applications, particularly in biosensors and environmental remediation, while GQDs find use in fluorescence-based sensors and electronics ^[6]. Graphene’s integration into composites boosts their mechanical, thermal, and electrical characteristics, with r-GO also being leveraged in similar applications for its balance between conductivity and functional compatibility ^[7].

1.1. Mechanical Properties

GO consists of stacked layers of graphene sheets that are held together by oxygen-containing functional groups, creating a layered, lamellar structure. The structure of graphene is a monolayer of two-dimensional (2D) one-atom-thick planar, sp2-hybridized carbon arranged in six-atom rings ^[8]. GO is a complex material due to its amorphous and non-stoichiometric atomic composition. Currently, there are no precise analytical techniques available for the thorough characterization of GO materials and their analogs. According to previous research, several structural models have been proposed, including models by Hofmann, Ruess, Scholz-Boehm, Nakajima-Matsuo, Lerf-Klinowski, and Dekany. In terms of regular lattices, they consist of discrete repeated units, and the Lerf-Klinowski model is currently considered the most widely accepted configuration ^[9]^[10]. Brittle fracture ensues when the material is subjected to a critical stress, typically around 130 GPa, in accordance with its intrinsic strength. Because of its high values of E (elastic modulus) and σint (intrinsic strength), graphene is regarded as an exceptionally robust material for structural applications. Graphene oxide paper, on average, exhibits a fracture strength of 80 MPa and an elastic modulus of 32 GPa ^[11].

1.2. Water Dispersibility

GO is highly hydrophilic and readily disperses in water and other polar solvents due to the presence of hydrophilic functional groups. This property is advantageous for various applications, such as nanocomposites and biomedical applications. The presence of oxygen-containing functional groups such as -OH, -COOH, and epoxide groups on the surface makes GO hydrophilic. Félix Mouhat et al. evidenced that GO is chemically active in water, acquiring an average negative charge of the order of 10 mCm⁻² ^[12]. The hydrophilicity of graphene oxide with different particle sizes and pH values was characterized by the water contact angle. And Xuebing Hu et al. found that the water contact angle of the different graphene oxides decreased from 61.8° to 11.6°, which indicates graphene oxide has excellent hydrophilicity ^[13].

1.3. Thermal Properties

Graphene stands out as an exemplary thermal conductor, demonstrating an impressive thermal conductivity range of 2000–5000 W/mK ^[14]. Nevertheless, the introduction of oxygen functional groups onto the surface of graphene oxide (GO) disrupts the lattice symmetry and induces localized strain, resulting in a substantial reduction in thermal conductivity by orders of magnitude (2–3 orders of magnitude, to be precise) ^[15]. A remedy for this attenuation in thermal conductivity involves the partial reduction of GO through chemical reactions with reducing agents, notably hydrazine and its derivatives. This process culminates in the creation of reduced graphene oxide (rGO) by effectively extracting oxygen functional groups. An interesting observation has been made regarding the thermal conductivity of GO, which exhibits a continuous decrease as the degree of oxidation escalates ^[16]. Studies show the successful formation of GO/RGO–protein complexes with enhancement in structural/thermal stability due to various interactions at the nano–bio interface and their utilization in various functional applications ^[17].

1.4. Electrical Properties

Graphene oxide is inherently non-conductive, necessitating the removal of a significant portion of its oxygen groups for conversion into reduced graphene oxide (rGO) to enhance its electrical conductivity. Researchers have observed a distinct difference in electric conductivity between R-I-Ph-GO/PI films and R-GO/PI films, primarily attributed to the formation of a sp2-hybrid carbon network within the graphene oxide structure ^[18]. Notably, the electrical properties of GO films exhibit sensitivity to both humidity levels and applied voltage amplitude ^[19]. At low humidity, GO films demonstrate poor conductivity, akin to insulators. Conversely, under high humidity conditions, GO film conductivity markedly increases because of enhanced ion conduction mechanisms, offering insights into tailored electrical properties for GO-based materials in applications influenced by environmental factors, particularly humidity.

1.5. Chemical Properties

GO offers superior dispersibility in various mediums, including water, diverse solid matrices, and organic solvents. This property makes it highly versatile. GO can be effectively combined with polymer or ceramic matrices to form composite materials, often resulting in improved electrical and mechanical properties ^[9]. However, GO does come with certain limitations, such as the potential for agglomeration or overlapping of GO sheets. Nonetheless, the thin and flat structure of GO sheets allows for flexibility in making structural and morphological modifications. This flexibility is further enhanced by the presence of oxygen functional groups in GO, which serve both as sites for functionalization and as spacers for molecular absorption. These attributes facilitate the incorporation of GO into various nano composites and nano-morphologies. By employing structural modifications and functionalization through covalent and noncovalent bonding interactions, GO finds applications in a wide array of real-world uses, including filtration membranes ^[20], electrochemical sensors ^[21], hydrogen storage devices ^[22], battery electrodes ^[23], supercapacitors ^[24]^[25], and microjet engines ^[26].

1.6. Optical Properties

GO has a range of remarkable optical properties driven by its electronic configuration. These properties include structure-dependent absorption and Raman spectra, which provide insights into its chemical composition and the extent of functionalization-induced disorder ^[27]. In contrast to pristine graphene, GO displays photoluminescence across a spectrum encompassing ultraviolet, visible, and near-infrared wavelengths, contingent upon its structural variations. Reduced graphene oxide (rGO), on the other hand, exhibits the capacity to absorb radiation across an extensive wavelength range spanning from ultraviolet to terahertz frequencies ^[28]. To investigate the effects of modifications on fluorescence behavior, various agents, such as polyethylene glycol (PEG) polymers, metal nanoparticles (including Au and Fe₃O₄), and folic acid (FA) molecules, have been employed to functionalize the surface of GO ^[29]. rGO was functionalized with L-arginine (L-Arg) that on the optically active support generated an effective optical chemosensor for the determination of Cd (II), Co (II), Pb (II), and Cu (II) ^[21]. The marriage between integrated photonics and GO has led to the birth of integrated GO photonics, which has become a very active and fast-growing branch of on-chip integration of 2D materials in order to achieve novel functionality of integrated photonic devices ^[28].

1.7. PH-Sensitivity

Graphene oxide-based nanomaterials can be affected by pH changes in their surface properties. The tumor environment is generally more acidic (pH 6.4~7) than normal cells (pH 7.4) ^[30]^[31]. A dual-targeting drug delivery and pH-sensitive controlled release system GO–Fe₃O₄ nanohybrid has been established ^[32]. β-cyclodextrin grafted L-phenylalanine functionalized graphene oxide is a versatile nanocarrier for pH-sensitive doxorubicin delivery ^[33]. GO was functionalized covalently with pH-sensitive poly(2-(diethylamino) ethyl methacrylate) (PDEA) by surface-initiated in situ atom transfer radical polymerization. Simple physisorption by π-π stacking and hydrophobic interactions on GO-PDEA can be used to load camptothecin (CPT), a water-insoluble cancer drug that is released only at lower pH levels normally found in a tumor environment but not in basic and neutral pH circumstances ^[34]. The constructed graphene oxide hybrid cyclodextrin-based supramolecular hydrogels could respond to NIR light, temperature, and pH, which could be beneficial for the controlled release of cargoes. Graphene oxide sheets not only acted as a core material to provide additional cross-linking but also absorbed NIR light and converted NIR light into heat to trigger the –sol–gel transition ^[35].

2. Graphene Oxide in Cancer Diagnosis

The most effective approach for curbing the advancement of cancer is the development of innovative diagnostic tools that enable the detection of the disease at its early stages. The early detection of carcinoma cells and the continuous monitoring of their activities hold significant importance in the realms of clinical diagnostics, toxicity monitoring, and safeguarding public health. Detecting and monitoring tumor cells during their early stages play a pivotal role in preventing the progression of cancer. This is particularly crucial in cases such as pancreatic cancer, which is challenging to diagnose at an early stage and often leaves limited possibilities for rescuing patients in advanced stages of the disease. Biomedical imaging technologies serve as highly efficient tools for tumor diagnosis, providing invaluable insights that can effectively guide tumor therapeutics. GO serves as a versatile agent for bioimaging functions due to its unique physical and chemical properties.

2.1. Magnetic Resonance Imaging

Magnetic resonance imaging (MRI) stands out as a non-invasive and non-ionizing diagnostic method, renowned for its exceptional spatial and temporal resolution. In the context of MRI, nanomaterials based on GO functionalized with paramagnetic metals have demonstrated great promise. Here, dendrimers featuring amino group caps (DEN) are skillfully grafted onto GO nanosheets which lateral sizes in the range of 40–380 nm (mean size ∼175 nm). This grafting process serves as a crucial step, enabling the subsequent functionalization of GO with gadolinium diethylene triamine pentaacetate (Gd-DTPA) and prostate stem cell antigen (PSCA) monoclonal antibody (mAb). Remarkably, the in vivo results obtained from magnetic resonance imaging validate the utility of GO-DEN(Gd-DTPA)-mAb as a targeted contrast agent for prostate tumor imaging ^[36]. Scientists have integrated GO with superparamagnetic iron oxide nanoparticles (Fe₃O₄ NPs). These Fe₃O₄ NPs serve a dual purpose, functioning as both biocompatible magnetic drug delivery enhancers and magnetic resonance contrast agents for MRI. The synthesized GO-Fe₃O₄ conjugates exhibit an average size of 260 nm and demonstrate low cytotoxicity levels, which are on par with those observed in GO alone ^[37]. Researchers focused on the synthesis of hybrid nanocomposites, specifically graphene oxide–zinc ferrite (GO-ZnFe₂O₄), which are further conjugated with doxorubicin (DOX) for applications in cancer therapy and MRI-based diagnosis. GO-ZnFe₂O₄ and GO-ZnFe₂O₄/DOX ranging from 5 to 100 μg/mL were investigated, and the key components are zinc ferrite (ZnFe₂O₄) nanoparticles (NPs), which serve as MR imaging contrast agents ^[38].

The size of magnetic nanoparticles (MNPs) in graphene oxide (GO) composites critically influences their performance, with smaller MNPs enhancing surface reactivity, ensuring superparamagnetic behavior, and improving biological penetration and distribution, while also affecting stability and toxicity profiles ^[39]. This size-dependent variation in physical and magnetic properties is fundamental in tailoring GO-MNP conjugates for specific applications, particularly in biomedical fields such as MRI ^[40].

2.2. Fluorescence Imaging

Fluorescence lifetime imaging (FLIM) is a non-invasive technique reliant on photons emitted by fluorescent probes, frequently employed for monitoring pathological tissue. A graphene oxide–MnO₂–fluorescein (GO–MnO₂–FL) nanocomposite was synthesized and applied for the detection of reduced glutathione (GSH). GSH, an essential endogenous antioxidant, plays a pivotal role in cellular defense against reactive oxygen species (ROS), thereby maintaining cellular activity. Notably, the GO–MnO₂–FL (100 μg/mL) nanocomposite exhibited selective imaging of cancer cells, owing to the higher GSH content observed in cancer cells as compared with normal cells ^[41]. A non-invasive and targeted technology for early diagnosis of oral squamous cell carcinoma (OSCC) involves the synthesis of nano-graphene oxide (NGO) nanoparticles. These nanoparticles are designed with specificity to the gastrin-releasing peptide receptor (GRPR), achieved through the incorporation of GRPR-specific peptides AF750-6Ahx-Sta-BBN. This approach enables precise and non-invasive near-infrared fluorescence imaging targeted at OSCC ^[42]. GO-based fluorescent DNA nanomaterials offer a promising avenue for the in vitro diagnosis and therapy of liver tumor cells ^[43].

2.3. Photoacoustic Imaging

Photoacoustic Imaging (PAI) stands as a robust diagnostic tool hinging on the photoacoustic (PA) effect. The distinctive capability of PAI lies in its ability to furnish optical absorption contrast and achieve high-resolution imaging, rendering it particularly well-suited for applications involving deep tissue and organ imaging ^[44]. PA imaging is a noninvasive imaging modality that depends on the light absorption coefficient of the imaged tissue and the injected PA-imaging contrast agents. PA imaging integrates the excellent contrast achieved in optical biomedical imaging with the deep penetrability of ultrasound (US) imaging. Thus, PA imaging can be used for the imaging of deeper tissue compared to other optical imaging technologies ^[45].

A nanotheranostic agent has been fabricated by direct deposition of Bi₂Se₃ nanoparticles on graphene oxide (GO) in the presence of polyvinylpyrrolidone (PVP) using a one-pot solvothermal method. GO/Bi₂Se₃/PVP nanocomposites (2 mg/mL) could serve as an efficient bimodal contrast agent to simultaneously enhance X-ray computed tomography imaging and photoacoustic imaging in vitro ^[46]. The reduced graphene oxide coated gold nanorods (r-GO-AuNRs) and highly efficient heat transfer process through the reduced graphene oxide layer, r-GO-AuNRs (0.125 mg/mL), exhibit excellent photothermal stability and significantly higher photoacoustic amplitudes; therefore, r-GO-AuNRs can be a useful imaging probe for highly sensitive photoacoustic images ^[47]. A sandwich-type gold nanoparticle coated reduced graphene oxide (rGO-AuNP) as an effective nanotheranostic platform for the second near-infrared (NIR-II) window photoacoustic (PA) imaging-guided photothermal therapy (PTT) in ovarian cancer ^[48]. With nanoparticles composed of a liquid gallium core with a reduced graphene oxide (RGO) shell (Ga@RGO) of tunable thickness, the high near-infrared absorption of RGO results in a photothermal energy conversion of light to heat of 42.4%. This efficient photothermal conversion, combined with the large intrinsic thermal expansion coefficient of liquid gallium, allows the particles to be used for photoacoustic imaging, that is, the conversion of light into vibrations that are useful for imaging ^[49].

Indocyanine green (ICG)-loaded, polyethylene glycosylated (PEG), reduced nano-graphene oxide nanocomposite (rNGO-PEG/ICG) is a new type of fluorescence and photoacoustic dual-modality imaging contrast. The nanocomposite is demonstrated to possess greater stability, longer blood circulation time, and superior passive tumor targeting capability, which can be a promising candidate for further translational studies on both the early diagnosis and image-guided therapy/surgery of cancer ^[50].

2.4. Raman Imaging

Raman scattering (SERS) is widely used due to its non-invasiveness, ultrasensitivity, and high spatial resolution. Since molecular vibrations are strongly related to the molecular structure, condition, and environment, the combination of spontaneous Raman scattering can be used to monitor both the location and condition of biological molecules in living cells ^[51]. GO possesses characteristic fingerprints in Raman spectra; therefore, it is also used for Raman imaging with Au and Ag nanoparticles loaded as SERS substrates ^[52]. GO/gold nanoparticle (AuNP) hybrids with folic acid (FA) binding are prepared as a multifunctional platform in bioimaging. FA is the targeting agent, AuNPs work as surface-enhanced Raman scattering substrates, and GO takes the role of both supporting the AuNPs with FA and acting as a Raman probe ^[53]. Methylene blue-loaded mesoporous silica-coated gold nanorods on graphene oxide (MB-GNR@mSiO₂-GO) (36 µg/mL) were developed as an all-in-one photo-nanotheranostic agent for intracellular surface-enhanced Raman scattering (SERS) imaging-guided photothermal therapy (PTT)/photodynamic therapy (PDT) for cancer ^[54].

Afua A. Antwi-Boasiako and colleagues reported the use of bioconjugated 2D graphene oxide (bio-GO) nanostructures, with the average lateral size of the layered GO sheets being approximately 0.08–0.1 μm. These were used as probes for breast cancer cells (SKBR3), demonstrating excellent discrimination over other types of circulating tumor cells by monitoring the ‘turn-off’ of the Raman signal ^[55]. Lin Yang et al. designed silver nanoparticles deposited on graphene oxide for ultrasensitive surface-enhanced Raman scattering immunoassay of cancer biomarkers, which made the detection of prostate-specific antigen (PSA) serum samples from prostate cancer patients satisfactory and thereby demonstrating that sensitive enzyme-assisted dissolved AgNPs SERS immunoassays of PSA have potential applications in clinical diagnosis ^[56].

2.5. Computed Tomograph

Computed tomography (CT) is a widely adopted disease diagnosis method in clinical settings because of its non-invasiveness and high spatial resolution properties, which are based on its high atomic number and X-ray absorption. Graphene oxide/gold nanorod (GO/GNR) nanohybrids were synthesized with a GO- and gold-seed-mediated in situ growth method. Upon injection of the GO/GNRs (50 μg/mL) into xenograft tumors, excellent CT imaging properties and photothermal effect were obtained ^[57]. Zhan Li et al. evidenced that Ag nanoparticles (AgNPs) are composited on the surface of GO to promote its X-ray absorption, and then simvastatin is coinjected in mice of renal dysfunction to eliminate in vivo toxicity-induced by AgNPs ^[58]. One new composite contrast agent based on Ln and graphene matrices was developed for multi-energy computed tomography ^[59].

Graphene nanoplatelets (GNPs), synthesized via potassium permanganate-based oxidation and exfoliation followed by reduction with hydroiodic acid (rGNP–HI), intercalated with manganese ions within the graphene sheets, and covalently functionalized with iodine, exhibit excellent potential as bimodal contrast agents for magnetic resonance imaging (MRI) and CT ^[60]. A novel system for synergistic cancer therapy was developed based on bismuth sulfide (Bi₂S₃) nanoparticle-decorated graphene functionalized with polyvinylpyrrolidone (PVP) (named PVP-rGO/Bi₂S₃). GO nanosheets with an average diameter of ~100 nm and a thickness of ~1.2 nm were prepared via a modified Hummer’s method. Due to the obvious NIR and X-ray absorption ability, the PVP-rGO/Bi₂S₃ nanocomposite could be employed as a dual-modal contrast agent for both photoacoustic tomography and X-ray computed tomography imaging ^[61]. By using a solvothermal method in the presence of polyethylene glycol (PEG), BaGdF₅ nanoparticles are firmly attached to the surface of GO nanosheets to form the GO/BaGdF₅/PEG nanocomposites, thus enabling effective dual-modality MR and X-ray computed tomography (CT) imaging of the tumor model in vivo and indicating the potential applications of dual-modality MR/CT imaging of cancers ^[62].

3. Graphene Oxide in Cancer Treatment

3.1. Delivery System

Drug Delivery

GO can be functionalized with polymers. Chitosan (CS) is an amino polysaccharide, a hydrophilic, biocompatible, non-toxic, and biodegradable polymer of glucosamine and acetylglucosamine ^[63]. To synthesis GO-CS is involved in amide coupling between the COOH group on the GO and the amino group of CS. CS improves the solubility of GO sheets in acidic media. Moreover, GO-CS results in changes in particle size and zeta potential as a function of pH ^[64]^[65]. Yan et al. prepared GO-CS and investigated its potential as a nanoadjuvant. GO-CS (50 μg/mL) significantly activated RAW264.7 cells and stimulated more cytokines for mediating cellular immune responses ^[66].

PEG is a polymer of repeating ethylene ether units that is widely used for several pharmaceutical and biomedical applications. It is soluble in aqueous and organic media, being defined as biocompatible, biodegradable, non-toxic, non-immunogenic, and is classified as “Generally Regarded as Safe” (GRAS) by the FDA ^[67]. Nano-graphene oxide (NGO) was synthesized its biological applications were explored in order to develop functionalization chemistry to impart solubility and compatibility to NGO in buffer solutions and other biological media by covalently grafting PEG star polymers onto its chemically activated surfaces and edges ^[68]. To evaluate it as a potential anti-metastatic agent, GO was modified with polyethylene glycol to form PEG-modified GO (PEG-GO). PEG-GO did not show apparent effects on the viability of breast cancer cells (MDA-MB-231, MDA-MB-436, and SK-BR-3) or non-cancerous cells (MCF-10A), but inhibited cancer cell migration in vitro and in vivo. An analysis of cellular energy metabolism revealed that PEG-GO significantly impaired mitochondrial oxidative phosphorylation (OXPHOS) in breast cancer cells but not in non-cancerous cells ^[69]. A de novo drug delivery nanosystem (~128 nm) based on gold nanoparticles (GNPs), decorated PEG, and folate (FA)-conjugated GO was designed to load with doxorubicin hydrochloride (DOX) as a model anticancer drug. Its drug-loading capacity as well as pH-dependent drug release behavior were investigated ^[70].

Hyaluronic acid (HA) is a naturally mucopolysaccharide, biocompatible, non-immunogenic, and biodegradable polysaccharide, consisting of alternating units of D-glucuronic acid and N-acetyl-D-glucosamine ^[71]. Numerous tumor cells overexpress several receptors that have a high binding affinity for HA, while these receptors are poorly expressed in normal body cells. Graphene quantum dots (GQD) were used as drug carriers, and HA was decorated on the surface of GQD to target cancer cells. At the same time, curcumin (CUR) was used as a drug model and loaded on the synthesized nanocarriers. GQD-HA-CUR reduces HeLa cell viability significantly because of the mediation of HA–CD44 for drug cell uptake ^[72]. Metformin was loaded upon GO via drop-wise addition of 2 mL (10 mg/mL) of metformin into 20 mL of GO dispersion (5 mg/mL). HA was grafted onto metformin-loaded GO nanoparticles as a CD44-targeted anti-cancer therapy for triple-negative breast cancer, which exhibited anti-cancer efficacy at a much lower dosage as compared with metformin alone ^[73]. Doxorubicin (Dox) and paclitaxel (Ptx) were successfully loaded onto GO-HA that covalently attached HA onto GO. The GO-HA-Dox/Ptx system was significantly better than the GO-Dox/Ptx system at specifically killing CD44-expressing MDA-MB-231 cells but not BT-474 cells without the expression of CD44 ^[74].

Polyvinyl alcohol (PVA) is a water-soluble polymer synthesized via hydrolysis and radical polymerization of vinylacetate ^[75]^[76]. Curcumin was loaded in PVA-sodium alginate/3D-GO hydrogels for studying in vitro drug delivery systems ^[77]. Magnetic magnesium iron oxide nanoparticles were synthesized via the coprecipitation chemical method and then composited with graphene oxide and modified by polyvinyl alcohol. Paclitaxel (PTX) and docetaxel (DTX) were loaded in the modified magnetic nanocomposites. The generally sustained and controlled release profile of DTX (or PTX) facilitates the application of modified nanocomposite for the delivery of anticancer drugs ^[78].

Polyacrylic acid (PAA) is a synthetic polymer of acrylic acid monomers, which is biocompatible, non-toxic, pH-sensitive, and mucoadhesive. In aqueous solutions, PAA has an anionic nature because of its carboxylic groups ^[79]. Nanocomposite systems, consisting of a reduced graphene oxide/polyacrylic acid as a nanocarrier, were integrated with a folic-acid-targeting agent and further modified by Deferrioxamine-M (M: Mn²⁺ or Gd³⁺) as the diagnostic MRI contrast agent or Temozolomide as the therapeutic agent. Release studies at a biological of pH 7.4 revealed good stability for TMZ immobilized on the GNs@PAA-FOA/TMZ nanocarrier ^[80]. Gemcitabine (GEM)—PAA—GO are developed in an explicit solvent medium at two different pH values, which can control drug biodistribution in response to changes in pH that are markers of the tumor environment ^[81].

Polyvinylpyrrolidone (PVP) is a water-soluble, non-ionic, non-toxic polymer surfactant. The coating of PVP is reported to improve the dispersibility and biocompatibility of GO in physiological buffers. Injectable hydrogel polymeric nanoparticles of PVP cross-linked with N, N′-methylene bis-acrylamide and encapsulating water-soluble macromolecules FITC–dextran (FITC–Dex) have been prepared in the aqueous cores of reverse micellar droplets, which serve as a potential carrier for hydrophilic drugs ^[82]. A stimuli-responsive polyvinylpyrrolidone-NIPPAm-lysine graphene oxide nano-hybrid was designed and fabricated for the delivery of chemotherapeutic agent fluorouracil (FU) to MCF7 breast cancer cells ^[83]. Nanocarriers comprising gelatin (G)-PVP coated GO were prepared and loaded with quercetin (QC). Additionally, a dual nanoemulsion water/oil/water with bitter almond oil was developed as a membrane around the nanocomposite to control further drug release. The pH-sensitive drug delivery system showed an 87.5% encapsulation efficiency and a 45% drug loading, which are among the highest values reported up to date. MTT assay and flow cytometry methods revealed a rate of cancer cell death of 53.14%, which was 36.51% in the apoptotic phase ^[84].

Dextran (Dex) is a hydrophilic natural polymer and a polysaccharide synthesized from the condensation of glucose. Cellular experiments uncover that DEX coating on GO offers remarkably reduced cell toxicity ^[85]. The non-covalent functionalization of GO with chitosan (CS) and Dex was successfully developed via a layer-by-layer self-assembly technique for anti-cancer drug delivery application. The CS/Dex functionalized GO nanocomposites (GO-CS/Dex) exhibited a diameter of about 300 nm and a thickness of 60 nm and showed a strong cytotoxicity to the cancer cells ^[86].

Graphene oxide/cationic polyethyleneimine/poly anionic dextran sulfate (GO/PEI/DS) was synthesized via a layer-by-layer self-assembly technique for transdermal anti-cancer drug delivery. DOX was loaded onto folic-acid-conjugated GO and methotrexate (MTX) was loaded onto dextran sulfate (DS). The results revealed that the synthesized dual drug-loaded material showed a good pH-dependent controlled and sustained release profile for both DOX and MTX via the transdermal route of administration in comparison with oral delivery ^[87]. GO-PEI complexes were loaded with a miR-214 inhibitor which efficiently inhibited cellular miR-214, resulting in a decrease in oral squamous cell carcinoma (OSCC) cell invasion and migration and an increase in cell apoptosis ^[88].

Gene Delivery

Gene therapy needs a vector that can protect genes from nuclease degradation and facilitate gene uptake with high transfection efficiency. Compared with viral vectors, non-viral gene carriers can avoid immune responses, toxicity, chromosomal integration, and so on. GO-based vectors for gene delivery have been considered as superior vehicles because of their good biocompatibility, biosafety, large surface area, adsorption capacity, and negative charges ^[89].

Polyethyleneimine (PEI) is a water-soluble cationic polymer with a large number of amino groups. GO was modified with PEG, PEI, and FA for the targeted delivery of small-interfering RNA (siRNA) that inhibits ovarian cancer cell growth ^[90]^[91]. Lactosylated chitosan oligosaccharide (LCO)-functionalized GO (GO-LCO) containing quaternary ammonium groups (GO-LCO⁺) was prepared to realize the hepatocyte-specific targeted delivery of anti-tumor drugs and genes. The GO-LCO⁺ could be used to load Dox with the loading efficiency of 477 μg/mg and fluorescein FAM-labeled DNA with 4 μmol/g, respectively. Results suggest that the functionalized GO can be used as a nanocarrier for the hepatocyte-targeted co-delivery of anti-tumor drugs and genes with low cytotoxicity, indicating its potential future applications in anticancer drug-and-gene combined therapy ^[92].

Glycyrrhetinic acid (GA) is employed as a liver-targeting ligand to construct GA, polyethylene glycol (PEG), polyamidoamine dendrimer (Dendrimer), and nano-graphene oxide (NGO) conjugates (GA-PEG-NGO-Dendrimer, GPND) for siRNA delivery. The GPND/siRNA nanocomplex has high safety, targeting, and transfection as well as a prolonged half-life ^[93]. A modified GO nanocarrier for the co-delivery of siRNA and DOX was designed for enhanced cancer therapy. GO-poly-l-lysine hydrobromide/folic acid (GPF)/DOX/siRNA exhibited gene silencing and tumor inhibition ^[94]. GO/3-aminopropyltriethoxysilane (APTES) was modified via spermine (GOAS), which acts as a gene delivery system to help the transfection of pEGFP-p53 into breast cancer cell lines ^[95]. Nanoparticles comprising GO/cationic lipid (GOCL) condense and stabilize plasmid DNA for transfection into human cervical cancer (HeLa) cells ^[96].

Antibody Delivery

A pH-responsive charge-reversal polyelectrolyte and integrin αⅤβ3 mono-antibody functionalized GO complex was developed as a nanocarrier for the targeted delivery and controlled release of DOX into cancer cells ^[31]. A GO platform was functionalized with magnetic nanoparticles and a monoclonal antibody specific to the carbonic anhydrase marker. CA IX is a cell surface hypoxia-inducible enzyme functionally involved in adaptation to acidosis that is expressed in aggressive tumors ^[97]. Multifunctional mesoporous silica nanoparticles (MSNs) have internal fluorescent conjugates and external polydopamine and GO layers. Monoclonal antibody (anti-human epidermal growth factor receptor)-conjugated MSNs showed a higher specificity, which resulted in more enhanced anticancer effects in vitro ^[98].

GO was modified with a non-toxicity cationic material (chitosan) and a tumor-specific monoclonal antibody (anti-EpCAM) for the delivery of survivin-siRNA (GCE/siRNA). It was demonstrated that GCE/siRNA had a strong antitumor effect in vitro ^[99]. An antibody-modified reduced graphene oxide (rGO) film efficiently captured circulating tumor cells (CTCs) and minimized the background of white blood cells without complex microfluidic operations ^[100]. The noncovalent association of anti-HER2 antibody trastuzumab (TRA) with GO generates stable TRA/GO complexes that are capable of rapidly killing osteosarcoma (OS) cells ^[101].

A single layer of carboxymethylcellulose (CMC) and poly N-vinylpyrrolidone (PVP) was cross-linked through a disulfide bond and deposited on graphene oxide nanoparticles (GO NPs). The NPs were functionalized via monoclonal antibody FA, which showed a high inhibition of Saos2 and MCF7 cell lines in vitro ^[102]. Yang et al. evidenced the efficient targeting of breast cancer metastasis in an experimental murine model featuring GO conjugated with a monoclonal antibody (mAb) against follicle-stimulating hormone receptor (FSHR), a highly selective tumor vasculature marker in both primary and metastatic tumors ^[103].

3.2. Phototherapy

Phototherapy, including photothermal therapy (PTT) and photodynamic therapy (PDT), is a newly developed and encouraging therapeutic strategy, which employs near-infrared (NIR) laser photoabsorbers to generate heat for thermal ablation of cancer cells upon NIR laser irradiation ^[104].

Photothermal Therapy

PTT operates by transforming radiant light energy into localized heat through external NIR laser irradiation. This process induces hyperthermia, raising the temperature at the tumor site and subsequently causing damage and apoptosis of tumor cells. Owing to its unique advantages of high specificity and minimal invasiveness, PTT has been evidenced as having great potential in treating cancer metastasis ^[104]. In contrast to conventional therapeutic methods such as chemotherapy, surgery, and radiotherapy, the utilization of NIR light within the 700–1100 nm range to induce hyperthermia holds particular appeal. This is because biological systems generally lack chromophores that absorb within the NIR region ^[105].

PTT necessitates a specific agent capable of being excited and transforming electromagnetic energy into heat upon exposure to a particular light source. Ideally, an ideal PTT agent should exhibit the following properties: (1) a high rate of photothermal conversion; (2) suitable biocompatibility; and (3) straightforward conjugation capacity. GO not only fully satisfies all of these requirements but also offers additional advantageous properties that are highly beneficial in the context of cancer PTT ^[106].

A biocompatible platform known as porphyrin-functionalized graphene oxide (PGO) has been synthesized and designed with a strong absorption capacity at 808 nm. This PGO platform, equipped with active functional groups, enables precise targeting in PTT for brain cancer treatment while preserving the well-being of healthy cells and tissues ^[107]. A theranostic nanomedicine, denoted as GO-PEG(TP), has been developed, comprising PEGylated nano graphene oxide co-loaded with photosensitizers (PS) and a two-photon compound, to combat cancer. The solutions of GO, GO-PEG, and GO-PEG(TP) (each with a concentration of 0.05 mg/mL of GO) were compared to demonstrate that this integrated therapeutic approach shows remarkable efficacy in targeting and eradicating 4T1 murine breast cancer cells, resulting in a significant induction of apoptosis among the cell population ^[108].

Gong et al. created nanocomposites by functionalizing magnetic graphene oxide (MGO) with triformyl cholic acid and folic acid (MGO-TCA-FA). This innovative approach establishes an efficient nanoplatform for photo-chemotherapy (PCT) for targeting liver cancer. The advantages of this platform include the capability for multiple-targeted drug delivery, drug release triggered by both pH levels and NIR, and remarkable efficiency in photothermal conversion ^[109]. GO is combined with PEG as a photothermal material to induce a heating effect in macrophages to enable its anti-tumor effect in vitro and in vivo ^[110].

A photothermal therapeutic agent has been developed using reduced graphene oxide for the targeted ablation of A549 lung cancer cells. The fabrication method involves a one-step, biocompatible process utilizing Memecylon edule leaf extract for the reduction of GO, ultimately yielding polyphenol-anchored reduced graphene oxide (RGO). RGO exhibits remarkable sensitivity to NIR irradiation, allowing precise in vitro targeting of lung cancer cells and delivering cytotoxic effects ^[111]. The plant extract of Salvia spinosa facilitates the conversion of graphene oxide (GO) to RGO. It significantly destroyed the PC cells (Panc02-H7) after exposing RGO-loaded PC cells to laser radiation ^[112]. A report evidenced the effects of a combination cancer therapy including RT (doses of 2 and 4 Gy) and PTT (808 nm laser irradiation) as a radio-photothermal therapy (RPTT) for a KB oral squamous carcinoma cell line in the presence of Fe₃O₄@Au/reduced graphene oxide (rGO) nanostructures (NSs) at different concentrations ^[113].

Photodynamic Therapy

PDT, a Food and Drug Administration (FDA)-approved cancer therapy, relies on photosensitizers that generate reactive oxygen species (ROSs) when exposed to specific light, effectively killing cancer cells. This minimally invasive treatment damages tumor vasculature, triggers an immune response, and boasts specificity and repeatability. To enhance its effectiveness, nanocarriers are utilized to deliver photosensitizers directly to the tumor site, making PDT a promising and targeted cancer treatment option.

GO was conjugated to amine-terminated six-armed PEG via amide formation and then loaded with Ce6 via supramolecular π-π stacking, which showed lower singlet oxygen generation efficiency than free Ce6. GO-PEG-Ce6 significantly enhances photodynamic cancer-cell-killing efficacy by facilitating an increased cellular uptake of Ce6 through the nanographene carrier ^[114]. Hyaluronic acid (HA)–GO conjugates, with a high loading of photosensitizers (Ce6), the PDT efficiencies of which were remarkably improved ∼10 times more than that of free Ce6, significantly influenced the co-treatment with an excess amount of HA polymers, illustrating their active targeting to HA receptors overexpressed on cancer cells ^[115]. A novel hybrid of GO and hypocrellin B (HB) generated efficient singlet oxygen via irradiation to damage tumor cells ^[116]. The interaction of methylene blue (MB) as a photosensitizer with GO has good performance in PDT during red-light-emitting diode (LED) irradiation, which showed cell-killing potential on MDA-MB-231 breast cancer cells ^[117]. Folic acid (FA) and chlorin e6 (Ce6) double-functionalized GO can penetrate rapidly into cancer cells and macrophages, exhibiting good photothermal properties and a high ROS generation capacity. Moreover, a combined effect of PTT and PDT leads to a higher killing efficiency toward different types of cells involved in cancer and other diseases ^[118].

Guo et al. developed a drug delivery system incorporating Paclitaxel (PTX) onto PEG-modified and oxidized sodium alginate (OSA)-functionalized GO nanosheets (NSs), called PTX@GO-PEG-OSA. The photothermal conversion ability was tested via subjecting GO-PEG-OSA NSs and PTX@GO-PEG-OSA NSs (GO-PEG-OSA concentration ~ 0.1 mg/mL) to 808 nm of NIR laser irradiation. After NIR irradiation, PTX@GO-PEG-OSA could generate excessive ROS, attack mitochondrial respiratory chain complex enzymes, reduce adenosine-triphosphate (ATP) supplements for P-glycoprotein(P-gp), and effectively inhibit P-gp’s efflux pump function, thereby inducing obvious antitumor effects on gastric cancer ^[119]. A pluronic-based graphene oxide-methylene blue (GO-MB/PF127) nanocomposite was activated by both 808 nm NIR light and a 660 nm LED source. In this system, the GO component induced photothermal ablation of cancer cells, while methylene blue (MB) generated singlet oxygen, thereby destroying cancer cells via oxidative stress in PDT ^[120].

Nitrogen-doped graphene oxide dots (NGODs) can effectively produce H₂O₂ under white light irradiation and their H₂O₂ rate is proportional to the ascorbic acid (AA) concentration. This AA-supplemented PDT effectively kills lung, head and neck, colon, and oral cancer cells; however, it is highly safe for normal cells ^[121]. Liu et al. reported that nanoscale graphene oxide (NGO) was synthesized and then loaded with gold nanoparticles (AuNPs) and thiol polyethylene glycol folic acid (SH-PEG1000-FA). Further modifications involved incorporating the photosensitizer MB or the anticancer drug 5-fluorouracil (5-Fu). These multifunctional nanoplatforms were designed to facilitate either photothermal–photodynamic synergy (NGO-AuNPs-FA/MB) or photothermal–chemotherapy synergy (NGO-AuNPs-FA/5-Fu). When exposed to laser irradiation, they demonstrated exceptional photodynamic and photothermal properties, resulting in excellent in vitro antitumor effects ^[122].

3.3. Angiogenesis and Anti-Angiogenesis Therapy

In recent studies, GO showed angiogenesis or anti-angiogenesis properties. Mukherjee et al. demonstrated that the intracellular formation of reactive oxygen species and reactive nitrogen species as well as the activation of phospho-eNOS and phospho-Akt might be plausible mechanisms for GO and rGO-induced angiogenesis ^[123]. GO/polycaprolactone (PCL) nanoscaffolds are fabricated to evaluate their pro-angiogenic characteristics. The AKT-endothelial nitric oxide synthase (eNOS)-vascular endothelial growth factor (VEGF) signaling pathway might play a major role in the angiogenic process ^[124]. However, GO also affected the consumption of niacinamide, a precursor of energy carriers, and several amino acids involved in the regulation of angiogenesis. The combination of the physical hindrance of internalized GO aggregates, induction of oxidative stress, and alteration of some metabolic pathways leads to a significant antiangiogenic effect in primary human endothelial cells ^[125]. GO containing 6-gingerol (Ging) modified with chitosan (CS)-FA nanoparticles (Ging-GO-CS-FA) have pro-oxidant power against cancer cells by reducing the amount of the superoxide dismutase (SOD) gene, its average length, and the number of blood vessels on angiogenesis ^[126].

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