Article

ISSN 0006-2979, Biochemistry (Moscow), 2024, Vol. 89, No. 8, pp. 1362-1391 © The Author(s) 2024. This article is an open access publication.

1362

REVIEW

Development of Graphene-Based Materials

with the Targeted Action for Cancer Theranostics

Konstantin N. Semenov

1,2,3,a

*, Olga S. Shemchuk

1,2

, Sergei V. Ageev

1,2

Pavel A. Andoskin

, Gleb O. Iurev

, Igor V. Murin

, Pavel K. Kozhukhov

Dmitriy N. Maystrenko

, Oleg E. Molchanov

, Dilafruz K. Kholmurodova

Jasur A. Rizaev

, and Vladimir V. Sharoyko

1,2,3,b

Pavlov First Saint Petersburg State Medical University, 197022 Saint Petersburg, Russia

Saint Petersburg State University, 199034 Saint Petersburg, Russia

Granov Russian Research Centre for Radiology and Surgical Technologies, 197758 Saint Petersburg, Russia

Samarkand Medical University, 100400 Samarkand, Uzbekistan

e-mail: knsemenov@gmail.com

e-mail: sharoyko@gmail.com

Received May 30, 2024

Revised July 11, 2024

Accepted July 13, 2024

Abstract— The review summarises the prospects in the application of graphene and graphene-based nanomate-

rials (GBNs) in nanomedicine, including drug delivery, photothermal and photodynamic therapy, and theranos-

tics in cancer treatment. The application of GBNs in various areas of science and medicine is due to the unique

properties of graphene allowing the development of novel ground-breaking biomedical applications. The review

describes current approaches to the production of new targeting graphene-based biomedical agents for the che-

motherapy, photothermal therapy, and photodynamic therapy of tumors. Analysis of publications and FDA data-

bases showed that despite numerous clinical studies of graphene-based materials conducted worldwide, there is

a lack of information on the clinical trials on the use of graphene-based conjugates for the targeted drug delivery

and diagnostics. The review will be helpful for researchers working in development of carbon nanostructures,

material science, medicinal chemistry, and nanobiomedicine.

DOI: 10.1134/S0006297924080029

Keywords: graphene, graphene-based nanomaterials, drug delivery, theranostics

Abbreviations: GBNs, graphene-based nanomaterials;

CYT, cytostatic drug cytarabine; FA, folic acid; GQDs,

graphene quantum dots; HAS, human serum albumin;

Pc,phthalocyanine; PEG,polyethylene glycol; PDT,photo-

dynamic therapy; PTT,photothermal therapy; rGO,reduced

graphene oxide; ROS,reactive oxygen species.

* To whom correspondence should be addressed.

INTRODUCTION

Graphene-based nanomaterials (GBNs), such as

graphene, graphene oxide(GO), reduced graphene ox-

ide(rGO), and graphene quantum dots(GQDs) (Fig. 1),

attract a significant attention due to their structure

and physicochemical properties. Some of the prom-

ising applications of GBNs in the field of biomedicine

include tissue engineering [1], bioimaging [2, 3] tar-

geted drug delivery [4-9], development of biosensors

[10-12] and antiviral [13-16], antibacterial [17-20],

and antifungal agents [21, 22], and delivery of biomol-

ecules, such as enzymes [23], proteins [24-26], genes

[27-29], RNA [30, 31], and DNA [32, 33] (Fig.2).

GBNs can be modified by covalent [34, 35] and

noncovalent [36, 37] functionalization to enhance their

electrical [38, 39], optical [40, 41], thermal [42, 43],

electronic [44-46], and mechanical [47, 48] proper-

ties. Monolayer graphene was first obtained in 2004

by Andre Geim and Konstantin Novoselov [49]. De-

pending on the method of synthesis, graphene can

be produced as mono- or multilayered flakes [50, 51].

It can be synthesized by chemical vapour deposition

[52-58], electrochemical exfoliation [59-62], mechano-

chemical exfoliation [63], and chemical and thermal

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BIOCHEMISTRY (Moscow) Vol. 89 No. 8 2024

Fig. 1. Classification of GBNs.

reduction of GO (synthesis of rGO) [64-70]. rGO is a

GO derivative in which almost all oxygen-containing

groups are reduced with hydrazine hydrate or biomol-

ecules [71] (see Fig. S1 in the Online Resource 1 for rGO

synthesis from GO using l-cysteine [71]).

Graphene consists of sp

-hybridised hexagonal

carbon atoms that form two-dimensional nanolayers,

while GO additionally has oxygen-containing groups

on the surface, e.g., carbonyl, lactol, and carboxyl

groups at the edges of GO layers and epoxy and hy-

droxyl groups on the basal plane (Fig. S2 in the Online

Resource 1) [72-74].

GBNs can be functionalized with molecules of var-

ious nature due to the presence of functional groups

on the GO surface and sp

-hybridised carbon atoms.

Reactions that can be carried out on the GO surface

(Fig. 3) include amidation, esterification, 1,3-dipolar

cycloaddition, and halogenation. Other types of inter-

actions are hydrogen bonding, π–π stacking, and hy-

drophobic interactions.

GQDs are graphene nanoparticles less than 100 nm

in size. Due to their exceptional properties, such as low

toxicity, stable photoluminescence, chemical stability,

and pronounced quantum confinement effect, GQDs

are considered as new promising materials for biolo-

gy, optoelectronics, energy industry, and environment

[75-78]. GQDs can be prepared using top-down or bot-

tom-up approaches (Fig.4) [79-81].

GBN CONJUGATES IN BIOMEDICINE

GBNs can be effectively used in the antitumor

therapy, e.g., for the development of platforms for the

delivery of drugs and genetic constructs, photodynam-

ic therapy (PDT), photothermal therapy (PTT), and ther-

anostics (Fig.5).

To efficacy of GBN-based antitumor nanodrugs

can be increased by using specific vectors for their de-

livery that are developed to recognise tumor-specific

receptors, such as HER2, CAIX, and receptors for Tat,

LHRH, folate, biotin, and asialoglycoprotein (Fig.6).

BIOCOMPATIBILITY

AND MECHANISMS OF ENDOCYTOSIS

Analysis of publications shows that function-

alization of graphene surface decreases hemolysis

and, therefore, increases material hemocompatibility.

Fig. 2. Publications on GBN applications.

SEMENOV et al.1364

BIOCHEMISTRY (Moscow) Vol. 89 No. 8 2024

Fig. 3. Reactions carried out on graphene surface.

Fig. 4. Approaches for GQD synthesis: top-down degradation from various carbon sources and bottom-up synthesis from small

molecules or polymers.

Thus, noncovalent functionalization of GO with chi-

tosan produced a material with no hemolytic activity.

Pintoetal. [82] showed that the noncovalent function-

alization of graphene surface with polymers [polyvinyl

alcohol, polyethylene glycol (PEG), polyvinylpyrroli-

done (PVP), hydroxyethylcellulose, chondroitin, glucos-

amine, and hyaluronic acid (HA)] decreased hemolysis

to 1.7% for all the resulting materials at concentra-

tions below 500μg·ml

–1

. Previously, we have studied

the effect of GO enriched (about 85%) with oxygen-

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Fig. 5. Application of GBNs in cancer treatment.

containing functional groups (edge-oxidized graphene

oxide, EOGO) on the extent of spontaneous hemolysis

and found that within the studied concentration range

 = 2.5-25mg·liter

–1

), this nanomaterial did not af-

fect the level of hemolysis after 1 and 3 h of incuba-

tion [83], while, as demonstrated in [84, 85], GO with a

lower content of oxygen-containing functional groups

(C/O ratio, 2 : 1) caused the rupture of erythrocyte

membranes with subsequent release of hemoglobin.

Our research group also showed that GO functional-

ized with L-methionine (GFM) [85], L-cysteine (GFC)

[86], glycine (GO-Gly) [87], or folic acid (GO-FA) [88]

caused no damage to the erythrocyte membrane at the

concentrations up to 25μg·ml

–1

In comparison with GO, GO functionalized with

amino groups caused no activation of platelet aggrega-

tion up to C = 2 µg·ml

–1

. The authors showed that GO-in-

duced aggregation was stronger than the thrombin-in-

duced aggregation [89]. Podolska etal. [90] found that

GO, rGO, and rGO-PEG (C = 50 μg mL

–1

) did not stimu-

late platelet aggregation in the presence of 2 μmol·ml

–1

adenosine diphosphate (ADP). GFC (up to 25 µg·liter

–1

)

caused no ADP-induced stimulation of platelet aggre-

gation, while GFM and EOGO demonstrated the anti-

platelet activity at the concentrations up to 25 and

100 µg·liter

–1

, respectively, in experiments on ADP- and

collagen-induced aggregation.

Ding et al. [91] showed that GO (dispersion con-

centration, C = 100 μg·ml

–1

) interacted with human

serum albumin (HSA) through various types of inter-

actions (covalent and hydrogen bonding, electrostatic

forces, hydrophobic interactions, and π–π stacking)

that resulted in the HSA dysfunction and its inability to

remove toxins due to conformational changes, which

indicated a potential toxicity of GO. Functionalization

of the GO surface with carboxyl groups (GO-COOH)

increased its biocompatibility, as GO-COOH caused no

functional changes in HSA. In contrast, Taneva et al.

[92] found that interaction of GO (8 mg·ml

–1

) with HSA

did not inactivate HSA in the blood plasma because

of the low affinity of GO for HSA. We demonstrated

that interaction of modified GO (GFM and GFC) with

HSA occurred mainly due to the formation of hydro-

gen bonds: the dissociation constants for the GFM and

GFC complexes with HSA were 185.2 [85] and 1600 [86]

μg·ml

–1

, respectively.

SEMENOV et al.1366

BIOCHEMISTRY (Moscow) Vol. 89 No. 8 2024

Fig. 6. Tumor-specific receptors and ligands used in GBN modification.

Liu et al. [93] found that GO at the concentrations

up to 100 μg ml

–1

induced mutagenesis due to its effect

on DNA replication and gene expression. Wang etal.

[94] reported that GO (up to 100 μg·ml

−1

) displayed a

significant genotoxicity toward human lung fibroblasts

because of the DNA damage resulting from the gen-

eration of reactive oxygen species (ROS) and surface

charge of GO. The authors showed that functionaliza-

tion of the GO surface with PEG and lactobionic acid

(LA) significantly reduced the genotoxicity.

Akhavan et al. [95] showed that the genotoxicity

depends on the lateral dimensions of graphene: rGO

nanoparticles with an average lateral dimension of

11 ± 4 nm were able to penetrate into the nuclei of

human mesenchymal stem cells, leading to DNA frag-

mentation and chromosomal aberrations even at low

rGO concentrations (0.1 and 1.0 mg·ml

–1

) after 1 h of

incubation. At the same time, rGO sheets with an av-

erage lateral size of 3.8 ± 0.4 µm did not exhibit geno-

toxicity at a concentration of 100 mg·ml

–1

after 24-h

incubation. Our research group showed that GFM and

GFC did not display genotoxicity at the concentra-

tions up to 25 μg·ml

–1

, while EOGO did not exhibit the

genotoxic effect up to C = 100 μg·ml

–1

. We also studied

the mechanism of endocytosis of GO conjugates with

1,3,5-triazine-based cytostatic drugs and showed that

the transport of these conjugates could occur via two

mechanisms– pinocytosis and clathrin-dependent en-

docytosis [96].

The possibility of selective delivery of the cytostat-

ic drug cytarabine (CYT) was shown in [88]. Using a

conjugate of GO with CYT and folic acid (FA) as a vec-

tor molecule, our research group demonstrated that

the GO-FA-CYT nanoparticles localized in the vicinity of

folate receptor-expressing pancreatic carcinoma cells

(PANC-1) (Fig.7).

DRUG DELIVERY,

PHOTOTHERMAL THERAPY (PTT),

AND PHOTODYNAMIC THERAPY (PDT)

Below, we will discuss the use of GBNs in tumor

chemotherapy. GBNs can be conjugated with anti-

cancer drugs by noncovalent functionalization of the

graphene surface (see Table1).

GBNs exhibit a high photothermal conversion ef-

ficiency, i.e., they efficiently convert absorbed light

into heat. In particular, they can absorb light in the

near-infrared (NIR) region, which is a transparency

region for biological tissues (750-1700 nm), thus allow-

ing deep tissue heating [118]. Such localized heating

can selectively damage or destroy cancer cells in PTT,

representing a minimally invasive medical treatment.

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Fig. 7. Fluorescence microscopic images of folate receptor-expressing PANC-1 cells incubated with GO-FA-CYT(a) and GO(b).

Thesize of GBNs promotes their permeability, reten-

tion, and selective clustering at the tumor loci [119].

Table2 summarises information on the use of GBNs in

chemotherapy and PTT.

GO is a highly efficient nanomaterial for PDT,

since its irradiation in the NIR region results in the for-

mation of ROS insitu, leading to tumor ablation. The

presence of functional groups (epoxy, carbonyl, car-

boxyl, and hydroxyl) on the GO surface allows to load

it with drugs, including photosensitisers, which greatly

enhances the efficacy of PDT. GQDs have a significant

singlet oxygen quantum yield. Because of their prop-

erties, such as suitability for bioimaging, drug loading

capacity, and high therapeutic efficacy in PDT, they

can be used as a multifunctional nanoplatform in ther-

anostics. These properties also create the possibility of

using GBNs in the treatment of cancer. Table 3 sum-

marises the data on the use of GBNs in PDT.

DESIGN OF GBN-BASED

THERANOSTIC APPROACHES

Hatamie et al. [161] synthesized GO/cobalt nano-

composites for inducing magnetic fluid hyperthermia

(MFH) and as contrast agents in magnetic resonance

imaging (MRI) [162]. The composites were obtained

by chemical synthesis (using GO as a source material)

and assembly of 15-nm cobalt nanoparticles; the con-

centration of cobalt in the nanocomposites was80%.

The studies of hyperthermia induction showed a su-

perior conversion of electromagnetic energy into

heat at a frequency of 350 kHz for the nanocompos-

ite dispersions with the concentrations of 0.01 and

0.005 g/liter. MRI showed that negatively charged GO/

cobalt nanocomposites were suitable for T1-weighted

imaging.

Su et al. [163] engineered a noncovalent based

mitomicine C–graphene–BODIPY (4,4-difluoro-4-bora-

3a,4a-diaza-s-indacene)–mPEG (MGBP) nanoconjugate

that ensured extensive ROS production and high pho-

tothermal conversion efficiency (48%) and demonstrat-

ed an excellent therapeutic efficacy in vitro (decreased

HeLa cell viability to 17%). Apart from the synergis-

tic photo/chemo therapy, MGBP can be used in flu-

orescence and photothermal dual-mode imaging, as

BODIPY emits fluorescence when exposed to laser irra-

diation (see Fig. S3 in the Online Resource 1 for the use

of MGBP in theranostics).

Taratula et al. [164] reported a novel cancer-tar-

geting nanoplatform for imaging and treatment of

unresected ovarian cancer tumors by intraoperative

multimodal phototherapy. To develop this theranostic

system, low-oxygen-containing graphene nanosheets

were chemically modified with polypropylenimine

dendrimers loaded with phthalocyanine(Pc) as a pho-

tosensitiser. Such molecular design prevented the

quenching of Pc fluorescence by graphene nanosheets,

providing the possibility of fluorescence imaging. Fur-

thermore, the developed nanoplatform was conjugated

with PEG to improve its biocompatibility and with lu-

teinising hormone-releasing hormone (LHRH) peptide

for the tumor-targeted delivery (Fig. S4 in the Online

Resource 1). Notably, a low-power NIR irradiation at a

single wavelength was used for both heat generation by

the graphene nanosheets (PTT) and ROS production by

Pc (PDT). Such combinatorial phototherapy resulted in

an enhanced destruction of ovarian cancer cells, with

a killing efficacy of 90-95% at low doses of Pc and low-

oxygen-containing graphene, presumably, due to the

synergistic cytotoxic effect of generated ROS and mild

hyperthermia. In vivo studies confirmed that Pc loaded

into this nanoplatform can be employed as a NIR flu-

orescence agent for the imaging-guided drug delivery.

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Table 1. Cytotoxicity of GBN conjugates with cytostatic drugs in in vitro experiments

Type of carbon nanoconjugate Drug load

Cell lines or

type of cancer

Applied concentrations and IC

or cytotoxicity

(approx. %) at the highest concentration

References

GO with FA-modified β-cyclodextrin (CD)

(GO–FA–β-CD)

doxorubicin (DOX), 168% HeLa 71% inhibition [97]

Ultrasmall nano-GO (NGO) with covalent

grafting of PEG and covalently conjugated

B cell-specific antibody Rituxan (RB)

(NGO–PEG–RB)

DOX, 40% Raji 80% inhibition [98]

GO with adriamycin (ADR)

(GO–ADR)

ADR, 93.6%

MCF-7

MCF-7/ADR

= 1.28 ± 0.26 µg/ml (MCF-7)

= 13.95 ± 0.53 µg/ml (MCF-7/ADR)

[99]

Hybrid of graphene nanosheets (GNSs),

carbon nanotubes (CNTs), and iron oxide

nanoparticles (GNS–CNT–Fe

)

0.27 mg/mg at 5-fluorouracil

(5-FU) concentration

of 0.5 mg/ml

HepG2 28% viability at 80 µg/ml [100]

Polyethyleneimine (PEI)-functionalized GO

(GO–PEI, covalent)

n/a HeLa

= 1.3 μg/ml (GO–PEI/scrambled siRNA)

= 1.3 μg/ml (GO–PEI/Bcl-2-targeting siRNA)

[101]

NGO–PEG (noncovalent)

1 g of NGO–PEG loaded

~0.1 g of SN-38 (7-ethyl-

10- hydroxycamptothecin)

HCT-116 IC

= 6 nM [102]

NGO covalently modified with

diazonium salt of p-aminobenzenesulfonic

acid (NGO–SO

DOX, more than 400% MCF-7

NGO-SO

H-DOX

Relative viability of 75% after 48h at 20µg/ml

(interms of DOX)

[103]

NGO covalently modified with diazonium

salt of p-aminobenzenesulfonic acid

and FA (NGO-FA)

DOX, more than 400%;

camptothecin (CPT) 4.5 %

MCF-7

NGO-FA-DOX

Relative viability of 30% after 48h at 20µg/ml

(in terms of DOX)

NGO-FA-CPT/DOX

Relative viability of 80 % after 48h at 200ng/ml

(in terms of CPT)

NGO-FA-CPT

Relative viability of 80 % after 48 h at 200 ng/ml

(in terms of CPT)

[104]

GO–chlorotoxin (CTX)

(GO–CTX, noncovalent)

570 mg DOX

per 1g of GO–CTX

C = 1-5 μg/ml

% of cytotoxicity, 60%

[104]

GO–sodium alginate (SA)

(GO–SA, covalent)

1.8 mg of DOX

per 1mg of GO–SA

HeLa

C = 5-20 μg/ml

% of cytotoxicity, 69%

[105]

GO nanoplatelets (GONPs), 50 × 50 nm

Cisplatin (CP) loading was

not determined

A549

C = 2.5-30 μg/ml

% of cytotoxicity = 90%

[106]

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Table 1 (cont.)

Type of carbon nanoconjugate Drug load

Cell lines or

type of cancer

Applied concentrations and IC

or cytotoxicity

(approx. %) at the highest concentration

References

GO–PEG–FA (noncovalent) CPT, 45% MCF-7

C = 20-100 μg/ml

% of cytotoxicity, 76%

[107]

GO–Fe

–β-CD (covalent)

DOX, 37.4%;

methotrexate(MTX), 23.4%

K562

C = 2-16 μg/ml;

% of cytotoxicity (DOX), 65%

% of cytotoxicity (MTX), 55%

[108]

GO–PEG–FA (noncovalent)

protocatechuic

acid (PCA), 23.47%;

chlorogenic

acid (CA), 18.33%

HT29, HepG2

C = 1.56-100 μg/ml

% of cytotoxicity (HT29), 58%;

(HT29) = 50.69 μg/ml

% of cytotoxicity (HepG2), 61%

(HepG2) = 40.39 μg/ml

[109]

GO–FA–bovine serum albumin (BSA)

(covalent)

DOX, 437.43μg

per 1mg of GO–FA–BSA

MCF-7

(FA-receptor-

positive)

A549

(FA-receptor-

negative)

C = (0.01-20) μg/ml

(MCF-7, 24 h) = 8.9 ± 0.7 μg/ml

(MCF-7, 48 h) = 0.048 ± 0.010 μg/ml

(A549, 24 h) = 5.3 ± 0.7 μg/ml

(A549, 48 h) = 0.279 ± 0.037 μg/ml

[110]

Pegylated folate-

and peptide (Pep)-decorated GO

GO–Pep–PEG–FA (covalent)

CPT, 90% HeLa IC

= 3.1 μM [111]

GQD–carboxymethyl cellulose (CMC)

hydrogel

(GQD–CMC)

DOX loading depended

on the GQD dose:

GQD(10%)–CMC, ~ 4.5%%;

GQD(20%)–CMC, ~5.5%%;

GQD(30%)–CMC, ~6%

K562

C = 2-32 μg/ml

(CMC/DOX) = 6.1 μg/ml

(GQD 10%/CMC/DOX) = 5.7 μg/ml

(GQD 20%/CMC/DOX) = 5.4 μg/ml

(GQD 30%/CMC/DOX) = 5.1 μg/ml

[112]

GO–PVP and GO–β-CD

0.17 g of SN-38

per 1g of GO–PVP;

0.14g of SN-38

per 1g of GO–β-CD

MCF-7

(GO–PVP–SN-38) = 97 μM

(GO–β-CD–SN-38) = 170 μM

[113]

GO–DOX DOX, 87%

HEK293

A549

PA-1

(HEK293) = 3.13 µM

(A549) = 3.84 µM

(PA1) = 3.35 µM

(T98G) = 11.80 µM

(SK-HEP-1) = 4.11 µM

[114]

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Table 1 (cont.)

Type of carbon nanoconjugate Drug load

Cell lines or

type of cancer

Applied concentrations and IC

or cytotoxicity

(approx. %) at the highest concentration

References

Multifunctional nanocomposite

of PEGylated GO with Pt(IV) complex

(NGO–PEG–Pt)

(c,c,t-[Pt(NH

)

(OH)

])

Pt(IV) content

in PEG–NGO–Pt varied

from 0.1 to 100mM,

which corresponded to the

concentration of NGO–PEG

(from 0.89 to 890mg/ml)

T98G

SK-HEP-1

HeLa

(24 h) = 13.88 µM

(48 h) = 6.01 µM

(72 h) = 3.56 µM

[115]

DOX–loaded aptamer–GO aggregate (GA)

(GA–DNA–DOX)

DOX–loaded aptamer–GO complex (GC)

(GC–DNA–DOX)

DOX, ~10% (wt/wt GO) HeLa

40% inhibition for dispersion containing 4μg/ml

GA–DNA–DOX (in relation to DOX), 48h

50% inhibition for dispersion containing 4μg/ml

GC–DNA–DOX (in relation to DOX), 48h

[116]

GO covalently modified with TNF-related

apoptosis-inducing ligand (TRAIL)

conjugated with furin-cleavable peptide

via PEG linker and noncovalently

modified with DOX

(fGO–TRAIL–DOX)

DOX, up to 43.8%%

A549 IC

(48h) = 14ng/ml (in relation to TRAIL)

[117]

furin-

deficient

LoVo cells

(48h) = 759ng/ml (in relation to DOX)

GO covalently modified with TRAIL

without furin-cleavable peptide

and noncovalently modified with DOX

(nGO–TRAIL–DOX)

n/a

A549 IC

= 33 ng/ml (in relation to TRAIL) [118]

furin-

deficient

LoVo cells

= 884 ng/ml (in relation to DOX) –

Table 2. Application of GBNs in chemotherapy and PTT

GBN Heat source; energy Cancer model References

Spark-generated carboxylic group-activated GO

(CGO)-coated hollow mesoporous silica nanoparticles

(HMSNs) loaded with topotecan (TPT)

(HMSN–NH

–TPT–CGO); TPT loading, 36wt.%

NIR irradiation (808nm); 2.0W/cm

, 5min

MDA-MB-231

(human breast cancer cell line)

[120]

results: minimal cytotoxicity was observed after treatment with blank nanoparticles; cell viability

with HMSN–NH

–CGO and CGO was ~91 and ~85%, respectively. After NIR irradiation, cell viability

after treatment with 200μg/ml HMSN–NH

–CGO decreased to ~53%. Cell viability was markedly

decreased after treatment with a low dose of HMSN–NH

–TPT–CGO (after exposure to NIR

irradiation), showing its advantage over treatment with free TPT

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Table 2 (cont.)

GBN Heat source; energy Cancer model References

GO nanoparticles modified with a conjugate

of the photothermal agent IR820 with LA

and loaded with DOX; the contents of DOX, IR820-LA,

and GO in the GO/DOX/IR820-LA nanohybrids

were 22, 42, and 36wt. %, respectively

NIR (808 nm) or visible (660nm)

irradiation; 1.0W/cm

, 5 min

Hep G2/Hep 1-6

(human/murine liver cells)

[121]

results: both free drug and GO/DOX/IR820-LA nanohybrids exhibited a concentration-dependent

antitumor effect. The inhibitory effect of GO/DOX/IR820-LA after laser irradiation was significantly

higher than the effects of DOX without laser irradiation and of IR820 and IR820-LA individually

after laser irradiation. To evaluate the photothermal capability of the GO/DOX/IR820-LA

nanohybrids and IR820 invivo, Hep 1-6 tumor mice were irradiated 6h after GO/DOX/IR820-LA

injection (with saline as a control). In the animals treated with the GO/DOX/IR820-LA nanohybrids,

the temperature rose to 52.9°C and the tumor growth was inhibited by 88.0%

rGO-based nanocomposites functionalized

with poly(allylamine hydro-chloride) (rGO–PAH)

and loaded with DOX; DOX loading, 36 wt. %

NIR irradiation (808 nm);

6.0W/cm

, 20min

MCF-7 [122]

results: the nanocomposites demonstrated a highly efficient synergistic chemo-photothermal effect

and at a concentration 5μg/ml caused the death of ~94% MCF-7 cells due to extensive ROS

generation, chromosome compression, and DNA disintegration

Nanohydrogel composed of chondroitin sulphate

multiple aldehyde (CSMA), branched polyethylenimine

(BPEI) and BPEI-conjugated graphene (BPEI–GO);

DOX loading, 60.1 wt. %

NIR irradiation (808 nm); 2.5W/cm

, 5min MCF-7 [123]

results: the synergetic chemo-photothermal effect promoted cell death, with 37.8, 22.8, and 9.2%

cell survival on days 1, 2, and 3 invitro. In animal treated with the DOX-loaded hydrogel,

the cancer recurred ~7 days later than in the animals treated with DOX only, indicating

that DOX loading into hydrogels provides sustainable drug release and prolonged cytotoxicity.

The combined chemo-photothermal treatment strategy yielded better results,

with only two out of six mice (33.3%) developing recurrent cancer

GO nanoparticles loaded with wedelolactone (WED)

and indocyanine green (ICG) on the surface;

WED loading, 84.91wt. %

NIR irradiation (808 nm); 2.0W/cm

, 1min HeLa [124]

results: cell viability in the presence of ICG–Wed–GO after laser irradiation was 12.65%.

In treated mice, the tumors reduced gradually and completely disappeared on day 10

GO nanoparticles functionalized with an amphiphilic

polymer based on poly(2-ethyl-2-oxazoline) (POx)

and co-loaded with DOX and d-α-tocopherol

succinate (TOS); DOX loading, 70 wt. %

NIR irradiation (808 nm); 1.7W/cm

, 5min MCF-7 [125]

results: combined application of DOX:TOS-loaded POx–GO and laser irradiation reduced

the viability of MCF-7 cells to 39%

GO nanoparticles conjugated poly(l-lysine) (GO–PLL)

deposited on cationic liposomes encapsulating DOX;

DOX encapsulation efficiency, 86.4 ± 4.7 wt. %

NIR irradiation (808 nm); 1.5 W/cm

, 2 min MDA-MB-231 [126]

results: MTT and live/dead cellular viability assays suggested that nanoconjugate ensured a dual

mode chemotherapy/PTT action. NIR light absorbed by GO and GO–PLL shells was converted to

heat and activated the gel leading to the liquid phase transition of the liposomal membrane and

release of encapsulated DOX. Alternatively, light absorbed by GO and GO–PLL provided the PTT

effect and killed cancer cells (cell viability was less than 20% at the DOX concentration of 5µg/ml)

SEMENOV et al.1372

BIOCHEMISTRY (Moscow) Vol. 89 No. 8 2024

Table 2 (cont.)

GBN Heat source; energy Cancer model References

Nanoparticles consisting of histidine (His)-modified

amorphous zinc oxide (aZnO) shell on gold

nanoparticles (AuNPs) (AuNP–His–aZnO), integrated

onto the planar structure of PEGylated GO (PEG–GO);

DOX loading, 25 wt. %

NIR irradiation (808 nm); 1.0 W/cm

10 min or 1.5 W/cm

, 5min

A549 [127]

results: the synergetic effect observed at the nanoconjugate concentration of 100μg/ml upon laser

irradiation resulted in almost 100% cell death

GO nanoparticles coated with FA and AuNPs

and loaded with DOX; DOX loading, 72.4 ± 2.5 wt. %

NIR irradiation (808 nm); 0.2 W/cm

;

5 min or 2.0 W/cm

; 5 min

MCF-7/HeLa [128]

results: the viability of MCF-7 and HeLa cells at the nanoconjugate concentration of 10μg/ml

was 32.5 and 33.9%, respectively. A significant reduction in the tumor volume was observed

in mice treated with DOX–GO–AuNPs and DOX–FA–GO–AuNPs (by 27 and 35%, respectively,

on day 21). Exposure of mice treated with DOX–GO–AuNPs and DOX–FA–GO–AuNPs

to NIR irradiation caused the photothermal effect resulting in even more pronounced tumor

reduction to 32 and 43%, respectively, on the 21st day of study

Nanoplatform consisting of ruthenium nitrosyl func-

tionalized N-doped GQDs and a triphenylphosphonium

moiety and loaded with nitric oxide (NO)

NIR irradiation (808 nm); 0.6 W/cm

10 min or 1.0 W/cm

, 10 min

HeLa [129]

results: the nanoplatform was fluorescence-trackable and capable of targeting mitochondria

in cancer cells. Irradiation of cells led to NO release and photothermal effect, resulting

in elimination of tumor cells both invitro (reduction in cell viability to ~10%) and invivo

(pronounced inhibition of tumor growth)

Mesoporous silica (MS)-coated polydopamine-

functionalized rGO (prGO) further modified with HA

and loaded with DOX; DOX loading, 145 ± 25 wt. %

NIR irradiation (808 nm); 1.5 W/cm

, 5 min HeLa [130]

results: DOX-loaded prGO–MS–HA nanocomposites produced a significant synergistic

chemotherapy/PTT effect upon NIR laser irradiation (cell viability, less than 20%)

and strongly suppressed of tumor growth invivo

GO-hybridised nanogels with alginate loaded with DOX;

DOX loading, 97.2 ± 1.2 wt. %

NIR irradiation (808 nm); 4 min A549 [131]

results: the antitumor cytotoxicity was enhanced by irradiation with an 808-nm laser

(cell viability decreased from 64.0 ± 3.6 to 39.6 ± 5.7%). The temperature of the nanogel aqueous

solution increased from 25 to 50°C

Amino-modified GO (A–GO)

NIR irradiation (808 nm); 6 W/cm

, 6 min

HSC-3 (oral squamous cell carcinoma

cell line)

[132]

results: Invitro, A–GO (15 μg/ml) reduced the viability of HSC-3 cells to 5% upon irradiation

(temperature increased to 58.4°C). A–GO strongly reduced the tumor size to 25% of the initial size

in 1 out of 4 mice and completely ablated tumors in 3 out of 4 mice

DEVELOPMENT OF GRAPHENE-BASED MATERIALS 1373

BIOCHEMISTRY (Moscow) Vol. 89 No. 8 2024

Table 2 (cont.)

GBN Heat source; energy Cancer model References

Dopamine (DOPA)-reduced GO functionalized

with sulfobetaine methacrylate (SB) brushes

and loaded with IR780 (IR780/SB/DOPA-rGO)

NIR irradiation (808 nm);

1.7W/cm

, 10 min

MCF-7 [133]

results: IR780/SB/DOPA–rGO elicited no cytotoxicity invitro (cell viability, >78%). In contrast,

a combination of IR780/SB/DOPA–rGO with NIR light decreased the viability of breast cancer

cells to 21%

DOPA-reduced GO covalently bound

with HA and loaded with DOX (DOX/HA–DOPA–rGO);

DOX loading, 91.2 wt. %

NIR irradiation (808 nm);

1.7W/cm

, 5 min

MCF-7 [134]

results: a combination of DOX/HA–DOPA–rGO with NIR light reduced cells viability to 23%

Ultrasmall GO (UGO) (average size, 30nm) loaded

with DOX; DOX loading, 52wt.%

NIR irradiation (808 nm);

1.5W/cm

, 300s

LO2 (human papillomavirus-related

cervical adenocarcinoma cell line)

[94]

results: a combination of enhanced chemotherapy and PTT induced cell death (cell viability, <15%)

in invitro cell tests and suppressed tumor growth in animals

MTX encapsulated into mesoporous silica

nanoparticles (MSNs) by polydopamine (PDA)

and embedded into GO nanosheets loaded

with naringin (NAR) and cystamine (CYS)

NIR irradiation, 300 min Saos-2 (osteosarcoma cells) [135]

results: in the absence of NIR irradiation, the IC

for NAR/CYS/MTX/MSNs@PDA@GO

and MTX/MSNs@PDA@GO were 10.3 and 27.5 mg/ml, respectively. Apparently, a significantly lower

of NAR/CYS/MTX/MSNs@PDA@GO was due to the synergistic effect of the two drugs (MTX

and NAR). Under NIR irradiation, the IC

of NAR/CYS/MTX/MSNs@PDA@GO decreased further

to 3.2 mg/ml, which can be attributed to the synergistic effect of chemotherapy and PTT

Table 3. The use of GBNs in PDT

Nanomaterial Conjugated

substance

Irradiation

characteristics

Cancer model Result References

Methylene blue (MB)–GO MB red diode radiation MDA-MB-231

MB–GO (C = 20 mg/ml)

reduced cell viability by 80%

[136]

GO–MB/pluronic F127 (PF127) MB, PF127

LED irradiation

at 660 nm

SiHa (squamous

cell carcinoma)

GO–MB/PF127 (C = 10 μg/ml)

reduced cell viability by 75%

[137]

Pyropheophorbidea (PPa)–

NGO– monoclonal antibody

against αvβ3 integrin (mAb)

mAb, PPa

laser irradiation

at 30J/cm

for 5 min

U-87 MG (human

glioblastoma)

PPa–NGO–mAb (C = 1.5 μg/ml)

reduced cell viability by 70%

[138]

NGO– methoxy PEG (mPEG)/

zinc phthalocyanine (ZnPc)

ZnPc, mPEG

laser irradiation

at 60J/cm

for 5 min

MCF-7

NGO–mPEG/ZnPc (C = 60 mg/l)

reduced cell viability by 35%

[139]

SEMENOV et al.1374

BIOCHEMISTRY (Moscow) Vol. 89 No. 8 2024

Table 3 (cont.)

Nanomaterial Conjugated

substance

Irradiation

characteristics

Cancer model Result References

rGO–ZnO–HA ZnO, HA

irradiation at 365 nm,

5mW/cm

for 30 min

MDA-MB-231

rGO–ZnO–HA (C = 50 μg/ml)

reduced cell viability by 50%

[140]

MB/GQDs and methylene

violet (MV)/GQDs

MB or MV

irradiation at 660 nm,

210mW/cm

for 5 min

MCF-7

MB/GQDs and MV/GQDs reduced cell

viability by 35% and 10-20%,

respectively, at C = 50 μg/ml

[141]

GQDs GDQs

irradiation at 365 nm

up to 5 min

MCF-7 and B16F10

mouse melanoma cells

GQDs reduced viability of MCF-7

and B16F10 cells by more than 90%

depending on concentration

[142]

GQDs GDQs

irradiation at 405

and 637 nm

HeLa

GQDs (C = 1.8 µM)

reduced cell viability by 80%

[143]

GO–PEG– chlorin e6 (Ce6) PEG, Ce6

irradiation at 660 nm,

0.1 W/cm

for 10 min

KB (human

nasopharyngeal

epidermal carcinoma)

GO–PEG–Ce6 (C = 0.011 mg/ml)

reduced cell viability by more than 95%

[144]

FA–GO–Ce6 FA, Ce6

irradiation at 632.8 nm

with a He-Ne laser

for 10 min

MGC803 (human

gastric carcinoma)

FA–GO–Ce6 (C = 100µM)

reduced cell viability by 90%

(FA–GO to Ce6 ratio, 1:1)

[145]

Hypocrellin B (HB)–GO HB

irradiation at 470nm

with He-Ne laser

for 10min

SMMC-7721 (human he-

patocellular carcinoma),

SGC-7901 (human gastric

cancer cell), HeLa, A549

HB–GO (HB–GO ratio, 1:1; C=5μM

in terms of HB) reduced cell viability

by 80 (SMMC-7721), 90 (SGC-7901),

75 (HeLa), and 80%, (A549)

[146]

Upconversion nanoparticles

(UCNPs)–NGO/ZnPc

UCNPs,

ZnPc,

and PEG

irradiation at 630 nm,

60 mW/cm

for 10 min

HeLa

UCNPs–NGO/ZnPc (C=320μg/ml)

reduced cell viability by more than 90%

[147]

GO–PEG–2-(1-hexyloxyethyl)-

2-devinylpyropheophorbide-

alpha (HPPH)

PEG, HPPH

irradiation at 671 nm,

8 mW/cm

for 3 min

4T1 (mouse mammary

carcinoma)

GO–PEG–HPPH (C = 1µM in terms

of HPPH) reduced cell viability

by more than 80%

[148]

GO–HA–Ce6 HA, Ce6

irradiation at 670nm,

50mW/cm

for 3min

A549

GO–HA–Ce6 reduced cell viability

by ~80% at C = 1.8 μM (Ce6)

[149]

GO–MB MB

portable continuous

wave diode laser system

655nm, 150mW/cm

HeLa

GO–MB reduced cell viability

by up to 50% at C = 10 μg/ml (GO)

and C = 2 μg/ml (MB)

[150]

Hypocrellin A (HcA)/SN-38/GO HcA, SN-38

irradiation at 470 nm,

25 mW for 5 min

A549

HA/SN-38/GO reduced cell viability

by ~95% at C = 6 µM (HA)

and C = 6 µM (SN-38)

[151]

DEVELOPMENT OF GRAPHENE-BASED MATERIALS 1375

BIOCHEMISTRY (Moscow) Vol. 89 No. 8 2024

Table 3 (cont.)

Nanomaterial Conjugated

substance

Irradiation

characteristics

Cancer model Result References

Magnetic and fluorescent

graphene (MFG)–hydropho-

bic silicon naphthalocyanine

bis(trihexylsilyl oxide) (SiNc

)

Fluorescent

graphene,

SiNc

irradiation at 775nm,

0.3 W/cm

for 60 min

HeLa

MFG–SiNc

decreased cell viability

by ~98% at C = 100 μg/ml

[152]

GO–PEG– sodium

sinoporphyrin (DVDMS)

PEG, DVDMS

irradiation at 630nm,

2J per well

PC-9 (human non-small

cell lung carcinoma)

GO–PEG–DVDMS (C = 3 μg/ml)

reduced cell viability by up to 80%

(GO–PEG: DVDMS ratio, 1:2)

[153]

p-Nanographene oxide

(pGO)–CuS/ICG

copper (II)

sulfide, ICG

irradiation at 808nm,

4 W/cm

for 5 min

MCF-7

pGO–CuS/ICG reduced cell viability

by ~65% at C = 50 μg/ml

[154]

GO–PEG–DVDMS PEG, DVDMS

irradiation at 630nm,

radiation dose = 50 J

U-87 MG

GO–PEG–DVDMS (C = 5 μg/ml) reduced

cell viability by more than 90%

[155]

ZnPc–PEG–Au@GO

nanocolloid (GON)

nanoparticles (NPs)

ZnPc, Au,

PEG

irradiation at 660 nm,

0.2 W/cm

for 10 min

HeLa

ZnPc–PEG–Au@GON NPs (C = 1.2 nM;

ZnPc content, 2.8·10

−11

M) reduced

cell viability by 90%

[156]

GO–808

PEG,

branched PEI,

heptamethine

indocyanine

dye IR-808

irradiation at 808nm,

2W/cm

for 5min (PTT

and PDT)

A549

GO–808 (C = 10 µM in terms of IR-808)

led to a reduced cell viability by ~90%

[157]

GO–PEG–FA PEG, FA

irradiation at 808 nm,

320 mW/cm

for 15 min

B16F0 (rat melanoma)

GO–PEG–FA (C = 75 μg/ml) reduced

cell viability by 60%

[158]

Hollow magnetic

nanospheres (HMNSs)

coated with the silica

shells and conjugated

with carboxylated GQDs,

loaded with DOX

and stabilized with liposomes

(HMNS/SiO

/GQD-DOX)

HMNSs,

liposomes,

GQDs, SiO

DOX

irradiation at 671nm

for 20min

Eca-109 (human

oesophageal carcinoma)

LP-HMNS/SiO

/GQD-DOX (C = 0.5 mg/ml

for HMNSs, 0.2 mg/ml for GQDs,

and 0.3 mg/ml for DOX) decreased

cell viability by ~90%

[159]

GO/gold nanostars

(AuNSs)–PEG/Ce6

PEG, AuNSs,

Ce6

irradiation at 660nm,

2 W/cm

for 15 min

EMT6 (mammary

carcinoma cell lines)

GO/AuNS–PEG/Ce6 (C = 3μg/ml for Ce6,

150μg/ml for GO/AuNS–PEG) decreased

cell viability by up to 80%

[160]

GO–UCNPs–Ce6 UCNPs, Ce6

irradiation at 808nm

for 10min

HeLa

GO–UCNPs–Ce6 (C = 800μg/ml)

decreased cell viability by up to 85%

[161]

SEMENOV et al.1376

BIOCHEMISTRY (Moscow) Vol. 89 No. 8 2024

Hence, the developed Pc-graphene nanoplatform has

a significant potential as an efficient NIR theranostic

probe for imaging and combinatorial phototherapy.

Lamb et al. [165] multifunctionalized graphene

nanoflakes (GNFs) with (i) peptide-based Glu–NH–C(O)–

NH–Lys ligand capable of binding prostate-specific

membrane antigen (PSMA), (ii) potent antimitotic drug

(R)-Ispinesib, (iii) chelator desferrioxamine B (DFO),

and (iv) albumin-binding tag used to extend the half-

life of the developed agent in vivo.

Ga-labelled con-

jugates were used in in vitro and in vivo experiments

to evaluate the performance of GNFs as a theranostic

agent (Fig.S5 in the Online Resource1).

Using the dose-response curves and flow cytometry

analysis, it was shown that GNFs loaded with (R)-Ispine-

sib inhibited the kinesin spindle protein (KSP) and in-

duced cell cycle arrest at the G2/M checkpoint. Experi-

ments on the cellular uptake and blocking demonstrated

that GNFs functionalized with the Glu–NH–C(O)–NH–Lys

ligand showed a specificity toward PSMA-expressing

cells (LNCaP cell line). The distribution profile and the

excretion rates of

Ga-labelled GNFs in athymic nude

mice were evaluated using the time–activity curves de-

rived by dynamic positron-emission tomography (PET).

Imaging experiments showed that GNFs demonstrated

low accumulation and retention in background tissues

and had a rapid renal clearance.

Tomasella et al. [166] used GO and reduced thiolat-

ed GO (rGOSH) as 2D substrates to fabricate nanocom-

posites with gold nanospheres (AuNSps) or nanorods

(AuNRs) via in situ reduction of the metal salt precur-

sor and seed-mediated growth processes. The plasmon-

ic sensing capability of the gold-decorated nanosheets

was evaluated by UV-visible spectroscopy. In vitro ex-

periments on the toxicity of the obtained nanocompos-

ites in human neuroblastoma SH-SY5Y cell indicated a

high potential of these hybrids as a plasmonic thera-

nostic platform.

Usman et al. [167] synthesized a bimodal GO-based

theranostic nanodelivery system using CA as an anti-

cancer agent, while Gd and AuNPs were used as con-

trast agents for MRI. CA and Gd were simultaneously

loaded on the GO nanolayers via hydrogen bonding and

π–π noncovalent interactions to form the GOGCA nano-

composite. Subsequently, AuNPs were doped on the

GOGCA surface by means of electrostatic interactions

(Fig. S6 in the Online Resource 1). Theefficacy (cytotox-

icity) of the resulting conjugate was demonstrated in

HepG2 hepatocellular carcinoma cells (IC

 = 25 μg/ml).

At the same time, the conjugate displayed no toxicity

toward normal 3T3 fibroblasts. TheT1-weighted im-

ages of the conjugate obtained by MRI demonstrated

contrast enhancement in comparison with the conven-

tional MRI contrast agent Gd(NO

)

Chawda et al. [168] engineered rGO nanoparticles

decorated with Gd

ions. The resulting Gd-containing

rGO nanosheets (Gd-rGONSs) were found to enhance

the loading of 5-FU (loading capacity, 34%) (Fig. S7 in

the Online Resource 1). The drug release was sustained

and reached ~92% within 72 h. Gd–rGONSs provided

a strong contrast in comparison to the optically re-

sponsive bare GO in the swept source optical coher-

ence tomography. The longitudinal relaxivity rate (r

)

for Gd–rGONSs at a magnetic field strength of 1.5 T

was 16.85 mM

−1

·s

−1

, which was four times higher

than that of the commercial contrast agent Magnevist

(4mM

−1

·s

−1

Samadian et al. [169] developed a drug delivery

nanosystem based on AuNPs, decorated PEG, and

FA-conjugated GO. Initially, the graphite powder was

oxidised to GO and then functionalized with chloroace-

tic acid to produce carboxylated graphene oxide (GO–

COOH). The obtained GO–COOH was functionalized

with the amine end-caped PEG, FA, and 3-amino-1-pro-

panethiol to produce GO–PEG–FA–SH. AuNPs were syn-

thesized through a citrate-mediated reduction and then

decorated onto/into GO–PEG–FA–SH through the forma-

tion of the Au–S bond to produce the GO–PEG–FA/AuNP

nanosystem (Fig.S8 in the Online Resource1).

The resulting nanosystem was loaded with

DOX·HCl (76 wt. %), and its drug-loading capacity and

pH-dependent drug release were investigated. The an-

ticancer activity of the developed theranostic agent

against MCF-7 cells was evaluated using the MTT assay

(IC

 = 20 µg/ml after 24 h). This nanomaterial can also

be used in the chemotherapy/PTT therapy of solid tu-

mors due to the presence of AuNPs.

Yang et al. [170] developed a biocompatible HA–

glutathione (GSH) conjugate (HG) with stabilised gold

nanoclusters (AuNCs) combined with GO and loaded

with 5-FU (25.3 wt. %) as a novel theranostic platform

(HG–AuNC/GO–5-FU) [170]. This multifunctional nano-

material possessed an excellent fluorescence, photo-

sensitivity, and ability to specifically target cancer cell.

Moreover, in the presence of lysosomal hyaluronidase

(HAdase) and laser illumination, the recovery of fluo-

rescence and

and complete release of 5-FU could

be achieved, which allows the use HG–AuNC/GO–5-FU

in imaging, tumor chemotherapy, hyperthermia treat-

ment, and PDT. This multifunctional complex holds a

great potential as a versatile theranostic platform for

application in bioimaging-assisted cancer therapy.

Guo et al. [171] double-functionalized GO with FA

and Ce6 for combined targeted PTT/PDT against MCF-7

cells and RAW264.7 macrophages (Fig. S9 in the Online

Resource 1). GO–FA/Ce6 exhibited good photothermal

properties and high ROS-generating capacity.

This nanomaterial penetrated rapidly into cancer

cells via folate receptor-mediated endocytosis, as well

as into macrophages. A combination of PTT and PDT

allowed to increase the therapeutic efficiency against

MCF-7 cancer cells (cell death, up to 65%) compared

DEVELOPMENT OF GRAPHENE-BASED MATERIALS 1377

BIOCHEMISTRY (Moscow) Vol. 89 No. 8 2024

toindividual treatment. GO–FA/Ce6 also efficiently elim-

inated RAW 264.7 macrophages due to the effect of

PTT/PDT (cell death, up to 94%).

Baktash et al. [172] designed and optimized a

hybrid theranostic nanosystem by combining Fe

magnetic nanoparticles (MNPs) for imaging and chi-

tosan-grafted GO as a pH-sensitive smart nanocarrier

(chitosans with different molecular weights and at dif-

ferent concentrations were used) and investigated the

drug (DOX) loading and release properties, biocompat-

ibility, and magnetic characteristics of the developed

/GO/chitosan nanosystem. It was determined that

grafting of the concentrated high-molecular-weight

chitosan on MNPs/GO provided efficient drug release

and improved DOX loading. Studying the effects of GO

and chitosan on the magnetic behavior of the Fe

GO system showed that GO decreased the contrast ef-

ficiency of the MNPs, while grafting of MNP/GO with

hydrophobic chitosan enhanced the contrast, as was

seen from a sharp decrease in the r

relaxivity, which

is very desirable for MRI applications (the r

value

for this composite was 28.95, while the r

values for

/GO and Fe

were 6.37 and 14.66, correspond-

ingly). The cytotoxicity assay using L929 cells (normal

mouse adipose fibroblasts) revealed a high biocompat-

ibility of the MNP/GO/chitosan nanosystem. Further

assays carried out using MNP/GO/chitosan loaded with

DOX demonstrated an improved performance of MNP/

GO grafted with-low-molecular weight chitosan against

MCF-7 cells (cell viability was 39% at 4 μg/ml DOX vs.

53% in the presence of DOX only).

Pan et al. synthesized a covalent conjugate based

on GO and silicon phthalocyanine (SiPc) (Fig.S10 in the

Online Resource1) [173].

In vitro studies of the GO–SiPc conjugate in cells

showed that this nanomaterial synchronously caused

the photothermal effect, intracellular fluorescence, and

ROS generation. Efficient photoablation of cancer cells

could be triggered by either 671- or 808-nm lasers due

to the synergistic PTT/PDT or NIR photothermal effect,

respectively. When systemically administered to MCF-7

xenograft mice, GO–SiPc efficiently accumulated at the

tumor loci and strongly inhibited tumor growth after

laser irradiation.

Chen et al. [174] reported a novel approach to a

one-step fabrication of magnetic graphene hybrid

nanocomposites GO–PEG–γ-Fe

(GPFs) using pulsed

laser ablation in liquid method [174]. Due to their good

magnetic and photothermal performance, GPFs were

employed as nanotheranostic agents for the multimod-

al imaging-guided chemo/photothermal synergistic

therapy. The results of multifunctional in vivo imaging

confirmed the GPF uptake by the tumors after intra-

venous injection. Moreover, using the GPF–DOX conju-

gate allowed to achieve a superior synergistic antitu-

mor effect via combined chemotherapy/PTT. Figure S11

inthe Online Resource 1 presents a photograph of he-

patocellular carcinoma (H22)-bearing nude mice under

different treatments (Fig.S12 in the Online Resource 1

demonstrates the difference in the relative tumor vol-

ume after the treatment).

A multifunctional theranostic nanoplatform based

on GO and MnWO

was developed by in situ growth of

MnWO

nanoparticles onto GO surfaces in a PEG-con-

taining hyperthermia polyol medium [175]. In compar-

ison with GO and MnWO

/PEG, the NIR absorbance of

the GO/MnWO

/PEG nanocomposite was significantly

improved, resulting in an enhanced photothermal con-

version capability and good photoacoustic (PA) imag-

ing performance. In addition, the longitudinal relaxivity

of GO/MnWO

/PEG reached 11.34 mM

−1

·s

−1

in a 0.5-T

magnetic field, which was significantly higher than

for ordinary Mn(II)-based T1 agents. In vivo MRI and

PA imaging studies demonstrated that GO/MnWO

/PEG

could be used as an efficient bimodal contrast agent

to guide cancer treatment. GO/MnWO

/PEG showed a

high loading capacity for DOX (550 mg/g); the resulting

conjugate demonstrated a pronounced cytotoxic activ-

ity towards 4T1 (human breast carcinoma) and HUVEC

(human umbilical vein endothelial cells) cell lines. For

example, cells incubated with 100 µg/ml GO/MnWO

PEG/DOX (containing 5 µg/ml DOX) and then exposed

to laser irradiation showed the highest mortality rate

(about 90%) vs. 50% in the case of DOX (C = 5 µg/ml)

orGO/MnWO

/PEG.

Prasad et al. [176] reported the results of in vivo

photo-triggered tumor regression induced by applica-

tion of a biodegradable red emissive nanotheranostic

composite based on liposomes fortified with GO flakes

and functionalized with FA (GO–Lipo–FA) and loaded

with DOX (Fig.S13 in the Online Resource1) [176].

The synthesized nanocomposite has a good aque-

ous dispersibility, quick photothermal response (54°C in

5 min), high biocompatibility, deep intracellular local-

ization, feasibility for 4T1 visualisation, and long-term

tumor-binding ability of the injected emissive nano-

hybrid. GO enhanced the stability of the drug-loaded

liposomes in the extracellular environment, which

prevented premature release of the loaded anticancer

drug from the liposomal cavity. In addition, the authors

demonstrated the developed nanocomposite caused tu-

mor regression (~300 to 25 mm

) in 4T1 Balb/c mice.

Foroushani et al. [177] developed a theranostic

system based on GO integrated with PDA, BSA, dieth-

ylenetriaminepentaacetic acid (DTPA)–Mn(II) contrast

agent, FA, and 5-FU for targeting CT-26 colon cancer

cells via folate receptors overexpressed on cancer cells.

According to the results of biodistribution assessment,

the conjugate was observed mainly in the tumors

and, therefore, provided highly efficient drug deliv-

ery to CT-26 cells. In vitro and in vivo MRI and thera-

py examination confirmed the ability of the conjugate

SEMENOV et al.1378

BIOCHEMISTRY (Moscow) Vol. 89 No. 8 2024

toenhance the contrast in tumor imaging (diagnostics)

and to inhibit the growth of cancer cells (therapy).

Luo et al. [178] proposed an easy method for

the synthesis of a theranostic agent based on super-

paramagnetic iron oxide nanoparticles loaded onto

GO nanosheets (SPIONs@GO) and cis-aconitic anhy-

dride-DOX prodrug (CAD) attached to the carboxylic

groups of GO through the 2-poly(amidoamine) dendrim-

er (G2.NH2) linker (Fig.S14 in the Online Resource1).

The release of DOX from the conjugate was pH-sen-

sitive: 66.91 ± 3.16% at pH 5.5 and 47.51 ± 1.87% at

pH 6.5 within 12 h. The viability of 4T1 cells after treat-

ment with CAD–SPIONs@GO for 24 h decreased cell vi-

ability from 93.8% to 38.3% at the DOX concentration

of 1.3-20 µM (similar to the treatment with freeDOX).

According to the results of biodistribution experiments,

4 h after injection, CAD–SPIONs@GO mainly localized to

the spleen and liver. The total Fe amount in all major

organs decreased greatly 12 h after injection, suggest-

ing that CAD–SPIONs@GO was cleared out of the body.

The authors proposed that the interface effect between

GO and in situ growth of SPIONs contributed to the sig-

nificant increase in the r

value and decrease in the

value. Invivo studies results confirmed a possibility

of conjugate application in high-resolution T1-weight-

ed MRI.

Shi et al. [179] synthesized a theranostic agent

based on rGO conjugated to the anti-CD105 antibody

(TRC105) and a complex of

Cu (PET label; half-life,

12.7 h) with 1,4,7-triazacyclononane-1,4,7-triacetic acid

(NOTA, chelator). Invivo experiments on the blockade of

the agent uptake by 4T1 cells with an excess of TRC105,

as well as flow cytometry and histology data, confirmed

the stability of

Cu–NOTA–rGO–TRC105 and its speci-

ficity for CD105 of the tumor vasculature. Noteworthy,

Cu–NOTA–RGO–TRC105 exhibited little extravasation

in 4T1 cells, indicating that targeting tumor vasculature

(instead of tumor cell) can be a valid and preferred

approach for the application of nanomaterials. Since

rGO can be used for PTT, the tumor-specific rGO con-

jugate may serve as a promising theranostic agent that

integrates imaging and therapeutic components.

Cheng et al. [180] developed a mild thermal an-

nealing procedure to induce blue fluorescence in GO

suspensions (Fig.S15 in the Online Resource1) [180].

The procedure preserved the oxygen functional groups,

which enabled conjugation of a cancer drug and re-

sulted in nontoxic and harmless nanomaterial. The

authors demonstrated the capability of GO to simulta-

neously act as a cellular imaging agent and a drug de-

livery agent in CT26 cancer cells without the need for

additional fluorescent protein labelling. The authors

also covalently annealed GO with CP (elemental con-

tent of Pt in the conjugate, ~3wt. %) and determined

that the annealed GO boosted the therapeutic perfor-

mance of CP in killing CT26 cancer cells.

Hu et al. [181] synthesized a new conjugate based

on rGO, PDA, and ICG for amplifying the PA imaging

and PTT effects for cancer phototheranostic (Fig. S16

in the Online Resource 1). The procedure for the

ICG–PDA–rGO preparation included the following

steps: (i)dopamine monomers were loaded on the GO

surface and spontaneously self-polymerised via the

Michael addition/Schiff reaction to form a PDA coat-

ing on the rGO surface, (ii)free ICG dye was absorbed

on the PDA–rGO surface via hydrogen bonds and π–π

stacking interactions.

ICG–PDA–rGO exhibited stronger PTT effect and

higher PA contrast than pure GO and PDA–rGO. After

PA imaging-guided PTT treatment, the tumors in 4T1

breast subcutaneous and orthotopic mice models were

suppressed completely; no treatment-induced toxicity

was observed.

Turcheniuk et al. [182] produced a theranostic

agent based on AuNRs coated with pegylated rGO

(AuNRs@rGO–PEG) and modified with sulfo-cyanine7

fluorescent dye (Cy7) and Tat protein (see Fig. S17 in

the Online Resource1).

Selective targeting of tumors was ensured by

specific interaction between the Tat protein and hu-

man glioblastoma astrocytoma cells (U87MG). Due to

the presence of NIR fluorescent dye integrated onto

the rGO shell, the conjugate acted as fluorescent cel-

lular marker. In vivo experiments in mice implanted

with U87MG cells showed that irradiation at 800nm

(0.7 W/cm

, 10 min) suppressed tumor growth after

5 days. Histological analysis of tumor tissues revealed

an active uptake of the nanoparticles by the tumor

stromal cells and selective damage of tumor vessels.

Wang et al. [183] synthesized a novel nanomate-

rial for the PTT/immunotherapy of cancer by the self-

assembly of oleate-capped Fe

nanoparticles (FNPs)

and rGO through electrostatic interaction, followed by

modification with PEG–NH

[182]. FNP/rGO–PEG nano-

composites can be used for the MRI-guided cancer

PTT/immunotherapy due to their excellent magnetic

properties. Under laser irradiation (805nm), FNP/rGO–

PEG improved the PTT efficacy by increasing the tem-

perature up to 60°C and killing 80% of 4T1 orthotopic

mouse breast tumor cells. In addition, FNP/rGO–PEG

nanocomposites could be used to stimulate immune

response by triggering the maturation of dendritic cells

(CD11c

CD86

) and secretion of cytokines (IL-12p70,

IL-6). Intratumoral injection of FNP/rGO–PEG nano-

composites in combination with NIR laser irradiation

significantly increased the median survival time of

tumor-bearing animals.

Bansal et al. [184] developed a theranostic agent

based on GQDs conjugated with a biosurfactant isolat-

ed from Candida parapsilosis through the amine-car-

boxyl coupling reaction and noncovalent modification

with FA. The obtained conjugate had a homogenous

DEVELOPMENT OF GRAPHENE-BASED MATERIALS 1379

BIOCHEMISTRY (Moscow) Vol. 89 No. 8 2024

dispersion and showed the photoluminescence proper-

ties and demonstrated enhanced uptake by cancerous

cells in comparison with non-modified GQDs. Inthe

MTT assay, the conjugate decreased the viability of

MCF-7 cells by more than 60% after 24 h of incubation

and by 75% after 48 h [184].

Ko et al. [185] synthesized GQDs for the diagnos-

tics and therapy of breast cancer via conjugation with

two precursors. DOX-disulfide-GQDs provided chemo-

therapy and PEG-disulfide-herceptin enhanced the

half-life and ensured the targeting of HER2 (Fig.S18 in

the Online Resource1) [184]. The cleavage of disulfide

links at a physiologically relevant glutathione concen-

tration in cancer cells provided controlled drug re-

lease. Theauthors demonstrated an enhanced cellular

uptake of the conjugate by SK-BR-3 cells (HER2-posi-

tive) in comparison with MDA-MB-231 cells (HER2-neg-

ative). As a result, the viability of SK-BR-3 cells was

significantly decreased (to <50%) at the conjugate con-

centration of 50mg/ml, whereas the viability of MDA-

MB-231 cells was reduced to >85%.

Iannazzo et al. [9] developed a novel conjugate

based on GQDs covalently modified with the tumor

targeting module biotin (BTN) and noncovalently mod-

ified with DOX (GQD-BTN-DOX, Fig.S19 in the Online

Resource 1), as well as the GQD-DOX conjugate [9]. The

DOX content in GQD-BTN-DOX and GQD-DOX was 16.6

and 17.8wt. %, respectively. GQD-DOX nanoparticles

were preferentially accumulated in the cytoplasm,

while DOX localized to the nuclei. At the same time,

GQD-BTN-DOX nanoparticles concentrated in the endo-

somal compartment after endocytosis-mediated inter-

nalisation. The cytotoxicity of GQD-BTN-DOX towards

A549 cells strongly depended on the uptake by the cells,

which was more pronounced and delayed for GQD-

BTN-DOX in comparison with GQD-DOX and DOX only.

Li et al. [186] synthesized a covalent GQD-FA con-

jugate and loaded it with IR780 iodide (33.19 wt. %)

via π–π stacking interactions (see Fig. S20 in the On-

line Resource 1). In vivo NIR fluorescence imaging and

biodistribution analysis demonstrated that in BALB/c

nude mice xenografted with HeLa cells, the conjugate

preferentially accumulated in the tumors. When irra-

diated with an 808-nm laser, IR780/GQDs-FA caused

hyperthermia (photothermal conversion efficiency,

87.9%) and induced apoptosis of cancer cells and tu-

mor necrosis, resulting in complete tumor disappear-

ance without relapse.

Ding et al. [187] developed a novel type of GQD-

based theranostic agent with a superior therapeutic

performance against 4T1 cancer cells both in in vitro

[IC

 (theranostic agent) = 1.5 g/ml, IC

 (DOX) = 4 g/ml]

and in vivo (the conjugate reduced the tumor volume

2.7 times more than DOX alone) due to the improved

tissue penetration and cellular uptake [187]. GQDs

were synthesized via facile chemical oxidation and

exfoliation technique using polyacrylonitrile carbon

fibres as a raw material. The NIR fluorescent molecule

Cy5.5 was covalently attached to GQDs via the cathep-

sin D-responsive peptide (Phe-Ala-Ala-Phe-Phe-Val-Leu-

Cys, P); functionalized GQDs were then loaded with

DOX via π–π interactions. The synthesized construct al-

lowed to track the delivery and release of the antican-

cer drug, as well as to monitor drug-induced apoptosis

of cancer cells through GQD, DOX, and Cy5.5 charac-

teristic fluorescence.

Badrigilan et al. [188] produced a theranostic agent

based on superparamagnetic iron oxide and bismuth

(III) oxide (Bi

) with GQDs for in vitro computed to-

mography (CT)/MR dual-mode bioimaging and PTT

(Fig.S21 in the Online Resource1).

The GQD-Fe/Bi nanocomposite had the following

advantages: (i) the photothermal conversion efficacy

was 31.8% with a high photostability upon irradiation

with a NIR 808-nm laser; (ii) photothermal ablation of

HeLa and MCF-7 cells in vitro resulted in a significant

decrease in cell viability (~50% at 100µg/ml) in com-

parison with laser treatment only (3.0%); (iii) obtained

nanoparticles exhibited a superior X-ray attenuation

capability (175%) in comparison with Dotarem (mac-

rocyclic gadolinium-based contrast agent), as well as

showed a strong T2-relaxation shortening capability

 = 62.34mM

−1

·s

−1

) as a contrast agent for CT/MRI.

The same authors synthesized GQD-coated bis-

muth nanoparticles and assessed the possibility of

their application for CT imaging and PTT [189].

Lee et al. [190] developed rGQDs derived by rGO

top-down oxidation and HA-GQDs (HGQDs) that were

hydrothermally synthesized by the bottom-up method

[190]. The obtained nanomaterials possessed substan-

tial NIR absorption and fluorescence throughout the

visible and NIR regions, which is beneficial for in vivo

imaging. Aqueous dispersions of rGQDs and HGQDs

added to HeLa cells and irradiated with NIR laser

(λ = 808 nm, 0.9 W/cm

, 10 min) facilitated an increase in

temperature up to 54.5°C, leading to the decrease in the

HeLa cell viability from 80% for RGQDs (C = 1.5 mg/ml)

and 60% for HGQDs (C = 1.7 mg/ml) without irradiation

down to ~40% (RGQDs) and ~20% (HGQDs) after irra-

diation.

Sung et al. [191] synthesized a unique conjugate

composed of porous carbon/silica nanosponge encap-

sulated with GQDs loaded with docetaxel (DTX) via π–π

interactions; then, the particles were capped with the

red blood cell (RBC) membrane and cetuximab via fu-

sion (see Fig.S22 in the Online Resource1).

The obtained conjugate has the following advan-

tages: (i) the stability of the RBC lipids and proteins

on porous particles was higher than that of lipids of

liposomal particles due to a high adhesion energy;

(ii) the porous surface of the particles exhibited an

excellent lateral bilayer fluidity, thus improving the

SEMENOV et al.1380

BIOCHEMISTRY (Moscow) Vol. 89 No. 8 2024

targeting efficacy; (iii) RBC-coated nanoparticles had

a considerably longer circulation time than PEGylated

nanoparticles due to the presence of transmembrane

protein CD47 that induces signalling through the

phagocyte receptor CD172a, inhibits immune response,

and suppresses particle recognition by the immune

system (see Fig. S23 in the Online Resource 1 for the

mechanism of conjugate action).

Due to the synergistic effect of biomimetic tar-

geting and penetration of DTX/GQD nanoparticles fol-

lowed by irradiation (1.5 W/cm

, 10 min), it was able

to achieve a significant reduction in the size of A549

tumor during the first 10 days of treatment.

Xuan et al. [192] synthesized nanoparticles for bio-

imaging and combined chemotherapy/PTT based on

AuNSp clusters (diameter of 50nm) coated with GQDs

covalently modified by FA using carbodiimide method

and noncovalently modified with DOX (94.39 ± 0.39%)

(see Fig.S24 in the Online Resource 1 for the scheme of

conjugate synthesis).

The obtained nanoparticles formed stable aque-

ous dispersions and demonstrated an excellent PA

and CT imaging performance, low cytotoxicity, and

PTT conversion efficiency up to 51.31%. In addition,

the authors showed a significant decrease in the rel-

ative tumor volume in BALB/c nude mice (SPF males,

4-week-old) inoculated with HeLa cells (Fig. S25 in the

Online Resource1).

Wu et al. [193] developed a new type of theranos-

tic agent named PC@GCpD(Gd) [192]. First, the authors

synthesized GQDs covalently modified with the Ce6

photosensitiser (GCpD) and coated with PDA layers,

yielding water-compatible and biocompatible nanopar-

ticles with a substantial photothermal/photochemi-

cal effect. Then, the Cy3-labelled nonmethylated CpG

oligodeoxynucleotide (5′-TCC ATG ACG TTC CTG ACG

TT-3′-Cy3) was condensed with the biodegradable cat-

ionic poly(l-lysine) (PLL) polypeptide to obtain immu-

noactive nanoparticles (PCs). GCpD nanocomposites

easily self-assembled on the surface of PC nanoimmu-

nocores and then were chelated with Gd

(see Fig. S26

in the Online Resource1).

The obtained photo/immunoactive hybrid PC@

GCpD(Gd) nanostructures decreased the viability of

cancer cells, released endogenous cancer cell antigens,

and contemporaneously regulated tumor microenvi-

ronment to facilitate the immunostimulatory effect.

The authors characterised the cellular uptake, MRI/flu-

orescence imaging, and phototherapeutic and immu-

nostimulatory activity towards the murine mammary

cancer EMT6 model, as well as the biosafety of PC@

GCpD(Gd) nanoparticles. It was shown that laser irra-

diation (660 nm, 1 W/cm

, 10 min) simulated the PTT

and PDT effects, leading to a significant decrease in the

EMT6 cell viability in mice, secretion of proinflammato-

ry cytokines, maturation of dendritic cells, and recruit-

ment of CD4

and CD8

T cells into the tumor, resulting

in a higher therapeutic efficacy. MRI/fluorescence imag-

ing traced specific accumulation and retention of PC@

GCpD(Gd) in the tumor-draining lymph nodes.

Ruiyi et al. [194] synthesized histidine (His)-

and octadecylamine (OA)-functionalized GQDs (His/

OA-GQDs). The obtained nanoparticles were used for

the fabrication of His/OA-GQD-NaYF

:Yb,Tm nano-

cages that exhibited a 140.2-fold enhancement of up-

conversion fluorescence, stability in aqueous solu-

tions, and high DOX-loading capacity (461.2% within

30 min) (see Fig. S27 in the Online Resource 1) [194].

The authors also developed a drug delivery system

(GYAuDOX) which included His/OA-GQD-NaYF

:Yb,Tm

gold nanoparticles as a core, and MGC-803 cell mem-

brane as a shell. The obtained material exhibited a

high biocompatibility, selective targeting of homotypic

tumor cells, pH- and light-stimulated DOX release, and

capacity for chemotherapy/PTT. The data on the effica-

cy of the obtained theranostic agent are presented in

Fig.S28 in the Online Resource1.

Liu et al. [195] synthesized GQDs with a strong ab-

sorption (1070 nm) in the NIR-II region (1000-1700 nm)

by a one-step solvothermal treatment using phenol

(carbon precursor) and hydrogen peroxide (oxidising

agent) in the magnetic field with an intensity of 9 T

(see Fig.S29 in the Online Resource1) [195].

The synthesized nanoparticles possessed a uni-

form size (3.6 nm), tunable fluorescence (quantum

yield, 16.67%), and high photothermal conversion ef-

ficacy (33.45%). The obtained nanomaterial ablated tu-

mor cells, inhibited tumor growth upon NIR-II irradia-

tion, and, at the same time, provided an enhanced NIR

imaging of tumors in mice.

Zhang et al. [196] developed a nanomaterial

(named R-NCNP) by coating a mesoporous carbon ni-

tride (C

) layer on a core–shell nitrogen-doped GQD

(N-GQD)@ HMSNs and decorated it with a P-PEG-RGD

polymer consisting of a purified hematoporphyrin

derivative photofrin (P) and the tumor-homing pep-

tide RGD (Arg-Gly-Asp) connected by PEG as a linker,

to achieve the targeted delivery (see Fig.S30 in the On-

line Resource1).

The obtained material has the following advantag-

es for biomedicine applications: (i) R-NCNPs catalyzed

water decomposition in the tumor microenvironment

with the generation of oxygen, thus decreasing local

hypoxia; (ii) the generated oxygen bubbles enhanced

generation of an echogenic signal, making them la-

ser-activatable ultrasound imaging agents; (iii) acti-

vation of the encapsulated photosensitisers and C

layered photosensitiser at λ = 630 nm stimulated ROS

formation; (iv) combination of PTT with PDT for tumor

eradication; (v) P-PEG-RGD promoted efficient accumu-

lation of particles in the tumor; (vi) R-NCNPs acted as

multimodal real-time monitoring agent.

DEVELOPMENT OF GRAPHENE-BASED MATERIALS 1381

BIOCHEMISTRY (Moscow) Vol. 89 No. 8 2024

Fig. 8. Directions of GBN scientific applications.

Prasad et al. [197] synthesized a theranostic agent

based on GQD-embedded mesoporous silica which dis-

played a high penetration and retention ability in sol-

id tumors (see Fig. S31 in the Online Resource 1). The

obtained material had a uniform particle size distribu-

tion, improved stability, high surface area (850 m

/g),

DOX loading capacity of 31%, and high photothermal

response. It was shown that administration of carbano-

silica in 4T1 female Balb/c mice led to a temperature

rise (to ~55°C after 5 min of exposure to NIR light), flu-

orescence intensity of 10

 p/s/cm

/sr, and as a result,

provided 68.75% tumor shrinking compared to 34.48%

without NIR irradiation.

Yang et al. [198] developed a self-assembly ap-

proach to the theranostic agent synthesis based on the

acidity-activated GQD nanotransformers (GQD NTs)

by mixing (i) GQDs (loading module) that provided

large surface area for the loading of photosensitiser

[tetrakis(4-carboxylphenyl) porphyrin, TCPP] and MRI

contrast agent (Mn-TCPP), (ii) RGD peptide as a tar-

geting module due to its affinity to α

integrin, and

(iii) linking module that connected the first two mod-

ules through the host–guest interactions between β-CD

and adamantine [198]. As seen from Fig.S32 in the On-

line Resource 1, the acidity of tumor microenvironment

triggered GQD NT transformation and drugs release.

The synthesized theranostic agent provided an ef-

ficient targeting and long-term retention in the tumor

(over 96 h), possibility of MRI/fluorescence imaging,

and photothermal effect, which enhanced cell mem-

brane permeability, as well as an efficient photosen-

sitiser uptake and repeated PDT at a photosensitiser

content 10-30 times lower than in previously published

papers. As seen from Fig.S33 in the Online Resource 1

(survival and tumor growth curves of A549 tumor-

bearing mice after different treatments), the developed

nanomaterial significantly inhibited tumor growth

and increased mouse survival.

CONCLUSION

Since their discovery in 2004, graphene and its

derivatives have become some of the most promising

materials due to a broad range of potential applica-

tions in various fields of science and technology, such

as biotechnology, biomedicine, tissue engineering,

bioanalysis, etc. (Fig.8).

Graphene has a unique two-dimensional flat struc-

ture, unique physical and chemical properties, and

high biocompatibility, which promotes its application

in the creation of high-tech materials for biomedical

purposes. The use of graphene and its derivatives for

the treatment of solid tumors is one of the promising

areas of modern oncology. Along with the advantages

of GBNs, there are also some limitations that need to

be considered. One of the main problems is the lack

of information about metabolic pathways and toxi-

cokinetics of graphene materials used in biomedical

applications. This limits the ability to fully evaluate the

safety and efficacy of these materials in living organ-

isms. Another important problem is poor reproducibil-

ity of the synthesis of graphene-based materials and

common lack of comprehensive studies on their struc-

ture and composition. Both these factors lead to a poor

reproducibility of biological effects of graphene-based

materials in living systems. Also, water dispersions of

GBNs are prone to aggregation, which affects their bi-

ological activity and mechanism of biological action.

Inthis regard, it is necessary to conduct a comprehen-

sive physico-chemical investigation of their stability,

including the studies of optimal stabilizers. Let us hope

that these problems will be solved in the XXI century–

the century of nanotechnology.

Supplementary information. The online version

contains supplementary material available at https://

doi.org/10.1134/S0006297924080029.

SEMENOV et al.1382

BIOCHEMISTRY (Moscow) Vol. 89 No. 8 2024

Contributions. K.N.S., I.V.M., J.A.R., and V.V.S. creat-

ed the study concept; K.N.S., I.V.M., J.A.R., and V.V.S. de-

veloped the study methodology; K.N.S., D.N.M., D.K.K.,

J.A.R., O.E.M., and V.V.S. supervised the study; V.V.S.,

D.N.M., O.E.M., and K.N.S. acquired the funding; O.S.S.,

S.V.A., G.O.I., and P.K.K. investigated and analyzed the

data; K.N.S., P.A.A., and V.V.S. curated the data; O.S.S.

wrote the draft and prepared the figures; K.N.S., S.V.A.,

and V.V.S. reviewed and edited the manuscript.

Funding. The work was carried out with the fi-

nancial support of the Ministry of Health of the Rus-

sian Federation (state assignment on the topic "Cre-

ation of a drug based on nanoforms of innovative

synthetic antitumor antibiotics, including heterocyclic

systems with a quaternized nitrogen atom and styryl

fragments in the form of conjugates with targeted de-

livery vectors to the tumor microenvironment" EGISU:

1023022200055-4-3.2.21;3.1.3).

Ethics declarations. This work does not contain

any studies involving human and animal subjects.

Theauthors of this work declare that they have nocon-

flicts of interest.

Open access. This article is licensed under a Cre-

ative Commons Attribution 4.0 International License,

which permits use, sharing, adaptation, distribution,

and reproduction in any medium or format, as long

as you give appropriate credit to the original author(s)

and the source, provide a link to the Creative Commons

license, and indicate if changes were made. Theimages

or other third-party material in this article are includ-

ed in the article’s Creative Commons license, unless

indicated otherwise in a credit line to the material.

Ifmaterial is not included in the article’s Creative Com-

mons license and your intended use is not permitted

by statutory regulation or exceeds the permitted use,

you will need to obtain permission directly from the

http://creativecommons.org/licenses/by/4.0/.

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