Supporting Information

Graphene Quantum Dots-Mediated Theranostic Penetrative Delivery of Drug and Photolytics in Deep Tumors by

Targeted Biomimetic Nanosponges

Shou‐Yuan Sung1, Yu‐Lin Su1, Wei Cheng1, Pei‐Feng Hu1, Chi‐Shiun Chiang1, Wen‐Ting Chen2, Shang‐Hsiu Hu1,* 

1Department of Biomedical Engineering and Environmental Sciences, National Tsing Hua University, Hsinchu, 300, Taiwan 

2Institute of Bioinformatics and Structural Biology, National Tsing Hua University, Hsinchu, 300, Taiwan 

E‐mail: shhu@mx.nthu.edu.tw 

Methods

Synthesis of graphene quantum dots (GQDs). Benzyl groups were bonded with covalent bonds

via oxidation of hexaphenylbenzene (HPB) to form hexabenzocoronene (HBC).S1 Then, HPB was used

to prepare the artificial graphite precursor (HBC) via reaction with FeCl3. HPB (0.2 g) was dissolved

in 70 mL of dichloromethane at a nitrogen atmosphere. 1.2 g of iron(III) chloride and 5 mL of

nitromethanide as an oxidant were placed into the mixture. Two hour laterh, the reaction was quenched

with methanol, and the particles were separated by centrifugation at 7,000 rpm. Next, the particles

were purified twice with ethanol. The particles were then dried in oven at 70 oC for 24 h to obtain

HBC. 50 mg of HBC were calcinated in a tube furnace at 600 °C or 1000 °C for 4 h. Finally, AG

powder was collected for analysis and application.

Preparation of artificial graphene oxide (AGO) and graphene quantum dots (GQDs). In brief,

via the Hummers’ method,S1 15 mg of AG was placed into 2 mL of sulfuric acid, and the solution was

mixed by stirring and sonicating for several times to obtain well dispersed solvent. Then, 80 mg of

potassium permanganate was mixed with the solution at 2 °C for 8 h. After reaction, the solution was

placed at room temperature for 8 h, and heated at 95 °C for another 24 h. Next, 0.7 mL of D.I. water

and 1.6 mL of hydrogen peroxide were mixed with the solution. Then, the resulting solution was added

to a dialysis bag (MWCO 1,000) to remove un-reacted chemical reagents, and AGO was obtained. 1

mL of AGO (0.2 wt %) solution was added to 4 L of hydrazine to carry out the reduction process at

90 °C for 18 h to obtain GQDs. The morphology, size distribution and features of AGO were evaluated

by transmission electron microscopy (TEM) (JEOL, JEM-2100) and photoluminescence spectroscopy

(FluoroMax®-4 spectrofluorometer, HORIBA Jobin Yvon).

Synthesis of porous carbon/silica nanoparticles (nanosponge). A solution was dissolved by

stirring 100 mg of CTAB into 30 mL of D. I. water at 50 °C for 30 min. When solution became clear,

n-octane (14.4 mL), lysine (0.146 mmol), styrene monomer (100 mg/mL), TEOS (4.7 mmol) (or

APTMS/TEOS 1:9), and AIBA (0.133 mmol) were added to the system. Then, octane was added to

the mixture at a ratio of octane:water=0.34:1. The weight ratio of H2O/TEOS/ lysine/CTAB was kept

at 300:11:0.25:1. Then, the reaction was carried to proceed for 3 h at 65 °C. After the reaction, the

mixture was cooled down to room temperature by removal of heating. Then, the mixture was stirred

for 16 h and collected by centrifugation at 8,000 rpm for 15 min. The suspension was purified by

excess of ethanol for several times. To introduce the sulfonation of polystyrene, a strong acid (H2SO4)

was slowly added to the suspension in D. I. water and kept at 40 °C. After 2 h, the acid solution was

removed by an excess of pure ethanol via three times washing. To form the porous carbon/silica

nanoparticles (nanosponge, NS), the calcination was carried out at 800 °C for 4 h under an inert gas

(N2) to carbonize the polymer. Porous silica particles was fabricated by calcinating the nanosponge at

800 °C for 4 h under air to eliminate carbon. Furthermore, Ct@NS was prepared by the chemical

conjugation. First, surface modification of NS was achieved by adding 30 mg of NS into 20 mL

suspension (ethanol:D.I. water is 2:1 v/v) containg 20 mg of 3-aminopropyl triethoxysilane (APTES).

The reaction was carried out on for 24 h under reflux at 80 oC. Then, the resulting APTES-funtionalized

NS were washed three times with ethanol to remove excess APTMS. To conjugate Ct, 3 mL freshly

prepared SMCC modified-Ct solution (approximate 24 mg Ct) was added into the suspension. The

conjugation process was carried out at 4 oC for 12 h. Finally, excess Ct was removed via centrifugation

and the resulting Ct@NS was stored at 4 oC before use.

RBC-membrane-derived vesicles. Whole blood was first withdrawn from female BALB/c nude

mice (6–8 weeks, purchased from National Laboratory Animal Center, NLAC, Taiwan) via cardiac

puncture applying a syringe containing 5 % EDTA. First, the plasma and the buffy coat was removed

from the whole blood by centrifugation at 800 g for 6 min at low temperature. The RBCs were collected

and purified by ice cold PBS for three times. Then, the resulting RBCs were placed into a hypotonic

process to eliminate the intracellular content, and then, the washed RBCs were suspended in 0.25×

PBS in an ice bath for 60 min and centrifuged at 800 g for 6 min. The released hemoglobin in

supernatant was removed by centrifugation at 1,000 g, and the pink pellet containing the RBC ghosts

was collected and washed by PBS for three times. To fabricate RBC-membrane-derived (RBCm)

vesicles, the resulting RBC ghosts were extruded with an extruder having 200 nm of pore size for ten

times (low protein binding). Finally, the resulting RBCm vesicles were then stored at 4 °C.

Fusion of the RBCm-enveloped nanosponge (NS). To prepare the RBC-NS, the dilute NH4OH

and H2O2 were treated with the NS in advance at 60 oC for 20 min, and then, washed by D. I. water

for three times. 200 L of RBCm vesicles was added to the NS (1 w/v %) by pipetting the solution for

30 sec. Next, the resultant solution was sonicated by ultrasonication for 20 min (FS30D bath sonicator)

at a frequency of 42 kHz and power of 100 W and extruded for another six times. Excess RBCm were

separated via centrifugating at 7,000 rpm for 10 min. The particles were washed three times with the

excess of PBS. Then, the RBC-nanosponge was dispersed in PBS solution. To prepare the Ct-

RBC@NS, cetuximab (Ct) was mixed with RBC-membrane-derived vesicles and then sonicated and

extruded with NS. The particles were gathered through centrifugating and dispersed in PBS.

For imaging tracking, CdSe quantum dots (QDs) were embedded in the NS before RBC-

membrane coating. In brief, the NS was added into 2 ml of n-butanol. Then, QDs were dispersed in

CHCl3, and the mixture was added with the NS solution. The mixture was vortexed and sonicated for

3 min, and the particles were separated by centrifugating at 7,000 rpm. The excess of ethanol was used

to washed the particles for three times.

Materials characterization. A scanning electron microscope (SEM, Jeol-7000, Japan) and

transmission electron microscope (TEM, JEM-2100, Japan) were applied to investigate the

morphologies of particles. Before electron microscope examination, the particles were freeze-dried at

-20 oC for 72 h on carbon-supported copper grids. TGA (Perkin Elmer) was used to investigate weight

loss under a nitrogen atmosphere (a flow rate of 60 mL/min) with temperature in the range of 50-

400 °C with the heating rates of 10 °C/min. The Raman spectra of GQDs were measured by a laser

with 514 nm of wavelength. The particle sizes and size distribution were investigated by dynamic light

scattering (DLS, Beckman Coulter). A Beckman-Coulter Delsa 440SX apparatus was used for the zeta

potential analyses. The analysis was maintained the particle solution at pH 7.0. The Brunauer–

Emmett–Teller (BET) method measured gas absorption isotherms (N2) at 77 K, and the porosity and

pore volume were determined through Barrett, Joyner, and Halenda (BJH) method. The particles were

treated at 80 °C under vacuum to remove the surface adsorption and were degassed at 200 °C for 2 h

before BET analysis. Fluorescence recovery after photobleaching was carried by a confocal scanning

laser microscope (Ziess LSM 780). The 50 mg of porous silica microbeads (~4 m) loaded with

polystyrene were carbonized by 800 °C heat treatment for 5 h under inert gas (Ar) to obtain carbon-

coated porous silica composites. 100 L of RBCm vesicles were mixed with particles and sonicated

for 10 min. The RBCm-coated particles were separated by centrifugating at 5,000 rpm for 5 min, and

then, washed by excess PBS for three times. RBCm was labeled by Rhodamin to evaluate lipid fluidity.

Loading docetaxel (DTX) into NS. GQD/Docetaxel (DTX, Scinopharm, Taiwan) loading was

performed by mixing 1 % DTX and 0.3 % GQD with NS in DMSO for 12 h. Then, the mixture was

placed into vacuum at 50 oC for 24 h to evaporate DMSO. The un-loaded DTX was then removed by

PBS washing for three times. To quantity the drug loading, high-performance liquid chromatography

(HPLC, Agilent Technologies 1200 series; the mobile phase: 40 % water and 60 % acetonitrile) with

a 150 mm ZORBAX Eclipse XDB-C18 (5 m) column at a wavelength of 204 nm was applied to

determine the concentration of DTX in PBS before and after loading. The loading capacity was also

calculated while identifying the concentration of DTX.

Cell culture and cytotoxicity. A549 (a lung cancer cell line) cells were cultured in Eagle’s

minimum essential medium with 10 % fetal bovine serum and 1 % penicillin/streptomycin in a 5 %

CO2-enriched environment at 37 °C. When the cells were incubated for one day, the particles were

added into the cells for distinct concentrations. The cytotoxicity treated by various time was evaluated

by a counting approach. Trypsin was applied to remove the cell from dish, and then, the cells were

scored under the microscopy. The live and dead cells were counted up to 6 times and three individual

experiments were evaluated for all conditions. Quantum dot-labeled particles were applied for tracking,

and the uptake of particles was then investigated by CLSM (Zeiss LSM 780). Flow cytometry analysis

(analyzed by CELLQUEST® software) was also used to evaluate the cell uptake of particles. Three-

dimensional tumor spheroids were fabricated on a tumor chip containing 400 tumor spheroids. The

tumor chip remodeled from wafer patterns was formed by polydimethylsiloxane (PDMS), and 1% of

polyhydroxyethylmethacrylate (pHEMA) was coated on its surface to avoid the cell adhesion. After

24 h-post of cell loading, tumor spheroids with a diameter of 200 m approximately were formed.

Before quantifying the amounts of cell uptake and fluorescence staining, the cells were washed by

PBS for three times to remove the free particles.

Iv vivo study. Cy®5.5 Mono NHS Ester (Merck) was applied to label the protein or RBC on NS

in PBS solution at 37 oC. After the conjugation, the excess of Cy®5.5 Mono NHS Ester was removed

by PBS washing for three times. All mice were purchased from BioLASCO Taiwan Co. (Taiwan). To

introduce tumors, 1×106 of A549 cells in 100 L PBS were injected into female nude mice (CAnN.Cg-

Foxn) that were 6 weeks old. While the tumor volume reached 50 mm3, 100 L of saline solution

containing 1 wt% carriers was injected into the mice through the tail vein. IVIS Spectrum (Caliper

Life Science, USA) was used to investigate the fluorescence signals of animals (Cy5.5, Ex: 640 nm,

Em: 720 nm). To quantify the amount of DTX in tissue and organ-drug, 100L of saline solution

containing Ct-RBC@D/NS and Ct-RBC@GQD-D/NS was injected intravenously via the tail vein to

the tumor-bearing mice (total drug: 20 mg/kg). Then, at 24 h postinjection, six mice from each group

were sacrificed. Subsequently, tumor tissues and major organs were collected and washed by saline

and dried. Then, 200 g samples of tissues were added to 3 ml of diethyl ether containing 50 l of 1.0

g/ml diazepam and extracted for 10 min. Then, the organic phase was collected by centrifuged at

6,000g and dried for HPLC analysis.S2

Antitumor efficacy. The optical-fiber-coupled NIR irradiation with 808 nm of wavelength was

utilized for tumor therapy. Before NIR irradiation, 100 L of solution containing 1 wt% of Ct-

RBC@GQD-D/NS (6 mg/kg) was injected intravenously to nude mice. The identical approach was

applied for other treated and control groups. Then, at 24 h post injection, NIR irradiation (power

density: 1.5 W cm−2) was irradiated to the tumor for treated groups for 10 min. At various time points

of post irradiation, the tumor volumes were examined by using a digital caliper. The tumor volumes

were determined by (length of tumor) × (width of tumor)2/2, and the relative tumor volumes (V/ V0)

were defined by the ratios of initial tumor volume V0 and the resulting tumor volume V. For histology

analysis, the tumor and major organs were collected and fixed in 10 % formalin, processed into paraffin,

and sectioned into slices. After staining with hematoxylin and eosin (H&E), the slices were evaluated

by optical microscope.

Orthotopic intracranial tumor study. To evaluate the accumulation and penetration efficiency

of hybrids, 2 μL ALTS1C1 cells (5 ×  107/mL) were implanted and inoculated intracranially into 6-8

week-old C57BL/6J. After two weeks, the animals were injected intravenously with 100 µL of NS,

RBC@GQD-D/NS or Ct- RBC@GQD-D/NS at 0.5 mg/mL. After 24 h, the treated groups were

applied with 10 min NIR irradiation (power density: 1.5 W cm−2). After 24 and 72 h, all animals were

anesthetized, heart blood collected, and then sacrificed. Brains were embedded in O.C.T. and sectioned

with the thickness~10 μm at -20 °C, and put onto slides (Leica CM1510-3). The tissue slides were then

fixed in the -20 °C methanol for 5 min and washed by PBS. To avoid non-specific binding of antibodies,

the tissues were immersed in the blocking buffer containing 4% FBS, 1% GS in PBS for 1 h at room

temperature.

Biodistribution and survival rate with synergistic chemotherapy in vivo.  To evaluate the

biodistribution and survival rate with synergistic chemotherapy, 2 μL ALTS1C1 cells (5 ×  107/mL)

were implanted and inoculated subcutaneously into 6 week-old C57BL/6J. After 14 days of tumor

growth, the animals randomly grouped into four groups (n=6) were injected intravenously with 100

μL of solution containing with 0.5 wt% RBC@NS or Ct-RBC@NS labeled by CdSe quantum dots

intravenously. Quantitative determination of Cd in each organs and tumors by ICP‐MS. The survival

rates of all groups were recorded every day from the day of ALTS1C1 cells implantation.

Raman spectra provide further information on AGO, GQD and NS (Figure S1). G band (in-phase

sp2 bond vibration) at 1580 cm−1 was detected for graphite; the D band (disorder band of graphene

edge functional group) at 1350 cm−1 are characteristic of GO present. Two characteristic peaks were

observed in all the products expect SiO2, which was pyrolyzed in air. The relative peak ratio of G/D in

rGO is higher than that in NS, which is probably caused by the blocking effects of covering the rGO

with other elements (larger disorder).S3,S4 TGA analysis indicated that the weight ratio of organic (Ct

and RBC) and inorganic (GO, SiO2 and carbon layer) ratio is approximately 25 % (Figure S4).

 

 Figure S1. (a) Raman spectra of AGO, GQD and NS. (b) AFM topography images and the height

profile of GQDs.

 

 

Figure S2. (a) N2 adsorption–desorption isotherms of NS and GQD-D/NS. (b) Pore diameter

distribution of NS based on Barrett-Joyner-Halenda (BJH) analysis. (c) Pore diameter distribution of

NS when polystyrene was removed from the synthetic process.

 Figure S3. (a) SDS-PAGE of RBC membrane, RBCm@NS, and Ct-RBC@GQD-D/NS followed by

Coomassie staining. (b) Western blot analysis of RBC, RBCm@NS, Ct-RBC@D/NS and Ct for

characteristic RBC makers CD47.

0 4 8 12 16 200.0

0.1

0.2

0.3

0.4

0.5

Pore

vo

lum

e (c

m3 /g

)

Pore Diameter (nm)

0 4 8 12 16 20

0.00

0.05

0.10

0.15

0.20

Pore

vo

lum

e (c

m3 /g

)

Pore Diameter (nm)

(b) (c)

(a)SurfaceArea (m2/g)

Pore Size (nm) 

NS 130 12

GQD‐D/NS 64 2.2

Relative Pressure (P/P0)

Qua

ntity

ads

orbe

d (c

m3 /g

STP

)

0.0 0.5 1.00

100

200

300NSGQD-D/NS

Figure S4. (a-e) Confocal fluorescent microscopy images of RBC@NS, where the anti-Band 3 and

anti-glycophorin were used to label RBC@NS. NS was loaded with QDs with red fluorescence in

advance. (f) Fluorescence intensity of RBC@NS before and after florescence labelling protein.

Figure S5. (a) Confocal fluorescent microscopy images of either a mixture of Ct@NS and RBC@NS

or of Ct-RBC@NS (red = RBC membrane, green = Ct). (b) Thermogravimetric analysis (TGA)

analysis of NS, Ct@NS, RBC@NS and Ct-RBC@NS. (c) UV-vis absorption spectrum of the GQD

and Ct-RBC@GQD-D/NS.

Figure S6. Colloidal stability of NS and Ct-RBC@GQD-D/NS in (a) water, (b) DMEM + 10% FBS

(100g/mL) and (c) fresh homologous serum over one week.

 

Figure S7. HPLC (for doxetaxel, DTX) analysis of untreated and NIR irradiation treated drugs.

Time (days)

Size

(nm

)

1 2 3 4 5 6 7 80

200

400

600

800NSCt-RBC@GQD-D/NS

Time (days)

Size

(nm

)

1 2 3 4 5 6 7 80

200

400

600

800NSCt-RBC@GQD-D/NS

a b

Time (min)

Rel

ativ

e in

tens

ity

0 2 4 6 8 10

Figure S8. (a) TEM images of GQD/NS and (b) the size distribution of supernatant of GQD/NS after

NIR irradiation at 1.5 W cm-2 for 3 min. (c) TEM images of the released GQDs, Ct and RBCm from

Ct-RBC@GQD-D/NS. The yellow arrows indicated the GQDs. After the Ct-RBC@GQD-D/NS was

irradiated by NIR irradiation at 1.5 W cm-2 for 3 min, the released particles (suspension) was collected

by centrifugation at 4,000 rpm for 5 min. (d) Photoluminescence spectra of rhodamin-labeled GQDs.

(e) The size distribution of released GQDs from Ct-RBC@GQD-D/NS where the release particles

from collected suspension were treated by calcination at 800 oC in an inert gas atmosphere (N2).

Figure S9. (a) Drug release from RBC@GQD-D/NS after NIR irradiation. Free DTX and DTX

attached on GQD were detected by HPLC after separation. (b) DTX penetration effect mediated by

GQD in a tissue-like prosthesis (10 wt% collagen) when DTX released from RBC@D-GQD/NS.   

 

 

NS conctration (g/mL)

Cel

l via

bilit

y (%

)

1 2 5 10 200

50

100

150

NSGQD@NSRBC@GQD/NSCt-RBC@GQD/NS

Figure S10. Cell viability of A549 cells after 24 h incubation with various concentrations of NS,

GQD@NS, RBC@GQD/NS and Ct-RBC@GDD/NS.

Figure S11. Flow cytometry analysis of Ct-RBC@NS with various numbers of Ct in A549 cell lines

for 30 min of incubation.

Figure S12. Cellular uptake of (a) Ct-RBC@NS and (b) RBC@NS in A549 cells for 30 min. QD

possessing red fluorescence was monitored in many regions of cytoplasm (green) and nuclei (blue)

after 2 h of incubation with Ct-RBC@NS. Cellular uptake of (c) Ct-RBC@NS and (d) RBC@NS in

control RAW 264.7 cells, exhibiting the low accumulation of QDs.

Figure S13. Control experiment on A549 cells without treating by any particles.

 

Figure S14. Tumor spheroids on a chip. CLSM images of 3D tumor spheroids on a chip. The tumor

spheroid is about 200 m in diameter.

Figure S15. TEM image of RBC@GQD/NS treated by 1 min of NIR irradiation (1.5 W cm-2).

 

Figure S16. Tumor spheroids after incubation with cRGD-NS without and with treated by 20 sec of

NIR irradiation at 1.5 W/cm-2. (c) GQDs was incubated with Tumor spheroids for 24 h.

Figure S17. In vitro photothermo-chemo and photolytic therapy induced by NIR irradiation.

Fluorescence images of A549 tumor spheroids incubated with Ct-RBC@GQD-D/NS for (a) 0, (b) 2,

(c) 4 and (d) 10 min of NIR irradiations (1.5 W cm-2).

Figure S18. Main clearance organs and tumors from mice 24 h post injection of NS, PEG@NS and

Ct-RBC@NS.

Figure S19. (a) Biodistribution of Ct-RBC@NS and RBC@NS at 24 h and 48 h post-injection. (b)The

PTX concentration in mice receiving Ct-RBC@D/NS and Ct-RBC@GQD-D/NS in tissues at 24 h

postinjection (n = 5). (c) Blood-circulation curves of NS, RBC@NS and Ct-RBC@NS in mice at

different time points post injection. (d) Biodistribution of Ct-RBC@NS and RBC@NS at 7 d and 14

d post-injection.

Figure S20. (a) Biodistribution of Ct @NS at 24 h and 48 h post-injection. (b) The fluorescence image

of tumor after the mice treated by Ct @NS at 24 h post-injection. Blood vessels labeled with CD 31

appear in green, and nuclei are represented in blue.

Figure S21. Tumor growth profiles of the A549-bearing mice after being treated with saline and

saline+NIR (1.5 W/cm -2+; 10 min of irradiation) (n=5).

Figure S22. (a) Tumor growth profiles of Ct-RBC@GQD/NS+NIR, Ct-RBC@GQD-D/NS, Ct-

RBC@D/NS+NIR, RBC@GQD-D/NS+NIR and Ct-RBC@GQD-D/NS+NIR for 56 days (n=5, mean

± s.d.). (b) The images of tumor bearing nude mice after treating by Ct-RBC@GQD/NS+NIR, Ct-

RBC@GQD-D/NS, Ct-RBC@D/NS+NIR, RBC@GQD-D/NS+NIR and Ct-RBC@GQD-D/NS+NIR.

Rel

ativ

e Tu

mo

r V

olu

me

(V/V

0)

 Figure S23. H&E-stained slices of clearance organs. The mice were sacrificed at 1-day post-NIR

irradiation.

Figure S24. Liver and (b) kidney function levels (alanine aminotransferase (ALT), alkaline

phosphatase (ALP), blood urea nitrogen (BUN) and serum creatinine (CRE)) after treating with PBS,

DTX and Ct-RBC@GQD-D/NS (7.5 mg/kg).

 

 

Figure S25. Animal study of RVG-hybrids in an ALTS1C1 orthotopic brain tumor-bearing C57B6/L

mouse model. (a) H&E staining of ALTS1C1 orthotopic brain tumor. (b) IVIS images of brains at 24

h postinjection after treatment with Cy5.5-labeled NS, RBC@GQD-D/NS, and Ct-RBC@GQD-D/NS

at 24 h postinjection. (c) Quantification of NS, RBC@GQD-D/NS, and Ct- RBC@GQD-D/NS. (d)

Liver function (ALT (alanine aminotransferase) and ALP (alkaline phosphatase)), and (e) kidney

function (BUN (blood urea nitrogen) and CRE (serum creatinine)) after treatment with NS,

RBC@GQD-D/NS, and Ct-RBC@GQD-D/NS (n=5) at 72 h postinjection in an ALTS1C1 orthotopic

brain tumor-bearing C57B6/L mouse model. (f) Survival curve profiles of ALTS1C1 tumor-bearing

C57B6/L mice after treatment with PBS, GQD-D/NS, RBC@GQD-D/NS, Ct-RBC@GQD-D/NS, and

Ct-RBC@GQD-D/NS (n=6).

Figure S26. The fluorescence images of tumors to evaluate the particles by immunohistochemistry

(IHC); the GQDs are shown in red, blood vessels labeled with CD 31 appear in green, and nuclei are

represented in blue.

 Figure S27. (a) Biodistribution of Ct-RBC@NS and RBC@NS at 24 h and 48 h post-injection in an

ALTS1C1 tumor-bearing C57B6/L mouse model. (b) Blood-circulation curves of NS, RBC@NS and

Ct-RBC@NS in mice at different time points postinjection.

 

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