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Metabolizable Small Gold Nanorods: Size-dependent Cytotoxicity, Cell Uptake and In Vivo Biodistribution Zhibin Li, Siying Tang, Bei-Ke Wang, Yong Li, Hao Huang, Huaiyu Wang, Penghui Li, Chengzhang Li, Paul K Chu, and Xuefeng Yu ACS Biomater. Sci. Eng., Just Accepted Manuscript • DOI: 10.1021/acsbiomaterials.5b00538 • Publication Date (Web): 25 Mar 2016 Downloaded from http://pubs.acs.org on April 1, 2016

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ACS Biomaterials Science & Engineering

Metabolizable Small Gold Nanorods: Size-dependent Cytotoxicity, Cell Uptake and In Vivo Biodistribution

Zhibin Li †, #, Siying Tang †, #, Beike Wang ‡, #, Yong Li †, Hao Huang †, Huaiyu Wang†,*, Penghui Li †, §, Chengzhang Li ‡,*, Paul K. Chu §,*, Xue-Feng Yu †

†

Institute of Biomedicine and Biotechnology, Shenzhen Institutes of Advanced

Technology, Chinese Academy of Sciences, Shenzhen 518055, Guangdong, P. R. China ‡

School and Hospital of Stomatology, Wuhan University, Wuhan 430079, Hubei, P. R.

China §

Department of Physics and Materials Science, City University of Hong Kong, Tat

Chee Avenue, Kowloon, Hong Kong #

These authors contributed equally to this work.

Keywords: gold nanorods, size effect, in vivo clearance, photothermal therapy, biodistrubution

EMAIL ADDRESS OF CORRESPONDING AUTHORS Corresponding Authors *E-mail addresses: [email protected] (H. Y. Wang), [email protected] (C. Li), [email protected] (P. K. Chu)

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Abstract Gold nanorods (AuNRs) with unique plasmonic properties in the near infrared region have promising biomedical applications but suffer from poor in vivo clearance due to the large size.

In this study, small AuNRs with a diameter of 7 nm (designated as

sAuNRs) are found to have low toxicity and high clearance rates in vivo. Compared to common AuNRs with a diameter of 14 nm (designated as bAuNRs), sAuNRs exhibit similar surface plasmon resonance bands and photothermal efficiency as bAuNRs but have lower cytotoxicity as well as higher cell uptake.

The in vivo

biodistribution study indicates that only 0.68% of the intravenously injected sAuNRs remain in the body after 30 days, but the residual amount in the body after injection of bAuNRs is as high as 12.3%.

The results demonstrate that the smaller AuNRs

having lower toxicity and increased clearance in vivo have large clinical potential.

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■ INTRODUCTION Nanomaterials have aroused interests in medical research due to their special properties enabling long-term in vivo imaging, treatment of cancer, and shedding light in the complex cellular environment.1

In particular, gold nanorods (AuNRs) have

good biocompatibility, are easily synthesized, and possess unique plasmonic properties.2

Generally, AuNRs are synthesized by the seed-mediated method

utilizing cetyltrimethylammonium bromide (CTAB) as the surfactant.3-5

Using this

method, the longitudinal surface plasmon resonance (LSPR) peak wavelength of the AuNRs in the near infrared (NIR) spectral region (preferred window for biomedical applications) can be tailored by adjusting the aspect ratio of the AuNRs.6 In addition, the extinction coefficient of AuNRs is an order of magnitude larger than those of other gold nanoparticles like gold nanospheres and nanoshells.7

Hence, AuNRs are

promising biomaterials especially pertaining to in vivo imaging,8-11 tumor photothermal therapy,12-15 disease diagnosis,16-19 drug and gene delivery,20-23 and laser welding.24,25 The ideal agents in diagnosis and therapy should be harmless and completely cleared from the human body within a reasonable period.26

In general, clearance via

the liver and kidney is the dominant mechanism but the effectiveness depends on the size of nanomaterials. Nanoparticles smaller than 10 nm can be cleared rapidly by renal clearance,27-29 but those 10–50 nm in size are absorbed and extracted by the reticuloendothelial system (RES, e.g. liver, spleen).30-32

If the nanoparticles are

larger than 50 nm, they can only be partially cleared by the liver.33,34

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AuNRs


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produced by the seed-mediated technique typically are 14~15 nm in diameter and more than 50 nm in length.3-5

Correspondingly, their hydrodynamic size is often

larger than 50 nm19 and clearance from the body in vivo is inadequate.

Furthermore,

although the surface-dependent cytotoxicity of AuNRs can be improved by replacing or covering the CTAB layer with polyethylene glycol, phospholipids, silica shells, and proteins,35-40 the size-dependent toxicological issues of AuNRs are still controversial. Herein, in order to lower the risks of AuNRs in biomedical applications, a seedless synthetic technique to prepare AuNRs as small as 7 nm in diameter (designated as sAuNRs) with a high yield is described.

The sAuNRs exhibit good

dispersibility and tailored LSPR band in the NIR region.

The sAuNRs are compared

to the common AuNRs with a diameter of 14 nm (designated as bAuNRs) from the perspectives of SPR bands, photothermal properties, cytotoxicity, cellular uptake, as well as clearance in vivo and the results indicate that the sAuNRs are better than bAuNRs in clinical applications.

■ MATERIALS AND METHODS Materials.

Chloroauric acid (HAuCl4·4H2O, 99.99%), silver nitrate (AgNO3,

99.8%), L-ascorbic acid (AA, 99.7%), sodium oleate (NaOL), and hydrochloric acid (HCl, 36-38%) were purchased from Sinopharm Chemical Reagent Co. Ltd. (Shanghai, China). Sodium borohydride (NaBH4, 96%), were obtained from Aldrich (America) and CTAB was purchased from Amresco Inc. (America).

Dulbecco’s

Modified Eagle medium (DMEM) and fetal bovine serum (FBS) were purchased from

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Gibco BRL.

MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide)

and bovine serum albumin (BSA) were obtained from Sigma corporation (America). Annexin V-FITC/PI cell apoptosis detection kit was purchased from TransGen Biotech Co., Ltd.

All the chemicals were used as received without purification.

Ultrapure water with a resistivity of about 18.25 MΩ. cm was used as the solvent in all the experiments. Seed-mediated Synthesis of bAuNRs.

The bAuNRs were synthesized by the

seed-mediated method in CTAB solutions as reported previously.3,19 Briefly, gold seed solution was obtained by quickly injecting 620 µL of the ice-cold and freshly prepared NaBH4 (10 mM) into the mixture of 5 mL of HAuCl4 (0.5 mM) and 5 mL of CTAB (0.2 M).

The solution was under vigorous stirring for 2 min and then left for

more than 2 h before use.

Subsequently, 50 µL of the prepared seed solution was

rapidly added into the growth solution containing HAuCl4 (5 mM, 6 mL), AgNO3 (0.1 M, 50 µL), CTAB (0.2 M, 30 mL), HCl (1.2 M, 50 µL) and L-ascorbic acid (10 mM, 3.5 mL), then the mixture was gently stirred and left undisturbed overnight.

After a

centrifugation at 10,000 rpm for 10 min, the supernatant was removed and the precipitate obtained was resuspended in ultrapure water. Seedless Synthesis of sAuNRs.

The sAuNRs with a smaller diameter were

synthesized by an improved seedless method.41

In particular, 500 µL of NaOL (0.1

M), 250 µL of AgNO3 (4 mM), 8 µL of concentrated HCl, 1 mL of HAuCl4 (5 mM), 4.5 mL of CTAB (0.2 M), and 4.5 mL of ultrapure water were mixed in a 50 mL tube, and 56 µL of L-ascorbic acid (0.1 M) was added into the mixture subsequently.

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After the addition of L-ascorbic acid, the mixture changed to colourless with a reduction of Au3+ to Au+.

Afterwards, 15 µL of the freshly prepared NaBH4 (10 mM)

was injected into the solution and the reaction was left undisturbed for 3 h at 35 oC. After a centrifugation at 16,000 rpm for 15 min, the supernatant was removed and the precipitate was resuspended in ultrapure water.

In this method, the length of the

sAuNRs could be readily adjusted by altering the amounts of NaOL. Surface Modification of AuNRs with Oleate (Oleate-AuNRs). NaOL was used to replace CTAB on the AuNRs by a method described previously.42

In brief, 100

µL of NaOL solution (0.1 M) was added into 1 mL of AuNR solution by stirring for 1 h at 85 oC.

The AuNRs precipitate with NaOL coating was collected by

centrifugation, then resuspended in 1 mL of ultrapure water. Surface Modification of AuNRs with BSA (BSA-AuNRs). BSA was used to modify the surface of the AuNRs involving the method described by Moustafa et al.37 Particularly, 1 mL of the BSA solution (0.25 mM) prepared by phosphate-buffered saline (PBS: 150 mM NaCl, 1.9 mM NaH2PO4, 8.1 mM Na2HPO4, pH 7.4) was added into 10 mL of the AuNRs solution under vigorous stirring to keep the reaction at room temperature for 8 h.

Afterwards, excess BSA was removed by centrifugation and the

precipitate was resuspended in ultrapure water. Characterization.

Transmission electron microscopy (TEM) was performed on a

JEOL 2010 (HT) transmission electron microscopy at an accelerating voltage of 200 kV.

The samples were prepared by placing drops of the AuNRs solutions on

carbon-coated TEM copper grids.

The absorption spectra were acquired on a

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Lambda 750 UVNIS/NIR spectrometer (PerkinElmer, USA), the zeta potentials and hydrodynamic diameters were measured on the Zeta potential measurement analyzer (Malvern Instruments Ltd.). Cellular Toxicity Assay.

The hepatic stellate cells (HSC, normal cells) and

hepatocellular carcinoma cells (HepG2, cancer cells) obtained from the Animal Center of Sun Yat-Sen University were cultured in a DMEM medium supplemented with 10% (v/v) fetal bovine serum (Gibco), 100 U/mL penicillin, and 100 U/mL streptomycin in a humidified atmosphere of 5% CO2 at 37 °C. To determine the cell cytotoxicity/viability, the cells were cultured on a 96-well plate at a density of 1 × 104 cells/well for 12h, then the medium was replaced with 200 µL of cuture medium containing 5 µg Au of the bAuNRs or sAuNRs (modified by CTAB, oleate or BSA, respectively).

Each sample was performed in

quintuplicate and the bAuNRs or sAuNRs samples were co-cultured with cells for 6, 12, 24, and 48 h.

The cell viability was assayed by adding 20 µL of 5 mg/mL MTT

to the PBS solution in each well and then incubated at 37 oC for 4 h to allow formazan formation.

The formazan crystals were dissolved in dimethyl sulfoxide and the

absorbance correlatable with the number of viable cells was measured on a Thermo Reader at 490 nm.

The following formula was used to calculate the conditions of

cell growth: Rate of cell viability (%) = (mean of Abs. value of treatment group/mean Abs. value of control) × 100%.

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Cell Apoptosis and Necrosis Assay. 1 × 105 of HSC cells or HepG2 cells were incubated with 50 µg Au/mL BSA-bAuNRs or BSA-sAuNRs, respectively.

After 12

h, the cells were rinsed thrice with PBS and the apoptotic cells an necrotic cells were analyzed by double staining using the annexin V-FITC (fluorescein isothiocyanate) and propidium iodide (PI) Kit (annexin V-FITC labeled apoptotic cells while PI labeled necrotic cells).

The stained cells were analyzed by a cell Lab Quanta SC

flow cytometry (Beckman coulter, USA) immediately. Cell Uptake Experiments. To measure the intracelluar concentration of AuNRs, 1 × 105 of HSC cells or HepG2 cells were plated on a 24-well plate and incubated with a culture media containing 50 µg Au/mL BSA-bAuNRs or BSA-sAuNRs for 6 h, repsectively.

Subsequently, the HSC and HepG2 cells were rinsed thrice with PBS

to remove the AuNRs on the outer membrane, then the cells were trypsinized and dispersed into 1 mL of the culture medium.

The cells were collected by

centrifugation and soaked in aqua fortis (nitric acid: hydrochloric acid 3:1) overnight. The suspension was heated to about 140 oC to get rid of nitrogen oxides until the solution was colorless and clear.43

The residue was added with 5 mL of an aqueous

solution containing 2% nitric acid and 1% hydrogen chloride and the total cellular gold content was determined by inductively-coupled plasma atomic emission spectroscopy (ICP-OES, 7000DV, PerkinElmer). Determination of Au Concentration in Tissues by ICP-OES.

The

BSA-bAuNRs and BSA-sAuNRs were injected into Balb/c mice (5 mg Au/kg) via the tail vein, respectively. After 1, 5, 10, 15, and 30 days, the mice (a total of 40 mice,

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and 4 mice per group) were euthanized and the tissues were excised, weighed, and digested in aqua fortis (nitric acid: hydrochloric acid 3:1), then the homogenized tissue lysates were heated to about 140 oC to get rid of nitrogen oxides until the solution was colorless and clear.

The residue was diluted in 10 mL of an aqueous

solution containing 2% nitric acid and 1% hydrogen chloride, filtered, and the Au contents were determined by ICP-OES (7000DV, PerkinElmer). Statistical Analysis. The values were presented as mean or mean ± standard deviation (SD).

All the experiments were performed at least three times with data

from a typical experiment shown.

The one-way analysis of variance (ANOVA)

combined with the Bonferroni’s post-test was utilized to determine the level of significance with p < 0.05 considered to be significantly different.

■ RESULTS AND DISCUSSION Synthesis and Characterization of AuNRs.

The bAuNRs are commonly

synthesized by the seed-mediated growth technique involving two steps.3,19

As

shown in Figure 1a, the seed solution is first generated under chemical supersaturation to facilitate quick nucleation and in the two-step process using CTAB as the surfactant, reduction (Au3+→Au+) is first conducted with ascorbic acid followed by a second reduction step (Au+→Au0) which requires the presence of seeds to increase the reducing capability of ascorbic acid (a weak reducing agent).

After reacting for

12 h, the bAuNRs with a diameter of about 14 nm are obtained.

In comparison, the

sAuNRs with a smaller diameter are synthesized by the improved “one-pot” seedless

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strategy.41 As shown in Figure 1b, nucleation and growth occur in the same solution. NaOL, the sodium salt of a long-chain unsaturated fatty acid, is used to form CTAB-NaOL which can reduce HAuCl4 sufficiently in the presence of ascorbic acid due to the strong reducing ability of the double bonds.

Afterwards, NaBH4, a strong

reducing agent is introduced to reduce Au+ to Au0 in the absence of seeds. the sAuNRs with a diameter of about 7 nm are synthesized.

After 3 h,

Figure 2 depicts the

representative TEM image of the sAuNRs revealing high product yield and that the seedless method is an efficient strategy to produce the sAuNRs. By using different amounts of NaOL in the seedless method, the length of the sAuNRs and LSPR band in the NIR region can be adjusted as shown in Figure 3. When 500 µL of NaOL are introduced, the sAuNRs have dimensions of (30±5 nm) × (7±1 nm) with an aspect ratio of ~4.1 and the LSPR peak is at 800 nm (Figure 3b). When the volume of NaOL is reduced to 100 µL, the sAuNRs have dimensions of (35±5 nm) × (7±1 nm) with an aspect ratio of ~5 and LSPR peak appears at 866 nm (Figure 3a).

On the contrary, if the NaOL volume is increased to 900 µL, the

dimensions of the sAuNRs are (20±3 nm) × (7±1 nm), aspect ratio is ~3, and LSPR peak position is 716 nm (Figure 3c).

Hence, the length of the sAuNRs depends on

the quantity of NaOL amount but the diameter does not change.

It should be noted

that AuNRs with a smaller diameter can also be synthesized but they are difficult to centrifuge. The sAuNRs with dimensions of (30±5 nm) × (7±1 nm) and LSPR band location at 800 nm are chosen in our subsequent experiments.

To explore the size-dependent

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effect, bAuNRs with dimensions of (56±8 nm) × (14±2 nm) serve as the control.

As

shown in Figure 4, although the diameter of the bAuNRs is twice that of the sAuNRs, the aspect ratio (~4.0) and LSPR peak wavelength (~800 nm) are similar.

Figure S1

in Supporting Information indicates that the photothermal conversion efficiency of the bAuNRs is also similar to that of the sAuNRs (21%) under 800 nm NIR light irradiation. The cytotoxicity of AuNRs generally originates from the CTAB surfactant on the surface.

Here, two kinds of molecules are used to modify the surface of the bAuNRs

and sAuNRs to explore the size-dependent cytotoxicity of AuNRs without CTAB. To obtain oleate-AuNRs, the original CTAB-AuNRs react with NaOL according to the surfactant exchange method reported recently.42

The CTAB bond on the

nanorod surface is almost totally replaced by oleate via surfactant exchange resulting in a small blue shift in the LSPR peaks (see Figure 4b).

Correspondingly, the zeta

potential changes from +39 to -56 mV on the bAuNRs and from +30 to -61 mV on the sAuNRs.

To obtain BSA-AuNRs, the original CTAB-AuNRs react with BSA by the

conjugation method described by Moustafa et al..37 Conjugation of BSA molecules onto the AuNRs surface7,37 leads to a slight red shift and broadening of the LSPR peaks (see Figure 4b). Correspondingly, the zeta potential changes from +39 to -25 mV on the bAuNRs and from +30 to -22 mV on the sAuNRs.

When nanoparticles

functionate in vivo, the proteins in physiological environment probably adhere to the surface of nanoparticles, and thus increasing the size of nanoparticles to affect their pharmacokinetics.

In this respect, BSA-bAuNRs and BSA-sAuNRs are further

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determined for their hydrodynamic diameter distributions after incubating in distilled water, culture medium and serum for 4 h, respectively.

Figure S2 in Supporting

Information indicates that the average hydrodynamic diameter of BSA-bAuNRs increases from 90 nm in water to 122 nm in serum, and that of BSA-sAuNRs increases from 32 nm in water to 37 nm in serum.

Evidently, the bAuNRs and

sAuNRs conjugated by BSA are dimensionally stable and have a good dispersion even in the complicated physiological environment. Cytotoxicity Investigation. To investigate the cytotoxicity of sAuNRs, MTT assay is employed and bAuNRs or sAuNRs (modified by CTAB, oleate or BSA, respectively) with the same Au concentration are determined by incubating them with HSC normal cells and HepG2 cancer cells for 6, 12, 24, and 48 h. the absence of AuNRs are considered to have 100% viability.

Cells cultured in

Figure 5 indicates that

the CTAB-bAuNRs have higher cytotoxicity than the CTAB-sAuNRs.

The viability

of HSC and HepG2 cancer cells on the former drops from (62.4±3.1)% and (74.6±3.4)% to (34.2±3.2)% and (48.7±3.3)% with the incubation time increasing from 6 to 48 h.

In contrast, the viability of HSC cells on the latter is as high as

(95.5±3.1)% after 6 h and more than 80% after 48 h.

Meanwhile, the viability of

HepG2 cancer cells on CTAB-sAuNRs changes from (91.8±3)% to (67.4±3.6)% when the incubation time is prolonged from 6 to 48 h.

There are many factors such

as size, aspect ratio and surface chemistry can affect the cytotoxicity of AuNRs.43-45 In particular, the surface-dependent cytotoxicity of AuNRs has been well studied previously, and it is acknowledged that the common method for AuNRs synthesis

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involves CTAB which is toxic to cells.44,45

By replacing or covering CTAB layer

with other biomolecules, the biocompatibility of AuNRs can be significantly improved.35-40 It is clear from Figure 5 that the cell viability of both CTAB-bAuNRs and CTAB-sAuNRs can be improved by the surface modification with oleate or BSA. After incubation for 48 h, the viability of HSC and HepG2 cells is (53.2±3.3)% and (51.4±2.9)% on the oleate-bAuNRs and (87.3±3.5)% and (81.2±3.1)% on the oleate-sAuNRs, respectively.

On the other hand, the viability of HSC and HepG2

cells on the BSA-bAuNRs is (57.2±3.4)% and (52.3±3.2)% and that on the BSA-sAuNRs is (91.9±3.5)% and (84.7±3.2)%, respectively.

To some extent, BSA

replacement is better than the oleate modification with regard to the cell viability of AuNRs.

In addition, the smaller sAuNRs have lower cytotoxicity than the bigger

bAuNRs after the same surface modification and by adjusting the nanorod diameter, the cytotoxicity of the AuNRs can be modified.

Noteworthily, Tatini, F. et al.46 have

reported that AuNRs with a diameter of

Metabolizable Small Gold Nanorods - ACS Publications - American

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