Highly Efficient and Controllable PEGylation of Gold Nanoparticles

ARTICLE pubs.acs.org/JPCC

Highly Efficient and Controllable PEGylation of Gold Nanoparticles Prepared by Femtosecond Laser Ablation in Water Wei Qian,* Makoto Murakami, Yuki Ichikawa, and Yong Che IMRA America, Inc., 1044 Woodridge Avenue, Ann Arbor, Michigan 48105, United States

bS Supporting Information ABSTRACT: This paper demonstrates a new method for fabrication of stable gold nanoparticle poly(ethylene glycol) (PEG) conjugates bearing a defined number of one or multiple types of PEG molecules. The PEG molecules are directly bound to the surface of gold nanoparticles with almost 100% conjugation efficiency, and the PEG surface coverage is tunable to be any percent value between 0 and 100%. The method comprises preparation of a colloidal suspension of naturally negative charged pure gold nanoparticles with a bare surface via a novel approach of femtosecond laser ablation of gold bulk target in deionized water first, and then the surface modification with PEG is carried out by adding PEG molecules containing thiol groups. It is revealed that because of their unique bare surface very efficient and controlled conjugation of PEG molecules to these gold nanoparticles could be achieved. The PEGylation process described in this paper just serves as one example to testify that the bare surface of gold nanoparticles provides significant benefits for their further surface modifications. The discussed strategies are of a general nature and could be readily applied in the same way to construct a mixed monolayer composed of other biologically important molecules onto the surface of a gold nanoparticle to form a multifunctional composite nanoparticle for offering improved performance in biomedical applications.

’ INTRODUCTION It is well accepted by scientists across the world that nanoparticles possess unprecedented potential for both ultrasensitive detection of diseases and subsequent treatment with high efficacy via targeted drug delivery.1 5 Over the past decade, gold nanoparticles have been attracting increasingly widespread interest and are emerging as the most important candidates in a wide variety of biomedical applications. For example, potential uses include biological imaging and detection,6,7 gene regulation,8 drug delivery vectors,9,10 and diagnostic or therapeutic agents for treatment of cancer in humans.11,12 The versatility of gold nanoparticles in a broad range of applications stems from several of their appealing properties, such as: (i) well-established methods for the synthesis and the ability to finely control size and shape; (ii) size- and shape-dependent strong optical absorption and scattering capable of tuning throughout the visible and nearinfrared (NIR) region; and (iii) little or no long-term toxicity in vivo allowing their high acceptance level in living systems. For most practical biomedical applications of gold nanoparticles, chemical stability in a biological medium, biocompatibility, and targeting efficacy are the key requirements. Surface modifications are essential for meeting these requirements since interactions of gold nanoparticles with complex biological environments and biomolecules both on the surface of and inside the cells highly depend on the chemical nature of their solventaccessible surface.13 Although various strategies for modification of the gold nanoparticle surface have been established, including additional coating, ligand modification, and ligand exchange, r 2011 American Chemical Society

after 10 years of extensive studies, the synthesis of functionalized gold nanoparticles still presents a major challenge, especially in the case that it is desired to conjugate a defined number of one or multiple types of biomolecules onto the surface of individual gold nanoparticles. In the present study, using functionalization with poly(ethylene glycol) (PEG) as an example, we address this challenge by demonstrating highly efficient and controllable surface modification of naturally negative charged gold nanoparticles with clean surface fabricated by femtosecond laser ablation of gold target in deionized water. Herein, PEG was chosen as a model molecule for the experiment because it is a very widely studied molecule, its interaction with gold nanoparticles is well-known, and it is widely used to optimize the surface properties and functionalities of gold nanoparticles. For instance, a layer of PEG on the surface of gold nanoparticles enhances their solubility and stability under physiological conditions by providing a steric barrier. Also, PEG molecules bound to the gold nanoparticles confer them a hydrophilic surface which prolongs their systemic blood circulation time after intravenous injection via preventing them from being recognized by the reticulo-endothelial system (RES) organs (mostly liver and spleen). Moreover, when heterobifunctional PEG derivatives having amine or carboxyl groups at the distal end are incorporated onto the surface of gold nanoparticles, these Received: August 18, 2011 Revised: October 15, 2011 Published: October 19, 2011 23293

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The Journal of Physical Chemistry C functional groups enable additional covalent surface modification via conventional carbodiimide coupling chemistry, which provides a route to further functionalization of these nanoparticles. As clarified in the following, the basis of the observed remarkable improvement in the efficiency and controllability of surface modification is the resulting bare surface of gold nanoparticles produced by the physical approach of femtosecond laser ablation of target in aqueous solution. Given the prominent importance of surface modification of gold nanoparticles in terms of their biomedical applications, our current work represents a significant step forward in the ongoing effort to develop innovative gold nanoparticle-based effective diagnostic and therapeutic agents. Pulsed laser ablation of a metal target immersed in a liquid has been used to fabricate colloidal metallic nanoparticles for many years.14,15 In contrast to the chemical procedures, this method offers the possibility of generating stable nanocolloids while avoiding chemical precursors, reducing agents, and stabilizing ligands, which would be problematic for the subsequent functionalization and stabilization of nanoparticles. Therefore, since it was pioneered by Henglein and Fojtik14 for preparation of nanosized particles in either organic solvents or aqueous solutions as well as by Cotton15 for preparation of water-borne surface-enhanced Raman scattering active metallic nanoparticles with bare surface in 1993, the application of pulsed laser ablation of metal targets in liquid has gained much interest, especially after the advent of the femtosecond laser, which is capable of eliminating some problems associated with the use of a nanosecond laser.16 Compared to laser ablation with pulses of longer duration (e.g., nanoseconds), the irradiation of metal targets by femtosecond laser pulses offers a precise laser-induced breakdown threshold and can effectively minimize the heat-affected zones since femtosecond laser pulses release energy to electrons in the target on a time scale much faster than electron phonon thermalization processes.17 20 Characterized by its simplicity of the procedure, versatility with respect to metals or solvents, and the nanoparticle growth in a controllable, contamination-free environment, pulsed laser-induced ablation from solid targets has evolved as a reliable alternative to chemical methods for obtaining colloidal metallic nanoparticles.21 25

’ EXPERIMENTAL SECTION The production of colloidal dispersion of metal nanoparticles with a narrow size distribution by laser ablation is still a great challenge as there is no separation between the nucleation and nanoparticle growth. Recent papers provided experimental evidence that femtosecond laser irradiation with low pulse energy near the ablation threshold led to much more satisfactory control over nanoparticle size and size distribution.26,27 In light of these reports, a commercially available Ytterbium-doped femtosecond fiber laser (FCPA μJewel D-1000, IMRA America) operating at 1.045 μm with a high repetition rate (up to megahertz level) and moderate microjoule (μJ) pulse energy was used in the present study for nanoparticle generation and offers a couple of advantages. For instance, on one hand, tightly focused μJ femtosecond pulses are intense enough for carrying out laser ablation of most materials at near-threshold fluences that enables efficient control of the sizes and size distribution of the generated nanoparticles. On the other hand, the very slow production rate associated with low laser fluence is compensated by a high pulse repetition rate.

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Figure 1. Extinction spectrum and TEM image of laser-generated gold nanoparticles prepared by femtosecond laser ablation of gold in deionized water. The scale bar in the TEM image denotes 200 nm.

In this paper, PEGylation was performed with two samples of colloidal gold nanoparticles. The first sample (abbreviated as laser-generated gold nanoparticle) was synthesized using laser ablation with the following laser parameters. Femtosecond pulses delivered from the above-stated laser system at a repetition rate of 100 kHz with 10 μJ pulse energy and 700 fs pulse width centered at a wavelength of 1.045 μm were focused onto a spot size of about 50 μm on a gold metal plate (99.99% purity), which was placed on the bottom of a glass vessel filled with 20 mL of deionized water (18 MΩ cm). The representative extinction spectrum and transmission electron microscopy (TEM) image of the laser-generated gold nanoparticle are shown in Figure 1. The extinction spectrum was characterized by the presence of a peak around 520 nm due to the localized surface plasmon resonance (LSPR), and the spectral feature below 450 nm reflects gold intraband transitions since this sample was prepared in deionized water without involving any chemical components except the gold target itself. The average diameter of gold nanoparticles was determined to be 20 nm by evaluating more than 500 nanoparticles. The second sample (abbreviated as chemically generated gold nanoparticle) was purchased from Ted Pella (Redding, CA) and was prepared via the standard sodium citrate reduction of tetrachloroaurate (HAuCl4) methodology. For comparison purposes, the diameter of chemically generated gold nanoparticles was also selected to be 20 nm. The colloidal stability of gold nanoparticles produced by both sodium citrate reduction of HAuCl4 and pulsed laser ablation of gold target are maintained by the negative charges on the surface of the nanoparticles. Here, it is worth emphasizing that the origin of these negative charges is different. The negative charge in the former case is due to capping material of citrate ions. Once citrate molecules detach from the surface of gold nanoparticles, suspension stability lowers, and the gold nanoparticles show signs of aggregation. On the contrary, because of being partially oxidized by the oxygen present in solution and followed by proton transfer to adjacent hydroxide ions, gold nanoparticles generated by pulsed laser ablation are naturally negatively charged.23 Therefore, additional chemical agents are not required to stabilize these chemically pure gold nanoparticles against aggregation. Because of the strong Au thiol bond (197.4 kJ/mol),28 which provides a strong anchoring that minimizes desorption of chemical species, the preferred strategy of PEG modification (PEGylation) is to covalently attach PEG chains directly on the surface of gold nanoparticles through the use of thiol-terminated PEG. The molecular weight of PEG used in our experiment is 20k, which was selected based on a recent observation that PEG molecules with higher molecular weight are rather beneficial for effectively 23294

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Figure 3. Colloidal stability of gold nanoparticles during surface modification with thiolated PEG characterized by monitoring the change of the absorbance of the localized surface plasmon resonance of gold nanocolloids at 520 nm. A schematic diagram shown on the top illustrates controllable PEGylation with surface coverage from 0 to 100% and the presence of excess nonconjugated free PEG in solution.

Figure 2. UV vis absorption spectra of (a) laser-generated gold nanoparticles and (b) chemically generated gold nanoparticles after mixing with various amounts of thiolated PEG 20k for 48 h.

slowing uptake of the nanoparticles in the RES organ.29,30 The two samples of colloidal gold nanoparticles were prepared with a final concentration of 1 nM as determined by correlating their measured extinction spectra to the experimentally determined extinction cross-section data (8.8  108 M 1 cm 1 for gold nanoparticle with diameter of 20 nm31). The PEGylation of gold nanoparticles was carried out by adding different amounts of thiolated PEG 20k into gold nanocolloids with the final molar ratio of PEG/gold nanoparticles ranging from 0 to 4000:1. After mixing, the solution was kept undisturbed at room temperature for 48 h to give enough time for PEG molecules to be conjugated by formation of Au thiol bonds. Then, the suspension stability of gold nanocolloids with a different input molar ratio of PEG to gold nanoparticles was quantified with UV visible absorption analyses since aggregation and/or precipitation of gold nanoparticles will be reflected by the decrease of the absorption around 520 nm.

’ RESULTS AND DISCUSSION The binding of thiolated PEG 20k to the surface of both lasergenerated gold nanoparticles and chemically generated gold nanoparticles was confirmed with FT-IR spectroscopy. As displayed in Figure S1 (Supporting Information), the FT-IR spectra of the PEGylated laser-generated gold nanoparticle and chemically generated gold nanoparticle with the molar ratio of PEG/Au nanoparticles being 300:1 and 2000:1, respectively, show all characteristic peaks for thiolated PEG 20k (dashed lines). The laser-generated and chemically generated gold nanoparticles were each mixed with various amounts of thiolated PEG 20k for 48 h, and the results are shown in Figures 2a and 2b. The results displayed in the Figure 2a and 2b are summarized in Figure 3, where the absorbance of PEGylated Au nanoparticles with a

different molar ratio of PEG/Au nanoparticle at 520 nm is expressed as a percentage of that of the control Au nanocolloid without adding PEG. The difference between two sets of data is very obvious. For the chemically generated gold nanoparticle, the absorbance at 520 nm varies depending on the molar ratio of PEG/Au nanoparticles. The absorbance at 520 nm decreases first as the ratio increases (with absorbance at 520 nm dropping to 0% when ratio is 200) and then recovers to 100% of that of the control sample as the ratio of PEG to gold nanoparticles goes over 2000. In contrast, for the laser-generated gold nanoparticles, a surprise finding in our experiment is that the absorbance at 520 nm does not change as compared with that of the control sample after mixing with thiolated PEG 20k with a molar ratio of PEG/Au nanoparticles varying between 10 and 4000 for 48 h. The lack of any detectable decrease and red shift of LSPR around 520 nm in all spectra reveals the superior colloidal stability of laser-generated Au nanoparticles during the PEGylation, which permits versatile and controllable functionalization using PEG molecules with tunable surface coverage from 0 to 100%. The zeta potential of laser-generated colloidal gold nanoparticles after mixing with various amounts of thiolated PEG 20k (the molar ratio of PEG molecules to gold nanoparticles ranging from 0 to 4000) for 48 h was also characterized, and the result is shown in Figure S2 (Supporting Information). As displayed in Figure S2 (Supporting Information), the absolute value of zeta potential of colloidal gold nanoparticles decreases with the increasing molar ratio of PEG molecules to Au nanoparticles and approaches to a minimum value of about 14 mV at a PEG/Au nanoparticle ratio over 300:1, which indicates that the mechanism of stabilizing laser-generated colloidal gold nanoparticles is changed from electrostatic repulsion to steric repulsion with PEG. The origin of this marked difference in the stability of PEGylation should be related to the surfactant. To justify this argument, we have investigated the effect of citrate on the colloidal stability of gold nanoparticles produced from laser ablation during the PEGylation. First, four colloidal gold nanoparticle samples were fabricated by using femtosecond laser 23295

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Figure 4. Effect of citrate in solution on the colloidal stability of gold nanoparticle during the PEGylation. Four colloidal gold nanoparticle samples were fabricated by using femtosecond laser ablation in the presence of trisodium citrate with concentration varying from 1 μM to 1 mM.

ablation in the presence of trisodium citrate with concentration varying from 1 μM to 1 mM. Then, the suspension stability of these four samples after mixing with various amounts of thiolated PEG 20k for 48 h was evaluated by monitoring the change of the absorbance of the LSPR of gold nanocolloids around 520 nm. The results are summarized in Figure 4. Intentionally increasing citrate concentration during the laser generation of colloidal gold nanoparticles causes the suspension to have the same properties and instability during addition of PEG as was observed for chemically prepared gold nanoparticles. The destabilization of colloidal gold nanoparticles synthesized with HAuCl4 and sodium citrate after addition of chemical compounds bearing thiol groups has been observed by several groups before.32 34 For example, Whitesides et al. have described the aggregation of gold nanoparticle dispersions upon chemisorption of alkanethiols.32 Since the underlying mechanisms of ligand exchange reaction are very complicated,35 it is still not clear yet why irreversible aggregation/precipitation occurred during the PEGylation of citrate-capped gold nanoparticles when the ratio of PEG/gold nanoparticles is below a certain number. A possible explanation is the competition of the original surfactant of citrate. Because of the competition of citrate for nanoparticle surface area, the quantity of the PEG molecules conjugated on the surface of gold nanoparticles was maintained by a dynamic equilibrium between free PEG molecules in the solution and conjugated PEG molecules on the surface of the gold nanoparticles. A recent report used ToF-SIMS imaging data with DLS and UV visible data confirmed that elimination of free PEG molecules from solvent by a dialysis procedure led to the aggregation of gold nanoparticles by detaching conjugated PEG from the surface of the gold nanoparticles.34 Free PEG molecules in solution help to prevent nanoparticles from aggregating. Therefore, the excess amount of PEG molecules has to be added to achieve stable and complete ligand exchange as reflected in reported protocols.36 In the case of PEGylation of laser-generated gold nanoparticles, there is no interference from the competition of original surfactants, and the nanoparticles are stable without any additives. As a result, aggregation/precipitation during the PEGylation did not occur. This observation indicates that in terms of surface functionalization and modification laser-generated gold nanoparticles hold huge advantages.

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Figure 5. Characterization of the amount of thiolated PEG 20k molecules necessary for forming a complete monolayer on the surface of a laser-generated gold nanoparticle with an average diameter of 20 nm. (a) Size increase measured by dynamic light scattering of PEGylated gold nanocolloids with a different final ratio of PEG molecule/Au nanoparticle. (b) Colloidal stability of Au nanoparticles with a different final molar ratio of PEG molecule/Au nanoparticle against 1 wt % NaCl characterized by absorbance of Au nanoparticles at 520 nm which was measured at 2 h after adding NaCl.

The amount of thiolated PEG 20k molecules necessary for forming a complete monolayer on the surface of a laser-generated gold nanoparticle with average diameter of 20 nm was experimentally determined. Such a parametric investigation is very significant. This information allows us to carry out partial PEGylation of the gold nanoparticle which will enhance its stability, reduce opsonization, and at the same time leave enough surface places for immobilization of other functional ligands to construct ligand-functionalized PEGylated gold nanoparticles with multiple functionalities. Dynamic light scattering (DLS) size analysis was used to quantitatively verify the minimum amount of thiolated PEG 20k for forming a complete monolayer on the surface of the laser-generated gold nanoparticle with an average diameter of 20 nm by monitoring the size increase after PEGylation. DLS is considered to be a standard tool for measuring the average nanoparticle size because of its wide availability, simplicity of sample preparation, and in situ measurement capability for fluid-born nanoparticles. Figure 5a displays the size increase of the laser-generated gold nanoparticle after mixing with PEG 20k with different input molar ratio of PEG/Au nanoparticles. The increase in size is the consequence of the presence of PEG on the nanoparticle surface. The curve of the size increase is indicative of monolayer adsorption, approaching the maximum at a PEG/Au nanoparticle ratio of approximately 300:1. As the PEG/Au nanoparticles ratio continues to increase, we observed very little further increase in nanoparticle size which was maintained at about 40 nm, indicating the saturation of PEG binding on the gold nanoparticle had occurred at a PEG/Au nanoparticles ratio of about 300:1. This observation provides evidence for not only the successful conjugation of PEG molecules but also the minimum number of PEG 20k necessary for forming a complete monolayer on the surface of a single gold nanoparticle with diameter of 20 nm being about 300. The stability of PEG-modified gold nanoparticles in NaCl was also used to quantitatively confirm binding of PEG molecules to gold nanoparticles. Due to a charge screening effect, as-synthesized gold nanocolloids prepared by both a physical and chemical approach immediately form aggregates at more elevated salt concentration. A layer of PEG molecules on the surface of gold nanoparticles improves their stability in the presence of NaCl by providing a steric repulsion between nanoparticles, and this stability approaches to maximum as the gold nanoparticle surface is completely coated with a layer of PEG molecules. PEGylated 23296

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The Journal of Physical Chemistry C laser-generated gold nanoparticle samples with molar ratio of PEG/Au nanoparticles ranging from 40:1 to 5000:1 were used in the experiment. NaCl was added to each sample to the final concentration of 1 wt %, which is an environment that immediately induces the aggregation/precipitation of unmodified gold nanoparticles. UV visible absorption spectroscopy was used to evaluate suspension stability of PEGylated gold nanoparticles in the presence of 1 wt % NaCl. Figure 5b displays the absorbance of PEGylated Au nanocolloids at 520 nm, which was measured 2 h after adding NaCl and was expressed as a percentage of the absorbance of the PEGylated gold nanocolloids without addition of NaCl. It is shown that the stability of PEGylated Au nanoparticles approaches maximum at a PEG/Au nanoparticles ratio of 300:1. Increasing the PEG/Au nanoparticles ratio beyond 300:1 up to 5000:1 does not further increase stability. This further confirms that the minimum amount of PEG 20k required for forming a complete monolayer on the surface of gold nanoparticles with a diameter of 20 nm is about 300:1, which is consistent with the result of the DLS experiment. Assessed by the fluorescence-based determination of thiolterminated oligonucleotides that were leached from the gold nanoparticle surface, Mirkin’s group has determined the footprint of thiol groups on the surface of gold nanopaticles.37 This value depends on the diameter of the gold nanoparticle. For 20 nm, it is 7.0 ( 1 nm2. Their result is in accord with work by Kataoka et al.38 who also investigated the footprint of thiol groups by using thermogravimetric analysis (TGA) to estimate the density of PEG 12k on the surface of gold nanoparticles. By referring to the literature value, the saturation amount of thiolterminated molecules adsorbed on the surface of a gold nanoparticle with a diameter of 20 nm is determined to be about 200, which is close to the results of our experiments. By taking advantage of their unique surface chemistry, Barcikowski’s group has pioneered the conjugation of laser-generated gold nanoparticles to different biomolecules for biomedical applications.24,25 The observed superior colloidal stability of laser-generated gold nanoparticles under PEGylation shown in Figure 3 indicates that we should be able to construct multiple functional ligands on the individual gold nanoparticles. As a proof of this concept, we have conjugated a gold nanoparticle to two functional molecules using dye-conjugated PEG, FITC-PEG 10k-SH, and Rhodamine-PEG 10k-SH, as model compounds. The laser-generated gold nanoparticles were conjugated to these two functional molecules in a sequential manner (FITC-PEG 10k-SH was first mixed with a suspension of gold nanoparticles for at least 3 h and then followed by addition of Rhodamine-PEG 10k-SH) with the input ratio of PEG/gold nanoparticles being 150:1 for both PEG molecules. DLS data confirmed the binding of both PEG molecules to the surface of gold nanoparticles by revealing that the first FITC-PEG 10k-SH coating increased the particle hydrodynamic size by 6 nm, and the Rhodamine-PEG 10k-SH coating step further increased the hydrodynamic size by 10 nm. To gain additional evidence in support of the success of sequential conjugation, fluorescence measurements were carried out too. In this experiment, the suspension of gold nanoparticles conjugated to two types of fluorophore-labeled PEGs was filtered using Millipore centrifuge filters with a molecular weight cutoff of 30 kDa. The obtained filtrate was excited at 488 and 532 nm, respectively, and we did not observe photoluminescence of filtrate from both FITC and Rhodamine. Providing that the spectrofluorometer used in our experiment had sensitivity capable of detecting less than 10% of total input fluorophore-labeled

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PEGs, the fluorescence measurement verified that both FITCPEG 10k-SH and Rhodamine-PEG 10k-SH added in a stepwise fashion were successfully immobilized onto the surface of gold nanoparticles with almost 100% conjugation efficiency.

’ CONCLUSION In summary, we have fabricated colloidal gold nanoparticles without involving chemical precursors, reducing agents, and stabilizing ligands by using femtosecond laser irradiation of the gold target with low pulse energy near the ablation threshold in deionized water and demonstrated a highly efficient assembly of PEG molecules onto these gold nanoparticles with improved stability and control of surface coverage as compared to chemically prepared gold nanoparticles. The same strategies could be readily applied to assemble other biorecognition or therapeutic agents, such as peptides, aptamers, and nucleic acids, onto the surface of gold nanoparticles and to enable their densities to be optimized. Clearly, the use of these chemically pure gold nanoparticles with a bare surface, which allows versatile and controllable surface modification, is of particular advantage for rational design of new bio/inorganic interfaces that exhibit highly complex and functional surface chemistries. Since both in vivo and in vitro performance of gold nanoparticles sensitively depend on their surface chemistries, our research represents a new breakthrough in the development of a high-performance gold nanoconjugate. We expect this work will open exciting opportunities leading to the increased utility of gold nanoparticles in biology and medicine that will accelerate progress in their clinical applications. ’ ASSOCIATED CONTENT

bS

Supporting Information. Fabrication of colloidal gold nanoparticles, FTIR spectra, and zeta potential data. This material is available free of charge via the Internet at http://pubs.acs.org.

’ AUTHOR INFORMATION Corresponding Author

*E-mail: [email protected]. Tel.: 734-930-2570. Fax: 734-669-7403.

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