Stimuli-disassembling gold nanoclusters for diagnosis of early stage oral cancer by optical coherence tomography
© The Author(s) 2018
Received: 5 December 2017
Accepted: 11 January 2018
Published: 26 January 2018
Unique and tunable optical properties [e.g., surface plasmon resonance (SPR) effect] without obstruction by photo-bleaching or photo-blinking have made plasmonic inorganic nanoparticles (NPs) an attractive, popularly-investigated nanomaterial for biomedical imaging applications including optical imaging . Resonant excitation of plasmonic inorganic NPs leads to a large enhancement of the incident electromagnetic field at the NP surface for nonlinear optical spectroscopies such as surface enhanced Raman spectroscopy. [1, 2] One category of plasmonic NPs, gold (Au) NPs do not induce cytokine secretion, making them highly biocompatible and applicable to a number of delivery, sensing, and imaging applications [3–6]. Au NPs have been most intensively investigated for imaging applications over the last few decades; well-established methods of Au NP synthesis and surface modifications have allowed for control over their morphology-dependent optical properties [7–13]. Among many imaging applications, optical coherence tomography (OCT) is a fast, non-invasive, and high resolution imaging modality that uses a Michelson’s interferometer with a low coherence light source . OCT’s two- and three-dimensional high resolution imaging capability is well-suited for detecting specific stages of diseases such as cancer [15–18]. However, the challenge of obtaining disease-specific molecular contrast undermines the many promising features of OCT [19–22]. This limitation particularly affects OCT diagnostic performance for early-stage cancer; however, it can potentially be overcome by using optical contrast agents such as Au NPs [3, 23–26]. For example, significantly enhanced OCT contrast in vivo was demonstrated by administering anti-epidermal growth factor receptor-conjugated Au NPs via a multimodal delivery method to neoplastic tissues .
Plasmonic Au nanoclusters (NCs) that transform their physical and optical properties upon detecting a stimulus (e.g., mildly acidic pH of tumor tissue [28–30]) in a diseased area are highly promising OCT contrast agents due to their ability to improve OCT imaging with enhanced SPR effects [31, 32]. Moreover, pH-transforming systems of Au NPs have previously been described in the literature; one approach includes Au NPs composited in pH-responsive polymers that expand under acidic conditions due to changes in electrostatic forces [33, 34]. In this study, we synthesized Au NCs by using an acid-cleavable linker to cluster individual Au NPs.
Hydrogen tetrachloroaurate (III) trihydrate (HAuCl4·3H2O) and trisodium citrate dihydrate (Na3C6H5O7·2H2O) were purchased from Sigma Aldrich (Milwaukee, WI). N-Succinimidyl 3-(2-pyridyldithio)-propionate (SPDP) and amino PEG monomethyl ether (2 kDa) were purchased from Pierce (Rockford, IL). 2-Aminoethanol, pyridinium p-toluenesulfonate, ethyl trifluoroacetate, and 2-methoxypropene were supplied by Acros (Morris Plains, NJ). Dimethly sulfoxide (DMSO), sodium azide, and bovine serum albumin were purchased from Fisher Scientific (Fair Lawn, NJ). Dithiothreitol (DTT) was supplied by Fisher Scientific (Pittsburgh, PA) and diethylene glycol bis (3-amino propyl) ether was obtained from TCI (Tokyo, Japan). Carboxy-SNARF-1 (SNARF) was purchased from Invitrogen AB (Frolunda, Sweden). A carbon-coated copper TEM grid was purchased from Electron Microscopy Sciences (Hatfield, PA).
2.2 Synthesis of Au NPs
Citrate-capped Au NPs (15 nm in diameter) were synthesized by following a previously reported protocol with slight modifications . Briefly, 100 milliliters of 1% (w/w) HAuCl4·3H2O in Milli-Q water (18.2 MΩ) was heated to its boiling point (100 °C) and added dropwise with 4 mL of 1% (w/v) Na3C6H5O7·2H2O in Milli-Q water (18.2 MΩ) with vigorous stirring. Upon addition of Na3C6H5O7·2H2O, the color of the mixture changed to deep red instantaneously. After reflux for an additional 15 min, the resulting solution was cooled down to room temperature with continuous stirring. After overnight incubation at 25 °C, the resulting Au NPs were characterized by using a Phillips CM 20 transmission electron microscope (TEM) (Philips Electronic Instruments, Mahwah, NJ) and ZEN3600 Zetasizer dynamic light scattering (DLS) particle analyzer (Malvern Instruments, Worcestershire, UK). It was shown that Au NPS were 15 nm (± 0.3 nm) in diameter and spherical in shape (TEM). The concentration of the resulting Au NPs was calculated to be 3.44 × 1012 particles/mL using a previously described UV/Vis spectroscopic method . All glassware used in the Au NP synthesis was cleansed in aqua regia, 3:1 (v/v) HCl:HNO3, and thoroughly rinsed with deionized (DI) water.
2.3 SPDP-activation of Au NPs
Ten milliliters of Au NPs (3.44 × 1012 particles/mL) were washed with Milli-Q water (18.2 MΩ) by repeated centrifugation at 10,000 rpm for 30 min and then re-dispersed in Milli-Q water (18.2 MΩ). After the 2 times wash steps, Au NPs were re-dispersed in 10 mL of 0.02 M sodium bicarbonate buffer (pH 8.73). Using a peristatic pump, ten milliliters of Au NPs (3.4 × 1012 particles/mL) in sodium bicarbonate buffer were steadily added at 7 μL/s to 2 μL of 20 mM SPDP solution in dimethyl sulfoxide (DMSO) (4.73 × 10−20 mol SPDP per Au NP) while the solution was stirred vigorously on ice. The reaction was left stirring at room temperature overnight. Unreacted SPDP was removed by centrifugation twice at 10,000 rpm for 30 min, and SPDP-activated Au NPs were re-dispersed in 10 mL of 0.02 M sodium bicarbonate buffer and briefly sonicated in a sonication bath for 30 s . When exposed to dithiothreitol (DTT), SPDP cleaves; this concept was used to quantify SPDP conjugation. SPDP conjugation of Au NPs was quantified by the release of a pyridine-2-thione group when incubated with dithiothreitol (DTT). Briefly, 1.5 mL of SPDP-activated Au NP solution (3.4 × 1012 particles/mL) was washed twice with DI water by repeated centrifugation at 10,000 rpm for 30 min and re-dispersion. Seventy-five microliters of 15 mg/mL DTT in DI water were added to 0.75 mL of SPDP-Au NP solution, followed by incubation for 15 min at room temperature. The released amount of pyridine-2-thione was quantified by the absorbance at 343 nm using a Varian Cary 50 UV/Vis spectrophotometer (Varian Inc., Palo Alto, CA). After subtracting the background absorbance of a DTT-free SPDP-Au NP solution at the same concentration, SPDP-conjugation was calculated to be 5.34 × 10−22 mol (= 321 mol) of SPDP per Au NP. The resulting SPDP-activated Au NPs were kept at 4 °C without exposure to light.
2.4 Au NC synthesis and characterization
Seven hundred fifty microliters of SPDP-activated Au NPs (6.8 × 1012 particles/mL) were added slowly into acid-cleavable diaminoketal (DAK) solution in 0.02 M sodium bicarbonate solution on ice with strong stirring. Then, the mixture remained at room temperature overnight with continuous stirring. The unreacted cross-linkers were washed away by centrifugation at 8000 rpm for 10 min and re-dispersed in 0.02 M sodium bicarbonate solution. DAK conjugated Au NPs were characterized by dynamic light scattering (DLS) and UV/vis spectrometer. 100 μL of DAK conjugated Au NPs were slowly added to 10 mL of SPDP-activated Au NPs on ice, and the mixture was kept stirring overnight. The final Au clusters were added to 160 μL of amine-functionalized PEG (MW = 2 k Da, 10 mg/mL) with strong stirring. The acid degradable Au clusters were separated from free, SPDP-activated Au NPs by centrifugation at 6000 rpm for 30 min . The non-acid degradable (control) Au clusters were synthesized by the same method except diethylene glycol bis (3-amino propyl) ether (0.05 g/mL) was used instead of DAK. The sizes of the Au NPs and Au NCs were determined using a Phillips CM 20 transmission electron microscope (TEM) (Philips Electronic Instruments, Mahwah, NJ) and ZEN3600 Zetasizer dynamic light scattering (DLS) particle analyzer (Malvern Instruments, Worcestershire, UK). The absorbance of Au NCs was measured using a Varian Cary 50 UV/Vis Spectrophotometer (Varian Inc., Palo Alto, CA).
2.5 OCT/DvOCT imaging configuration
Spectral-domain optical coherence tomography (SD-OCT)  was used to image the scattering and Doppler variance of the acid-degradable and non-acid degradable Au NCs in droplets and hamster cheek pouch tissues. Doppler variance OCT images (DvOCT) were also obtained based on the power spectrum of the temporal fluctuations of the OCT magnitude using the SD-OCT system. Low-coherence light with a 1310 nm center wavelength and 90 nm full width at half maximum (FWHM) was used, and imaging depth and depth resolution were 3.4 mm and 8 µm in air, respectively. A 2-axis scanner with two galvanometers was located at the same sample arm. All SD-OCT and DvOCT images were obtained with the same focal point. A 130 nm wide spectrum was sampled by a 1 × 1024 InGaAs detector array at a 7.7 kHz frame rate. Acid degradable Au-NCs (1.62 × 109 particles/mL) were mixed with pH 5 solution in 37 °C. Then, SD-OCT and DvOCT images were obtained every 30 min with 3 µL of aliquot solution for 2 h.
2.6 OCT/DvOCT imaging of Au NCs incubated in DI water and pH 5.0 acetate buffer
The acid-degradable and control Au NCs (960 μL, 7.05 × 109 particles/mL) were concentrated to 10 μL of solution by centrifugation at 2000 g for 30 min. The resulting solution (3 μL) was mixed with 6 μL of DI water as a control, and 7 μL of the solution was mixed with 14 μL of pH 5.0 acetate buffer to hydrolyze the Au clusters. After 2 h of incubation at 37 °C, a 3 μL aliquot of each sample was dropped on the polyethylene substrate, and OCT/DvOCT images were obtained. The droplet OCT/DvOCT images with different pH conditions were quantified with the Scion Image Process (Scion Corporation).
2.7 SNARF-conjugation on Au clusters
Au NP clusters were rinsed with Milli-Q water (18.2 MΩ) by repeated centrifugation at 6000 rpm for 30 min and re-dispersion in Milli-Q water (18.2 MΩ). In order to functionalize with amino groups, 1.5 mL Au NP clusters (7.05 × 109 particles/mL) in Milli-Q water (18.2 MΩ) were then reacted on ice with vigorous stirring with 3.75 μL of 0.05 g/mL diethylene glycol bis (3-amino propyl) ether in Milli-Q water (18.2 MΩ) (molecular ratio of diethylene glycol bis (3-amino propyl) ether to SPDP is 1.4 x 105). After removing unreacted diethylene glycol bis (3-amino propyl) ether by two centrifugation steps (6000 rpm for 30 min), 1.5 mL of Au NP clusters (7.1 × 109 particles/mL) re-dispersed in Milli-Q water (18.2 MΩ) were added to 0.05 g/mL SNARF succinimidyl ester in Milli-Q water (18.2 MΩ) on ice, followed by stirring at room temperature overnight without exposure to light. SNARF-conjugated Au NP clusters were obtained in Milli-Q water (18.2 MΩ) after removing un-conjugated dyes by centrifugation at 6000 rpm for 30 min. DLS, UV/vis spectrometer, and TEM were used for the characterization after the SNARF-conjugation.
2.8 In vivo OCT imaging
To establish the oral cancer model, golden Syrian hamsters (Mesocricetus auratus, Harlan Sprague–Dawley, San Diego, CA) were topically treated with 0.5% (w/v) 9, 10-dimethyl-1,2-benzanthracene (DMBA, Sigma) in mineral oil three times per week for 4-6 weeks to induce dysplasia in one cheek pouch in each animal. The contralateral cheek pouch of the hamster received mineral oil application only. All animal protocols were approved by the Institutional Animal Care and Use Committee (IACUC, 97-1972) at the University of California, Irvine. Acid degradable and control Au clusters were synthesized, characterized, and applied on the hamster cheek pouches using a multi-modal delivery method (microneedles for penetration and ultrasound for distribution of Au NCs). OCT/DvOCT was used to observe the optical property changes of stimuli-responsive Au clusters. All the OCT/DvOCT Imaging was performed in the cheek pouch of the anesthetized hamster by gently clamping the tissues to a microscope stage using a custom-built, ring-shaped clamp. CR3 roller microneedles (MTS dermaroller with 200 μm depth; Clinical Resolution Laboratory, Inc., Beverly Hills, CA) were rolled on both the DMBA-untreated and control sides of the hamster cheek pouches three times at three different angles. Then, 200 μL of Au cluster solution (7.05 × 109 particles/mL) were administration by dropping it directly into the 1-cm-diameter aperture of the ring-shaped clamp. After 10 min Au cluster topical administration, ultrasonic force (0.3 W/cm2 of 1 MHz) was applied to the cheek pouch using the Dynatron 125 ultrasonicator (Dynatronics Corporation, Salt Lake City, UT) for 1 min in the presence of ultrasound gel, followed by OCT/DvOCT imaging. After OCT/DvOCT imaging, all the OCT/DvOCT images were quantified with the scion image process (Scion Corporation).
3 Results and discussion
3.1 Synthesis and characterization of acid-disassembling Au NCs
In order to meet the design goals of this study, Au NCs needed to be composed of small Au NPs of the minimally required size for detection by OCT and DvOCT. Although higher OCT/DvOCT signals can be obtained using large Au NPs , the resulting Au NCs should be small enough (e.g., less than 100 nm ) to penetrate and readily disperse in target tissues. In a previous study, we demonstrated that ~ 70 nm Au NPs could be detected at the site of early-stage oral dysplasia in vivo after topical delivery by combined microneedle (penetration through stratum cornea) and ultrasound (dispersion in oral dysplasia) delivery . Therefore, the design goal of this study was to create Au NCs that were smaller than 100 nm and able to disassemble into individual 15 nm Au NPs under mildly acidic conditions.
3.2 Acid-responsive transformation of Au NCs and optical signal changes
3.3 Confirmation of mildly acidic pH in early-stage oral dysplasia
In addition, no adverse effects (e.g., inflammation) from the Au NCs were observed in either cheek pouch tissue sample, implying high biocompatibility of the administration methods. The results shown in Figs. 5 and 6 confirm that mild acidification (pH 6.2) is indeed a promising pathological trigger in early-stage oral dysplasia for Au NC disassembly. We previously reported that the ketal linkage used in synthesizing Au NCs in this study readily hydrolyzes not only at pH 5.0 but also at pH 6.0 in cell culture . Therefore, acid-triggered Au NC disassembly and simultaneous generation of optical signal changes are anticipated in early-stage oral dysplasia (pH 6.2).
3.4 Pinpointed, multi-modal, optical diagnosis of early-stage oral cancer using acid-disassembling Au NCs
This study demonstrates the high feasibility of identifying neoplastic change by employing stimuli-responsive contrast agents for a clinically relevant optical imaging system (i.e., optical coherence tomography). A clustered form of Au NPs (i.e., Au NCs) exhibited enhanced scattering and slow Brownian motion in normal tissue, while Au NCs reverted to individual Au NPs and showed diminished scattering and fast Brownian motion upon acid-hydrolysis of the clustering linkers in mildly acidic early-stage dysplastic tissue. This study’s hypothesis of obtaining multiple, stimuli-responsive optical signal changes using molecularly engineered inorganic NPs can further be expanded to drug delivery and other imaging applications. Stimuli-transforming clusters can be synthesized using a variety of nanomaterials and tuned to be responsive to specific pathological stimuli (e.g., hyperthermia, enzymes, and hypoxia) as well as external triggers (e.g., magnetic force, electric field, and light). Combined incorporation of therapeutic and diagnostic (imaging) nanomaterials can be used to develop novel theranostic agents.
CSK planned and executed this study and wrote the manuscript. DI fabricated nanoclusters, completed in vitro studies, and assisted in writing the manuscript. PW and ZC served as expert consultants throughout the duration of the study. YJK directed the study, designed experiments, and wrote the manuscript. All authors read and approved the final manuscript.
The authors thank undergraduate researchers (Travis Tucker, Joseph Youssef, and Steven Duong) in Dr. Petra Wilder-Smith’s group for their assistance in animal handling for in vivo studies. Also, the authors acknowledge Dr. Tatiana Krasieva for confocal imaging, Laurie Newman for animal care, and Hongrui Li for histology of tissue samples, at the Beckman Laser Institute at UC Irvine. DI was support by an NSF GRFP Fellowship. ZC has a financial interest in OCT Medical, Inc., which, however, did not support this work.
The authors declare that they have no competing interests.
Availability of data and materials
The authors have no data to share since all data are shown in the submitted manuscript.
This work was financially supported by the NIH (3R21DE19298-02S1, R01EB-10090, P41EB-015890), AFOSR (FA9550-04-0101), the Beckman Laser Institute Endowment, the UC Cancer Center Support Grant (5P30CA062203-13), UC CRCC 53082, and a Council on Research Computing and Libraries award (UCI).
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