In this study, we develop a novel photoacoustic imaging technique based on gold nanorods (AuNRs) for quantitatively monitoring focused-ultrasound (FUS) induced blood-brain barrier (BBB) opening in a rat model in vivo. This study takes advantage of the strong near-infrared absorption (peak at ∼ 800 nm) of AuNRs and the extravasation tendency from BBB opening foci due to their nano-scale size to passively label the BBB disruption area. Experimental results show that AuNR contrast-enhanced photoacoustic microscopy (PAM) successfully reveals the spatial distribution and temporal response of BBB disruption area in the rat brains. The quantitative measurement of contrast enhancement has potential to estimate the local concentration of AuNRs and even the dosage of therapeutic molecules when AuNRs are further used as nano-carrier for drug delivery or photothermal therapy. The photoacoustic results also provide complementary information to MRI, being helpful to discover more details about FUS induced BBB opening in small animal models.
A microbubble-based imaging/therapeutic agent is introduced. Specifically, gold nanoparticles (AuNRs) are
encapsulated in microbubbles (MBs) for both ultrasound (US) imaging and laser-induced thermotherapy (LIT). In
addition, this agent, AuNR-MB, takes albumin microbubble as a carrier and includes the AuNRs that maintain the
original absorption peak at around 760nm. AuNR-MBs in different sizes are synthesized. Imaging is first performed to
evaluate its feasibility. The enhanced PA and US signals in polyacrylamide gel for in vitro study are measured. The PA
spectroscopy is then performed and the results generally agree with the measured optical absorption although its peak is
slightly broadened and shifted possibly due to mixing. In phantoms, the contrast is 1.531, 2.447, 2.085, 1.994, 0.768, and
0.573 at wavelength of 720, 760, 800, 860, 900, and 940 nm respectively. Finally, the application of the new agent to
LIT is presented. A continuous wave laser at 800 nm is used to heat the samples with the power at 1W. The
photoacoustic (PA) intensity in the region of interest (ROI) is increased by an average of 5.2dB. The increased signal
level implies that the temperature in the ROI can be increased to 44.3°C in aqueous filled setup. Furthermore, the dual-modality
agent has the potential to be used in HIFU therapy, drug delivery and loading of DNA for gene transfer.
Blood brain barrier (BBB) prevents most of the drug from transmitting into the brain tissue and decreases the treatment
performance for brain disease. One of the methods to overcome the difficulty of drug delivery is to locally increase the
permeability of BBB with high-intensity focused ultrasound. In this study, we have investigated the feasibility of
photoacoustic microscopy of focused-ultrasound induced BBB opening in a rat model in vivo with gold nanorods
(AuNRs) as a contrast agent. This study takes advantage of the strong near-infrared absorption of AuNRs and their
extravasation tendency from BBB opening foci due to their nano-scale size. Before the experiments, craniotomy was
performed on rats to provide a path for focused ultrasound beam. Localized BBB opening at the depth of about 3 mm
from left cortex of rat brains was achieved by delivering 1.5 MHz focused ultrasound energy into brain tissue in the
presence of microbubbles. PEGylated AuNRs with a peak optical absorption at ~800 nm were then intravenously
administered. Pre-scan prior to BBB disruption and AuNR injection was taken to mark the signal background. After
injection, the distribution of AuNRs in rat brains was monitored up to 2 hours. Experimental results show that imaging
AuNRs reveals BBB disruption area in left brains while there are no changes observed in the right brains. From our
results, photoacoustic imaging plus AuNRs shows the promise as a novel monitoring strategy in identifying the location
and variation of focused-ultrasound BBB-opening in a rat model.
Gold nanoparticles have been used as contrast agent in photoacoustic imaging to increase the detection sensitivity. For
example, gold nanorods (AuNRs) have been used in time-intensity based flow estimation and used as nanoprobes to
target cancer cells for early diagnosis and effective treatment. In this study, we aimed at the design and synthesis of a
new type of gold nanoparticles with enhanced photoacoustic response. The key hypothesis is to create a nanostructure
that allows anisotropic heat release. Specifically, such a structure results in higher heat flux transmitting outwards from
the ends of the particle and therefore a greater temperature gradient can be created. To achieve this, a layer of SiO2 was
coated along the longer axis of the gold nanorods, leaving both ends uncovered. These new particles are labeled as
AuNR@nu-SiO2 with non-uniform ("nu") coating of silica. Experiments were performed to demonstrate the enhanced
photoacoustic response from AuNR@nu-SiO2. The optical illumination was delivered by a Ti: Sapphire laser pumped by
an Nd:YAG laser. A home-made photoacoustic transducer with a center frequency of 20 MHz detected the resulted
acoustic signal. First, new types of particles coated with and without SiO2 were compared to bare AuNR in order to show
the ability of the new nanostructure to enhance photoacoustic response. Second, the shape stability of the new particles
was evaluated by measuring the photoacoustic responses versus time after high power laser irradiation. Third, the effect
of thickness of SiO2 of AuNR@nu-SiO2 ranges from 1 nm to 15 nm was also evaluated. Results show that the mean
intensity in photoacoustic image increase about 5 dB for AuNR@nu-SiO2 compared to bare AuNR. Also, it reveals that
the normalized intensity for AuNR drops to below 0.6 while it is mostly larger than 0.7 in the case of AuNR@nu-SiO2
under pulse laser irradiation. In other words, the new type of nanoparticles is less susceptible to shape transformation.
Moreover, it is indicated that the photoaocustic response increases slightly with the thickness of SiO2 and approach to an
maximum response at 9 nm thickness. In short, these new particles can be used to achieve the same level of
photoacoustic response with a fewer amount of particles, which means that there is less toxicity.
In this study, photoacoustic imaging is utilized to probe information from oncogene surface molecules of cancer cell with
the aid of specific targeting. The ultimate goal is to provide prediction of clinical outcome and treatment response of
anti-cancer drugs. Different from single targeting in most research, we accomplished multiple targeting to obtain a
molecular profile potentially representing tumor characteristics or to locate the heterogeneous population in one lesion.
By conjugating different antibodies to gold nanorods corresponding to different peak absorption bands, multiple
targeting and simultaneous detection with photoacoustic imaging can be achieved with laser irradiation at the respective
peak optical absorption wavelength. Her2 and EGFR were chosen as our primary target molecules. The targeting
complex was evaluated in two types of oral cancer cells, OECM1 and Cal27. The OECM1 cell line overexpresses Her2
but has low expression of EGFR, while Cal27 cell line expresses both antibodies. Also, the targeting efficacy to OECM1
can be further improved by using mixed nanoprobes. The cancer cells were induced on the back of the mice by
subcutaneous injection. The captured images show that both cancer cells exhibit a higher photoacoustic response
(maximum 3 dB) than control groups with specific targeting, thus demonstrating the feasibility of multiple selective
targeting with bioconjugated gold nanorods. Images of multiple targeting with mixed nanoprobes of OECM1 cells also
reveal further enhancement of targeting (4 dB). The results showed potential of in vivo photoacoustic molecular imaging,
providing a better guidance for diagnosis and treatment of cancer.
A time-intensity based method for photoacoustic blood flow measurements was proposed in last year's meeting. The method made use of the strong photoacoustic response of gold nanospheres and the "wash-out" characteristics of the nanospheres were analyzed. In this paper, we develop a new quantitative technique for measuring blood flows based on the "wash-in" characteristics of the nanoparticles. In particular, the technique makes use of the shape dependence of the optical absorption of gold nanorods (i.e., cylindrical nanoparticles) and the transitions in their shape induced by pulsed laser irradiation. The photon-induced shape transition of gold nanorods involves mainly a rod-to-sphere conversion and a shift in the peak optical absorption wavelength. The application of a series of laser pulses with the same laser energy will induce shape changes in gold nanorods as they flow through a region of interest, with quantitative flow information being derived from the photoacoustic signals from the irradiated gold nanorods measured as a function of time. To demonstrate the feasibility of the technique, an Nd:YAG laser operating at 1064 nm was used for irradiation and a ultrasonic transducer with a center frequency of 1 MHz was used for acoustic detection. Excellent agreement between the measured velocities and the actual velocities was demonstrated, with a linear regression correlation coefficient higher than 0.9. Compared to the wash-out analysis, the wash-in analysis is more suitable for measuring flows in microcirculation.
Cancer cells presented altered surface molecules to encourage their growth and metastasis. Expression of oncogeneic surface molecules also play important roles in the prediction of clinical outcome and treatment response of anti-cancer drugs. It is thus conceivable that imaging of cancer lesions while simultaneously obtaining their pathogenic information at molecular level of as many oncogenic proteins as possible is of great clinical significance. Gold nanoparticles have been used as a contrast agent for photoacoustic imaging. In addition, gold nanoparticles can be bioconjugated to probe certain molecular processes. An intriguing property of gold nanoparticles is its ability to tailor its optical properties. For
example, size effects on the surface plasmon absorption of spherical gold nanoparticles have shown that the peak optical absorption red-shifts with the increasing particle size. In addition, the optical absorption spectrum of cylindrical gold nanoparticles (i.e., gold nanorods) exhibits a strong absorption band that is directly related to the aspect ratio. With these unique characteristics, selective targeting can be achieved in photoacoustic molecular imaging. Specifically, gold nanorods with different aspect ratios can be bioconjugated to different antibodies. Multiple targeting and simultaneous detection can then be achieved by using laser irradiation at the respective peak optical absorption wavelength. In this study, photoacoustic multiple targeting using gold nanorods is experimentally demonstrated. We have chosen Her2 and CXCR4 as our primary target molecule as Her2 expression is associated with growth characteristics and sensitivity to Herceptin chemotherapy. On the other hand, CXCR4 expression predict the organ-specific metastatic potential of the cancer cells for clinical intervention in advance. Monoclonal antibody (mAb) against Her2/neu was conjugated to nanorods with several different aspect ratios. The agarose gel is suitable for photoacoustic signal acquisition. A wavelength tunable Ti-Sapphire laser was used for laser irradiation and a 1 MHz ultrasound transducer was used for acoustic detection. The optical wavelength of the laser was tuned between 800 nm and 940 nm, corresponding to gold nanorods of an aspect ratio ranging from 3.7 to 5.9. The results clearly show the potential of photoacoustic molecular imaging with multiple targeting in revealing different oncogene expression levels of the cancer cells.
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