Nanoparticles as Contrast Agents for Molecular Photoacoustic Imaging

Qu, M. Mehrmohammadi, R. Truby, I. Graf, K. Homan, S. Emelianov, "Contrast-enhanced magneto-photo-acoustic imaging in vivo using dual-contrast nanoparticles," Photoacoustics 2 (2), 55-62 (2014).

Summary: Magneto-photoacoustic imaging can be used for in vivo mapping of targeted plasmonic nanoparticles to enable early detection of various pathologies.

Liposomal nanoparticles that have both optical absorption as well as magnetic properties were injected into a murine tumor model and visualized using in vivo MPA imaging. Compared to conventional Photoacoustic imaging, Magneto-photoacoustic imaging shows significantly enhanced contrast between the nanoparticle-labeled tumor tissue and the background.

Kim, Y.-S. Chen, G. Luke, S. Emelianov, "In-vivo ultrasound and photoacoustic image- guided photothermal cancer therapy using silica-coated gold nanorods," Ultrasonics, Ferroelectrics and Frequency Control, IEEE Transactions on , vol.61, no.5, pp.891,897 (2014).

Summary: Ultrasound and photoacoustic imaging can be used along with silica-coated gold nanorods as contrast agents to effectively guide photothermal therapy.

Three-dimensional ultrasound and spectroscopic photoacoustic imaging of a mouse with a tumor was performed before and after i.v. injection of silica-coated gold nanorods. Photothermal therapy was performed with an 808-nm continuouswave laser.  Peak temperatures of 53°C was achieved in the tumor, which is expected to result in significant cell death.

Hannah, G. Luke, K. Wilson, K.A. Homan, S. Emelianov, “Indocyanine green-loaded photoacoustic nanodroplets: dual contrast nanoconstructs for enhanced photoacoustic and ultrasound Imaging,” ACS Nano, 8(1):250-259 (2014).

Summary: ICG-loaded perfluorocarbon nanodroplets can be used as contrast agents for various imaging modalities. Being biocompatible, nontoxic and biologically safe, they show significant promise in theranostic applications.

Indocyanine green-loaded perfluorocarbon nanodroplets were synthesized and characterized for use as photoacoustic contrast agents.  An enhanced photoacoustic contrast was demonstrated through optically triggered phase transition of PFC nanodroplets and ultrasound contrast from the resulting PFC bubbles.

Yeager, Y.-S. Chen, S. Litovsky, S. Emelianov, “Intravascular photoacoustics for image-guidance and temperature monitoring during plasmonic photothermal therapy of atherosclerotic plaques: a feasibility study,” Theranostics, 4(1):36-46 (2014).

Summary: Plasmonic gold nanoparticle contrast agents can be used to detect and monitor atherosclerotic plaques using combined intravascular ultrasound and photoacoustic (IVUS/IVPA) imaging.

IVUS/IVPA is a novel imaging modality capable of visualizing both morphology (via IVUS) and cellular/molecular composition (via IVPA) of atherosclerotic plaques with the help of exogenous and endogenous contrast agents. Plasmonic gold nanoparticles have been used as IVPA contrast agents to study phagocytically active macrophages that predict the risk of plaque rupture. In this study, a continuous wave laser was incorporated into the IVUS/IVPA integrated catheter and utilized to selectively heat the nanoparticles with simultaneous IVPA temperature monitoring demonstrating that IVUS/IVPA provides a platform for detection and temperature monitoring of atherosclerotic plaques through the selective heating of plasmonic gold nanoparticle contrast agents.

C.L. Bayer, S.Y. Nam, Y.-S. Chen, S.Y. Emelianov, “Photoacoustic signal amplification through plasmonic nanoparticle aggregation,” Journal of Biomedical Optics, 18(1), 016001 (2013).

Summary: Using aggregated silica-coated gold nanoparticles can enhance photoacoustic signal in comparison to using disperse silica-coated gold nanoparticles.

Photoacoustic imaging, using targeted plasmonic metallic nanoparticles, is a promising noninvasive molecular imaging method. The photoacoustic signal from aggregated silica-coated gold nanoparticles is considerably enhanced in comparison to disperse silica-coated gold nanoparticles. Because cellular uptake and endocytosis of nanoparticles results in gold nanoparticle aggregation, this result has major implications for the application of plasmonic metallic nanoparticles towards quantitative molecular imaging.

Cook, W. Frey, and S. Emelianov, “Quantitative photoacoustic imaging of nanoparticles in cells and tissues,” ACS Nano, ACS Nano, 7 (2):1272–1280 (2013).

Summary: Quantitative photoacoustic imaging may be used in many applications including the determination of the efficiency and effectiveness of molecular targeting strategies for cell studies and animal models, the quantitative assessment of photoacoustic contrast agent biodistribution, and the validation of in vivo photoacoustic imaging.

Quantitative visualization of nanoparticles in cells and tissues, while preserving the spatial information, can be challenging. A photoacoustic imaging technique to depict the presence and quantity of nanoparticles was developed based on the dependence of the photoacoustic signal on both the nanoparticle quantity and the laser fluence. Quantitative photoacoustic imaging was first applied to nanoparticle-loaded cells, and quantitation was validated by inductively coupled plasma mass spectrometry. Quantitative photoacoustic imaging was then extended to xenograft tumor tissue sections and agreement with traditional histopathological analysis was demonstrated, suggesting potential for other applications.

Y.-S. Chen, W. Frey, C. Walker, S. Aglyamov and S. Emelianov, “Sensitivity enhanced nanothermal sensors for photoacoustic temperature mapping,” Biophotonics DOI: 10.1002/jbio.201200219 (2013).

 Summary: Silica-coated gold nanorods can provide a multi-fold improvement in sensitivity of the photoacoustic temperature mapping compared to gold nanorods without silica coating.

For photoacoustic imaging, developing an accurate photoacoustic technique to measure the temperature distribution during thermal therapy is crucial. Silica-coated gold nanorods are able to serve as a nanothermal sensor to accurately and quantitatively visualize temperature distributions during photothermal therapy. Photoacoustic imaging using these nanorods has the ability to better visualize the delivery of nanoparticle contrast agents, image the temperature distribution inside living tissue, and confirm tissue coagulation.

G.P. Luke, A. Bashyam, K.A. Homan, S. Makhija, Y.-S. Chen, S.Y. Emelianov, “Silica-coated gold nanoplates as stable photoacoustic contrast agents for sentinel lymph node imaging,” Nanotechnology, 24, 455101 (2013).

Summary: Silica-coated gold nanoplates exhibit low cytotoxicity and high photothermal stability when exposed to pulsed and continuous wave laser irradiation, making them well suited for in vivo photoacoustic imaging.

A biopsy of the sentinel lymph node to which a tumor drains is often used to identify micrometastases. The use of images to guide a sentinel lymph node biopsy could improve its accuracy and decrease its morbidity. Silica-coated gold nanoplates (Si-AuNPs) can be used as a stable contrast agent for photoacoustic image-guided SLN biopsies. The Si-AuNPs were used to map the SLN in a mouse model where they exhibited a strong, sustained photoacoustic signal. Real-time ultrasound and photoacoustic imaging revealed that the Si-AuNPs quickly drain to the SLN, gradually spreading throughout a large portion of the node.

C.L. Bayer, J. Kelvekar, S.Y. Emelianov, “Influence of nanosecond pulsed laser irradiance on the viability of nanoparticle-loaded cells: implications for safety of contrast-enhanced photoacoustic imaging,” Nanotechnology, 24(46), 465101 (2013).

Summary: Low fluence pulsed laser excitation of accumulated nanoparticles at low concentration does not impact cell growth and viability.

Photoacoustic imaging can use highly-absorbing plasmonic nanoparticles to provide high contrast images of molecular features. One primary application is photoacoustic imaging for tissue therapy, but this requires that the imaging method avoid causing cellular damage. This study identifies thresholds at which higher nanoparticle concentrations and fluences produce clear evidence of cell death, showing that a low fluence pulsed excitation of al low concentration of nanoparticles is not detrimental to the health of cells.

Wilson, K. Homan, S. Emelianov, “Biomedical photoacoustics beyond thermal expansion using triggered nanodroplet vaporization for contrast-enhanced imaging,” Nature Communications, 3(618), (2012).

Summary: Exogenous contrast agents that use vaporization mechanisms can be used as an alternative to other methods of generating photoacoustic signals.

Photoacoustic signals can be generated through thermal expansion, vaporization, photochemical processes and optical breakdown. Of these, thermal expansion is traditionally used because it is proven to be a biologically safe mechanism. However, thermal expansion typically has low signal amplitude. Liquid perfluorocarbon, a nanoparticle that vaporizes when exposed to pulsed laser irradiation, can serve as an alternative contrast agent that is both biologically safe and provide significantly higher signal amplitude than thermal expansion. 

Homan, M. Souza, R. Truby, G. P. Luke, C. Green, E. Vreeland, and S. Emelianov, "Silver nanoplate contrast agents for in vivo molecular photoacoustic imaging," ACS Nano, 6(1), 641-650 (2012).

Summary: Silver nanoplates have the potential to be used for in vivo applications as a molecularly sensitive photoacoustic contrast agent.

Silver nanoplates are a photoacoustic contrast agent that can be easily functionalized for molecular photoacoustic imaging in vivo. They can be synthesized, functionalized, and stabilized using biocompatible reagents. The nanoplates can have antibodies conjugated to them that have been proven to show molecular sensitivity. Cell viability tests show the antibody-conjugated silver nanoplates are nontoxic at concentrations up to 1 mg/mL. The synthesized silver nanoplates are well suited for a host of biomedical imaging and sensing applications.

Y.-S. Chen, W. Frey, S. Aglyamov, and S. Emelianov, "Environment-Dependent Generation of Photoacoustic Waves from Plasmonic Nanoparticles," Small, vol. 8, pp. 47-52, (2012).

Summary: The photoacoustic signal of gold nanospheres with varying silica shell thicknesses is shown to be dominated by the heat transfer between the nanoparticles and the surrounding environment.

Nanoparticle-augmented photoacoustics is an emerging technique for molecular imaging. In many situations the photoacoustic response is not from the nanosized absorber but the very low-absorbing surrounding material and therefore photoacoustic imaging can provide information about the nanoparticle surface, and the immediate environment surrounding the particle, which is of high importance to molecular imaging. The information that can be gained includes the interfacial resistance, as well as the thermodynamic characteristic of the environment.

S.Y. Nam, L.M. Ricles, L.J. Suggs, S.Y. Emelianov, “In vivo ultrasound and photoacoustic monitoring of mesenchymal stem cells labeled with gold nanotracers,” PLoS ONE 7(5): e37267. doi:10.1371/journal.pone.0037267 (2012).

Summary: Ultrasound-guided photoacoustic imaging can be used to monitor mesenchymal stem cells labeled with gold nanotracers.

Longitudinal monitoring of cells is required in order to understand the role of delivered stem cells in therapeutic neovascularization. However, there is not an imaging technique that is capable of quantitative, longitudinal assessment of stem cell behaviors with high spatial resolution and sufficient penetration depth. In vivo and in vitro experiments were performed to demonstrate ultrasound-guided photoacoustic imaging can be an alternative approach in stem cell imaging capable of noninvasive, sensitive, quantitative, longitudinal assessment of stem cell behaviors with high spatial and temporal resolutions at sufficient depths.

S.Y. Nam, L.M. Ricles, L.J. Suggs, S.Y. Emelianov, “Nonlinear photoacoustic signal increase from endocytosis of gold nanoparticles,” Optics Letters, 37(22), 4708-4710 (2012).

Summary: Nonlinear effects can be exploited in molecular/cellular photoacoustic imaging.

Nonlinear photoacoustic effects, rarely seen in biomedical photoacoustic imaging of tissues, can manifest themselves strongly when plasmonic nanoparticles are used as imaging contrast agents. Specifically, nonlinear behavior of photoacoustic signal with modest laser fluences can occur when nanoparticles undergo cellular endocytosis and aggregation leading to thermal coupling and subsequent localized temperature enhancement. For in vitro tissue models containing cells, while the photoacoustic signal amplitude was linearly proportional to the cell/nanoparticle concentration, the photoacoustic signal increased nonlinearly as the laser fluence increased.

S.J. Yoon, A.M. Murthy, K.P. Johnston, K.V. Sokolov, and S.Y. Emelianov, “Thermal stability of biodegradable plasmonic nanoclusters in photoacoustic imaging,” Optics Express, 20(28):29479-87 (2012).

Summary: Biodegradable plasmonic nanoclusters can be effectively used for photoacoustic imaging and photothermal therapy.

The photothermal stability of plasmonic nanoparticles is critically important to perform reliable photoacoustic imaging and photothermal therapy. Three different sizes of biodegradable nanoclusters were synthesized and the optical properties and photothermal stability of the nanoclusters were studied and compared to that of gold nanorods. The results indicate that 40 nm and 80 nm biodegradable nanoclusters demonstrate higher photothermal stability compared to gold nanorods. Moreover, 40 nm nanoclusters produce higher photoacoustic signal than gold nanorods at a given concentration of gold.

L. Bayer, Y. S. Chen, S. Kim, S. Mallidi, K. Sokolov, and S. Emelianov, "Multiplex photoacoustic molecular imaging using targeted silica-coated gold nanorods," Biomedical optics express, vol. 2, pp. 1828-35, (2011).

Summary: Silica- coated gold nanorods can be used to distinguish cell inclusions in vitro.

Non-invasive multiplex molecular imaging technique capable of high resolution at significant tissue depths can be used to diagnose and monitor diseases such as cancer. A molecular imaging approach that is based on multispectral photoacoustic imaging of silica-coated gold nanorod contrast agents targeted to specific cell receptors allows for molecular imaging. Among other applications, silica-coated gold nanorods can be used to identify multiple cell types within heterogeneous tissue.  

P. Luke, D. Yeager, and S. Y. Emelianov, "Biomedical Applications of Photoacoustic Imaging with Exogenous Contrast Agents," Annals of biomedical engineering, (2011).

Summary: Photoacoustic imaging shows significant promise in its ability to assist in diagnosis, therapy planning, and monitoring of clinical outcomes for cancer, cardiovascular disease, and other pathologies.

 Photoacoustic imaging is a biomedical imaging modality that provides functional information, and, with the help of exogenous contrast agents, cellular and molecular signatures of tissue. Dyes, noble metal nanoparticles, and other constructs are contrast agents which can be combined with photoacoustic imaging for preclinical and clinical applications ranging from detection of cancer cells, sentinel lymph nodes, and micrometastasis to angiogenesis to characterization of atherosclerotic plaques. Multi-functional agents have also been developed, which can carry drugs or simultaneously provide contrast in multiple imaging modalities.

Y.-S. Chen, W. Frey, S. Kim, P. P. Kruizinga, K. Homan, and S. Emelianov, “Silica-coated gold nanorods as photoacoustic signal nano-amplifiers,” Nano Letters, 11(2), 348-354 (2011).

Summary: Silica-coated gold nanorods can be used to amplify the contrast in photoacoustic imaging.

Silica coated gold nanorods of the same optical density are capable of producing about 3-fold higher photoacoustic signals than nanorods without silica coating. In addition, silica coated gold nanorods can amplify the photoacoustic response without altering the optical absorption of nanoparticles other than shifting it slightly to the red.

Homan, S. Mallidi, E. Cooley, S. Emelianov. “Combined Photoacoustic and Ultrasound Imaging of Metal Nanoparticles In Vivo,” in: Nanoimaging (ed Goins BA and Phillips WT), Pan Stanford Series on Biomedical Nanotechnology Vol 3 Pan Stanford Publishing, Singapore, Chapter 12 (2011).

Summary: Photoacoustic imaging combines the advantages of optical and ultrasound imaging methods, resulting in the ability to detect metal nanoparticles deep in tissue in comparison with pure optical techniques.

Nanoparticles can be detected in vivo through photoacoustic imaging, which combines the benefits of optical and ultrasound imaging methods. In addition, gold and silver nanoparticles can be fabricated, functionalized, and utilized as contrast agents to enhance imaging quality.

Mallidi, M.Mehrmohammadi, K. Homan, B. Wang, M. Qu, T. Larson, K. Sokolov and S. Emelianov, “Ultrasound Based Molecular Imaging using Nanoagents", in Nanoplatform‐Based Molecular Imaging”, edited by Xiaoyuan Chen, John Wiley and Sons (2011).

Summary: Photoacoustic and magnetoacoustic imaging modalities can be integrated with ultrasound imaging systems.

Combined ultrasound, photoacoustic, and magnetoacoustic imaging allows for noninvasive, nonionizing, descent spatial resolution, and extended penetration depth. These complementary imaging modalities can simultaneously provide anatomical, optical, and biomechanical properties of tissue.

Ricles, S. Y. Nam, K. Sokolov, S. Y. Emelianov, and L. J. Suggs, "Function of mesenchymal stem cells following loading of gold nanotracers," International journal of nanomedicine, vol. 6, pp. 407-16, (2011).

Summary: Loading mesenchymal stem cells with gold nanotracers does not alter cell function, making long-term imaging and tracking of mesenchymal stem cells feasible.

Implementing a noninvasive, long-term imaging technique to track stem cells in vivo is required to obtain a better understanding of the wound healing response.  One imaging approach tracks mesenchymal stem cells (MSCs) in vivo after delivery via a polyethylene glycol modified fibrin matrix (PEGylated fibrin matrix) using MSCs loaded with gold nanoparticles as nanotracers. This enables imaging MSCs in vivo, such as with optical or photoacoustic imaging, to better understand the participation and role of MSCs in neovascularization.

Y.-S. Chen, W. Frey, S. Kim, K. Homan, P. P. Kruizinga, K. Sokolov, and S. Emelianov, “Enhanced thermal stability of silica-coated gold nanorods for photoacoustic imaging and image guided therapy,” Optics Express 18(9), 8867-8878 (2010).

Summary: Silica-coated gold nanorods are a multifunctional molecular imaging and therapeutic agent suitable for image-guided photothermal therapy

Under intense irradiation with nanosecond laser pulse, silica-coated gold nanorods showed increased photothermal stability and retained their superior optical properties under much higher fluences. Silica-coated gold nanorods provide a stable photoacoustic signal, which implies better imaging capabilities and make silica-coated gold nanorods a promising imaging and therapeutic nano-agent for photoacoustic imaging and image-guided photothermal therapy.

Homan, J. Shah, S. Gomez, H. Gensler, A. Karpiouk, L. Brannon-Peppas, and S. Emelianov, “Silver Nanosystems for Photoacoustic Imaging and Image-guided Therapy,” Journal of Biomedical Optics,15(2), 021316 (2010).

Summary: Silver nanosystems can be used as multifunctional agents capable of augmenting image-guided therapy techniques

A silver nanosystem is a potential contrast agent for photoacoustic imaging and image-guided therapy. The nanosystem consists of a porous silver layer deposited on the surface of spherical silica cores ranging in diameter from 180 to 520 nm. The porous nature of the silver layer allows for release of drugs or other therapeutic agents encapsulated in the core in future applications. The silver nanosystem is shown to be nontoxic in vitro at concentrations of silver up to 2 mg/ml. Additionally, the near-infrared absorbance properties of the nanosystem are demonstrated by measuring strong, concentration-dependent photoacoustic signal from the silver nanosystem embedded in an ex vivo tissue sample.

J. Yoon, S. Mallidi, J. M. Tam, J. O. Tam, A. Murthy, K. P. Johnston, K. V. Sokolov, and S. Y. Emelianov, "Utility of biodegradable plasmonic nanoclusters in photoacoustic imaging," Optics Letters, vol. 35, pp. 3751-3753 (2010).

Summary: Biodegradable gold nanoclusters can be used as effective contrast agents in photoacoustic imaging.

Plasmonic metal nanoparticles are used in photoacoustic imaging as contrast agents because of their resonant optical absorption properties in the visible and near-IR regions, but they can accumulate and result in long-term toxicity in vivo, because they are generally not biodegradable. Biodegradable plasmonic gold nanoclusters, consisting of sub-5 nm primary gold nanoparticles and biodegradable polymer stabilizer, are an alternative. Using photoacoustic and ultrasound imaging of a tissue-mimicking phantom with inclusions containing nanoclusters at various concentrations, biodegradable plasmonic gold nanoclusters are shown to be a feasible photoacoustic contrast agent.

Mallidi, T. Larson, J. Tam, P. P. Joshi, A. Karpiouk, K. Sokolov, and S. Emelianov, "Multiwavelength photoacoustic imaging and plasmon resonance coupling of gold nanoparticles for selective detection of cancer," Nano Lett, vol. 9, pp. 2825-2831 (2009).

Summary: Highly selective and sensitive detection of cancer cells is possible using multiwavelength photoacoustic imaging and molecular specific gold nanoparticles.

Gold nanoparticles targeting epidermal growth factor receptor via antibody conjugation undergo molecular specific aggregation when they bind to receptors on cell surfaces, leading to a red shift in their plasmon resonance frequency. Using subcutaneous tumor-mimicking gelatin implants in ex-vivo mouse tissue, multiwavelength photoacoustic imaging and plasmon resonance coupling of gold nanoparticles are shown to be an efficient molecular specific photoacoustic imaging technique.

Wang, E. Yantsen, T. Larson, A. B. Karpiouk, S. Sethuraman, J. L. Su, K. Sokolov, and S. Y. Emelianov, "Plasmonic intravascular photoacoustic imaging for detection of macrophages in atherosclerotic plaques," Nano Lett, vol. 9, pp. 2212-7 (2009).

Summary: Plasmonic imaging can assess the macrophage-mediated aggregation of nanoparticles and therefore identify the presence and the location of nanoparticles associated with macrophage-rich atherosclerotic plaques.

To detect macrophages in atherosclerotic plaques, plasmonic gold nanoparticles are introduced as a contrast agent for intravascular photoacoustic imaging. Phantom and ex vivo tissue studies show that the individual spherical nanoparticles, resonant at 530 nm wavelength, produce a weak photoacoustic signal at 680 nm wavelength while photoacoustic signal from nanoparticles internalized by macrophages is very strong due to the plasmon resonance coupling effect. The results indicate that intravascular photoacoustic imaging can be used to identify the location of nanoparticles that aggregate in macrophage-rich atherosclerotic plaques.

Nanoparticles for Non-Invasive Molecular Imaging and Other Applications

L. Truby, S. Y. Emelianov, and K. A. Homan, "Ligand-mediated self-assembly of hybrid plasmonic and superparamagnetic nanostructures," Langmuir : the ACS journal of surfaces and colloids, vol. 29, pp. 2465-70 (2013).

Summary: Self-assembled hybrid plasmonic and superparamagnetic nanostructures are suitable for biomedical imaging and therapy applications

An aqueous-based, self-assembly approach to synthesizing hybrid plasmonic-superparamagnetic nanostructures uses plasmonic gold nanorods (AuNRs) and superparamagnetic iron oxide nanoparticles (SPIONs) as its building blocks. The AuNRs are functionalized via carboxyl-bearing surface ligands, and the SPIONs are kept unmodified after synthesis via a surfactant-free thermal decomposition reaction in triethylene glycol. Hybrid SPION-studded AuNR nanostructures are produced upon simple mixing of the components. This synthesis strategy is modular in nature and can be expanded to build hybrid nanostructures with a multitude of other plasmonic nanoparticles.

P.P. Joshi, S.J. Yoon, W.G. Hardin, S. Emelianov, K.V. Sokolov, Conjugation of antibodies to gold nanorods through fc portion: synthesis and molecular specific imaging,” Bioconjugate Chemistry 24(6):878-88 (2013).

Summary: Directional antibody conjugation to gold nanorod surfaces can address shortcomings of current conjugation methods.

The tunability and strong extinction cross sections in the near-infrared to red spectral region of anisotropic gold nanorods have created significant interest in the development of antibody conjugation methods for synthesis of targeted nanorods for a number of biomedical applications, including molecular specific imaging and therapy. However, the current conjugation methods have several downsides including low stability and potential cytotoxicity of bioconjugates that are produced by electrostatic interactions, as well as lack of control over antibody orientation during covalent conjugation. Directional antibody conjugation to gold nanorod surfaces has the potential to avoid these downsides.

P.P. Joshi, S.J. Yoon, Y.-S. Chen, S. Emelianov, and K.V. Sokolov, “Development and optimization of near-IR contrast agents for immune cell tracking,” Biomedical Optics Express, 4(11):2609-2618 (2013).

Summary: Silica-coated nanorods can potentially be used with photoacoustic imaging to track immune cells.

Gold nanorods (NRs) are attractive for in vivo imaging due to their high optical cross-sections and tunable absorbance. However, the feasibility of using NRs for cell tracking has not been fully explored. Dye doped silica-coated NRs are a potential multimodal contrast agent for imaging of macrophages - immune cells which play an important role in cancer and cardiovascular diseases.

Wu CH, Huang YY, Chen P, Hoshino K, Liu H, Frenkel EP, Zhang JXJ, Sokolov KV. Versatile Immunomagnetic Nanocarrier Platform for Capturing Cancer Cells, ACS Nano v. 7(10): 8816-8823 (2013).

Summary: The combination of immunotargeted magnetic nanocarriers with microfluidics provides an important platform that can improve the effectiveness of current circulating tumor cell assays.

Recently, efforts have been directed toward development of antibody-capture assays based on the expression of the common biomarker-the epithelial cell adhesion molecule (EpCAM) of epithelium-derived cancer cells. Despite some promising results, the assays relying on EpCAM capture have shown inconsistent sensitivity in clinical settings and often fail to detect circulating tumor cells (CTCs) in patients with metastatic cancer. An assay based on hybrid magnetic/plasmonic nanocarriers and a microfluidic channel addresses these problems. In this assay, cancer cells are specifically targeted by antibody-conjugated magnetic nanocarriers and are separated from normal blood cells by a magnetic force in a microfluidic chamber, and immunofluorescence staining is used to differentiate CTCs from normal blood cells.

Murthy AK, Stover RJ, Hardin WG, Schramm R, Nie GD, Gourisankar S, Truskett TM, Sokolov KV, Johnston KP. Charged Gold Nanoparticles with Essentially Zero Serum Protein Adsorption in Undiluted Fetal Bovine Serum, JACS v. 135(21): 7799-7802 (2013).

Summary: Charged gold nanoparticles have essentially zero protein adsorption in pure fetal bovine serum.

The adsorption of even a single serum protein molecule on a gold nanosphere used in biomedical imaging may increase the size too much for renal clearance. Charged ~5 nm Au nanospheres coated with binary mixed-charge ligand monolayers do not change in size upon incubation in pure fetal bovine serum (FBS). This lack of protein adsorption is unexpected in view of the fact that the Au surface is moderately charged.

Murthy AK; Stover RJ; Borwankar AU; Nie GD; Gourisankar S; Truskett TM; Sokolov KV; Johnston KP. Equilibrium Gold Nanoclusters Quenched with Biodegradable Polymers, ACS Nano v.7(1): 239-251 (2013).

Summary: Equilibrium Au nanoclusters of controlled size can be assembled by tuning colloidal interactions with a polymeric stabilizer.

Although sub-100 nm nanoclusters of metal nanoparticles are of interest in many fields including biomedical imaging, sensors, and catalysis, it has been challenging to control their morphologies and chemical properties. A new concept is presented to assemble equilibrium Au nanoclusters of controlled size with the polymeric stabilizer, PLA(1k)-b-PEG(10k)-b-PLA(1k). The close spacings of the Au nanoparticles in the clusters produce strong NIR extinction over a broad range of wavelengths from 650 to 900 nm, which is of practical interest in biomedical imaging.

Ma LL, Borwankar AU, Willsey BW, Yoon KY, Tam JO, Sokolov KV, Feldman MD, Milner TE,  Johnston KP. Growth of textured thin Au coatings on iron oxide nanoparticles with near infrared absorbance, Nanotechnology v. 24: 025606 (2013).

Summary: Thin Au coatings on iron oxide nanoparticles can be synthesized in order to shift surface plasmon resonance to the near infrared with large extinction coefficients.

A homologous series of Au coated iron oxide nanoparticles with hydrodynamic diameters smaller than 60 nm can be synthesized with very low Au-to-iron mass ratios, as low as 0.15. This approach produces unusually thin coatings by lowering autocatalytic growth of Au on Au, as shown by transmission electron microscopy. The coatings are sufficiently thin to shift the surface plasmon resonance to the near infrared with large extinction coefficients, despite the small particle hydrodynamic diameters observed from dynamic light scattering to be less than 60 nm.

Jenkins JT, Halaney DL, Sokolov KV, Ma LL, Shipley HJ, Mahajan S, Louden CL, Asmis R, Milner TE, Johnston KP, Feldman MD. Excretion and toxicity of gold–iron nanoparticles, Nanomedicine v. 9(3): 356-365 (2013).

Summary: Nanoclustering of gold and iron oxide as a nanoparticle (nanorose)  biodegrades into subunits to facilitate rapid excretion and reduces the potential for toxicity.

Gold nanoparticles have been classically considered bio-inert, but recent studies have questioned their safety.  A clustering gold and iron oxide nanoparticle (nanorose), which biodegrades into subunits to facilitate rapid excretion can result in reduced toxicity. The clustering design of nanorose enhances the excretion of these nanoparticles, making it a viable strategy to limit the potential toxicity of gold nanoparticles for clinical applications.

Huang YY, Hoshino K, Chen P, Wu CH, Lane N, Huebschman M, Liu H, Sokolov K, Uhr JW, Frenkel EP, Zhang JXJ. Immunomagnetic nanoscreening of circulating tumor cells with a motion controlled microfluidic system, Biomed. Microdevices v. 15(4): 673-681 (2013).

Summary: Microchip-based immunomagnetic system shows great promise as a clinical tool for cancer diagnosis and prognosis.

Using the power of immunomagnetic assay and microfluidic microchip operations, it is possible to successfully detect rare CTCs from clinical blood samples. The microfluidic system is operated in a flip-flop mode, where a computer-controlled rotational holder with an array of microfluidic chips inverts the microchannels. The developed immunomagnetic microchip-based screening system exhibits high capture rates (more than 90%) for SkBr3, PC3, and Colo205 cell lines in spiked screening experiments and successfully isolates CTCs from patient blood samples.

Murthy AK, Stover RJ, Hardin WG, Schramm R, Nie GD, Gourisankar S, Truskett TM, Sokolov KV, Johnston KP. Charged Gold Nanoparticles with Essentially Zero Serum Protein Adsorption in Undiluted Fetal Bovine Serum, JACS v. 135(21): 7799-7802 (2013).

Summary: Charged gold nanoparticles have essentially zero protein adsorption in pure fetal bovine serum.

The adsorption of even a single serum protein molecule on a gold nanosphere used in biomedical imaging may prevent renal clearance. Charged ~5 nm Au nanospheres coated with binary mixed-charge ligand monolayers do not change in size upon incubation in pure fetal bovine serum (FBS). This lack of protein adsorption is unexpected considering the fact that the gold surface is moderately charged.

Chung, S.Y. Nam, L.M. Ricles, S.Y. Emelianov, and L.J. Suggs. “Evaluation of gold nanotracers to track adipose-derived stem cells in a PEGylated fibrin gel for dermal tissue engineering applications,” International Journal of Nanomedicine, 8:325-36 (2013).

Summary: Utilization of gold nanotracers can be an effective strategy to monitor the regenerative process of a stem cell source in a 3D gel for vascular and dermal tissue engineering applications.

Adipose-derived stem cells (ASCs) as a mesenchymal cell source to regenerate skin and blood vessels due to their potential for proliferation, differentiation, and production of growth factors; however, tracking and monitoring ASCs in a 3D scaffold, such as a PEGylated fibrin gel, have not yet been fully investigated. Nanoscale gold spheres (20 nm) can be used cell tracers for ASCs cultured in a PEGylated fibrin gel. The ASCs take up gold nanotracers and can be detected up to day 16 with high sensitivity using photoacoustic imaging,  detrimental effects on the ASCs.

Larson TA, Joshi PP, Sokolov K. Preventing Protein Adsorption and Macrophage Uptake of Gold Nanoparticles via a Hydrophobic Shield, ACS Nano v. 6(10): 9182-9190 (2012).

Summary: Physiological concentrations of cysteine and cystine can prevent protein adsorption and cell uptake in macrophages.

Polyethylene glycol (PEG) surface coatings are widely used to render stealth properties to nanoparticles in biological applications. The physiological concentrations of cysteine and cystine can displace methoxy-PEG-thiol molecules from the gold nanoparticle (GNP) surface that leads to protein adsorption and cell uptake in macrophages within 24 h. Incorporating an alkyl linker between the PEG and the thiol moieties further reduces protein adsorption on GNPs and their macrophage uptake. This has important implications for the design of GNP for biological systems.

Yokoyama T, Tam J, Kuroda S, Scott AW, Aaron J, Larson T, Shanker M, Correa AM, Kondo S, Roth JA, Sokolov K, Ramesh R. EGFR-targeted hybrid plasmonic magnetic nanoparticles synergistically induce autophagy and apoptosis in non-small cell lung cancer cells, PLoS ONE v.6(11): e25507 (2011).

Summary: The molecular mechanism of EGFR-targeted hybrid plasmonic nanoparticles  induces cytotoxic effects in lung cancer cells thus increasing efficacy of therapy against non-small cell lung cancer cells.

To develop more effective therapies for lung cancer, the anti-EGFR antibody (Clone 225) can be used as a molecular therapeutic with hybrid plasmonic magnetic nanoparticles (NP). C225-NP exhibited a strong and selective antitumor effect on EGFR-expressing non-small cell lung cancer (NSCLC) cells by inhibiting EGFR-mediated signal transduction, induced autophagy and apoptosis in tumor cells. The molecular mechanism of C225-NP induced cytotoxic effects in lung cancer cells that are not characteristic for free molecular therapeutics thus increasing efficacy of therapy against NSCLC.

Mehrmohammadi M, Qu M, Ma LL, Romanovicz DK, Johnston KP, Sokolov KV, Emelianov SY. Pulsed magneto-motive ultrasound imaging to detect intracellular trafficking of magnetic nanoparticles, Nanotechnology v. 22(41): 415105, (2011).

Summary: Pulsed magneto-motive ultrasound  imaging can not only detect the presence of magnetic nanoparticles but also provide information about their intracellular accumulation non-invasively and in real-time

Magnetic nanoparticles, despite their wide range of clinical applications, do not exhibit plasmonic-resonant properties and therefore their intracellular aggregation cannot be detected by optics-based imaging techniques. A novel imaging technique-pulsed magneto-motive ultrasound (pMMUS) can be used to identify intracellular accumulation of endocytosed magnetic nanoparticles. In pMMUS imaging a focused, high intensity, pulsed magnetic field is used to excite the cells labeled with magnetic nanoparticles, and ultrasound imaging is then used to monitor the mechanical response of the tissue. pMMUS imaging can identify interaction between magnetic nanoparticles and living cells.

Ma LL, Tam JO, Willsey BW, Rigdon D, Ramesh R, Sokolov K*, Johnston KP* Selective targeting of antibody conjugated multifunctional nanoclusters (nanoroses) to epidermal growth factor receptors in cancer cells, Langmuir v. 27(12): 7681-7690  (2011).

Summary:  The ability to load intense multifunctionality conjugation of an antibody monolayer in addition to a strong magnetic resonance imaging contrast can be used in the development of theranostic agents for combined molecular specific imaging and therapy.

The ability of antibody (Ab) nanoparticle conjugates smaller than 100 nm to target and modulate the biology of specific cell types may enable major advancements in cellular imaging and therapy in cancer. A key challenge is to load a high degree of targeting, imaging, and therapeutic functionality into small, yet stable particles. Thin autocatalytic growth on substrate (TAGs) can be used to form ultrathin and asymmetric gold coatings on iron oxide nanocluster cores producing exceptional near-infrared (NIR) absorbance, along with AlexaFluor 488 labeled Abs that are used to correlate the number of Abs conjugated to iron oxide/gold nanoclusters (nanoroses) with the hydrodynamic size. The nanoclusters conjugated with monoclonal Abs specific for epidermal growth factor receptor (EGFR) show targeted efficiency and intense NIR scattering.

Doiron, K. Homan, S. Emelianov, L. Brannon-Peppas, “Poly(Lactic-co-Glycolic) Acid as a Carrier for Imaging Contrast Agents,” J Pharm Res, 26(3), 674-82 (2009).

Summary: The biodegradable polymer PLGA is an extremely versatile nano- and micro-carrier for several imaging contrast agents with the possibility of targeting diseased states at a molecular level.

With the broadening field of nanomedicine poised for future molecular level therapeutics, nano- and microparticles intended for the augmentation of either single- or multimodal imaging are created with PLGA as the chief constituent and carrier. Emulsion techniques can be used to encapsulate hydrophilic and hydrophobic imaging contrast agents in PLGA particles. The imaging contrast properties of these PLGA particles can be further enhanced by reducing silver onto the PLGA surface, creating a silver cage around the polymeric core.

Aaron, K. Travis, N. Harrison, and K. Sokolov, "Dynamic imaging of molecular assemblies in live cells based on nanoparticle plasmon resonance coupling," Nano Lett, vol. 9, pp. 3612-8 (2009).

Summary: Nanoparticle plasmon resonance coupling can be used in dynamic imaging of molecular assemblies in life cells.

Molecular-specific gold nanoparticles can be used to monitor epidermal growth factor receptors (EGFR) in live A431 cells over time. Dark-field hyperspectral imaging, electron microscopy, and electrodynamic modeling correlate optical properties of EGFR-bound plasmonic nanoparticles with receptor regulation state. Receptor trafficking results in a progressive red shift of greater than 100 nm in the nanoparticle plasmon resonance wavelength over a time period of 60 min. Changes in peak scattering wavelengths of gold nanoparticles from 546 +/- 15 to 574 +/- 20, and to 597 +/- 44 nm are associated with EGFR trafficking from the cell membrane. Changes in scattering spectra of EGFR-bound nanoparticles and a straightforward statistical analysis of RGB-channel color images of labeled cells can be used to create near real-time maps of EGFR regulatory states in living cells.

Kumar, J. Aaron, and K. Sokolov, "Directional conjugation of antibodies to nanoparticles for synthesis of multiplexed optical contrast agents with both delivery and targeting moieties," Nat Protoc, vol. 3, pp. 314-20 (2008).

Summary: A novel conjugation technique can be used to control the binding orientation of antibodies on the surface of gold nanoparticles to maximize antibody functionality.

A heterobifunctional linker, hydrazide-polyethylene glycol-dithiol, is used to directionally attach the Fc, or nonbinding region of the antibody, to the gold nanoparticle surface. The conjugation strategy allows for multiplexing various glycosylated antibodies on a single nanoparticle. Preparing multifunctional nanoparticles by incorporating targeting and delivery moieties on the same nanoparticle can address the challenge of imaging intracellular biomarkers.

Aaron, N. Nitin, K. Travis, S. Kumar, T. Collier, S. Y. Park, M. Jose-Yacaman, L. Coghlan, M. Follen, R. Richards-Kortum, and K. Sokolov, "Plasmon resonance coupling of metal nanoparticles for molecular imaging of carcinogenesis in vivo," J Biomed Opt, vol. 12, p. 034007 (2007).

Summary: EGFR-mediated aggregation of gold nanoparticles dramatically increasing contrast in images of normal and precancerous epithelium in vivo beyond values reported previously for antibody-targeted fluorescent dyes

Molecular imaging of carcinogenesis can be done using an in vivo application of plasmon coupling. Labeling with gold bioconjugates gives information on the overexpression and nanoscale spatial relationship of EGF receptors in cell membranes, both of which are altered in neoplasia. EGFR-mediated aggregation of gold nanoparticles in neoplastic cells results in more than a 100-nm color shift and a contrast ratio of more than tenfold in images of normal and precancerous epithelium in vivo.

Kumar, N. Harrison, R. Richards-Kortum, and K. Sokolov, "Plasmonic nanosensors for imaging intracellular biomarkers in live cells," Nano Lett, vol. 7, pp. 1338-43 (2007).

Summary: Multifunctional nanosensors can be adapted to target various intracellular processes especially where transfection or cytotoxic labels are not feasible.

Multifunctional gold nanoparticles which incorporate both cytosolic delivery and targeting moieties on the same particle can be used for an intracellular molecular imaging platform. The utility of these intracellular sensors can be demonstrated by monitoring actin rearrangement in live fibroblasts. Strong molecular specific optical signal are associated with effective targeting of actin filaments.

Sokolov, M. Follen, J. Aaron, I. Pavlova, A. Malpica, R. Lotan, and R. Richards-Kortum, "Real-time vital optical imaging of precancer using anti-epidermal growth factor receptor antibodies conjugated to gold nanoparticles," Cancer Res, vol. 63, pp. 1999-2004 (2003).

Summary: Gold conjugates as contrast agents have potential to extend the ability of vital reflectance microscopies for in vivo molecular imaging

Gold bioconjugates a new class of molecular specific contrast agents for vital reflectance imaging based on gold nanoparticles attached to probe molecules with high affinity for specific cellular biomarkers. Gold conjugates can be delivered topically for imaging throughout the whole epithelium. These contrast agents can potentially enable combined screening, detection, and therapy of disease using inexpensive imaging systems; such tools could allow mass screening of diseases such as cancer in resource-poor settings.

Photoacoustic (Optoacoustic) Imaging and Associated Devices/Methods

Luke and S. Emelianov, "Optimization of in vivo spectroscopic photoacoustic imaging by smart optical wavelength selection," Opt. Lett. 39, 2214-2217 (2014).

Summary: Spectroscopic photoacoustic (sPA) image quality is more accurately preserved when wavelengths are chosen based on the spectral features of the absorbers instead of selecting evenly spaced wavelengths.

sPA imaging is an emerging biomedical imaging modality which can be used to simultaneously visualize multiple optical absorbers in tissue.  This study show the positive effect the wavelength selection has on in vivo sPA imaging in terms of reducing image acquisition time while maintaining image quaity.

Bouchard, O. Sahin, S. Emelianov, “Ultrasound-guided photoacoustic imaging: current state and future development,” IEEE Transactions on Ultrasonics, Ferroelectrics and Frequency Control, 61(3): 450-466 (2014).

Summary: Photoacoustic imaging, frequently combined with ultrasound imaging can provide functional and cellular/molecular information about tissue in addition to morphological information provided by ultrasound imaging.

The future of photoacoustic imaging in clinical applications is closely intertwined with ultrasound imaging with the biggest advantage being its ability to provide real-time visualization of soft tissue.

Stover, A. Murthy, S. Gourisankar, G. Nie, M. Martinez, T. Truskett, K. Sokolov, K. Johnston, “Plasmonic biodegradable gold nanoclusters with high NIR-absorbance for biomedical imaging ", Proc. SPIE 8955, Colloidal Nanoparticles for Biomedical Applications IX, 89550T (2014).

Summary: A novel method to assemble equilibrium gold nanoclusters using 5 nm primary gold nanospheres, which exhibit high near-infrared (NIR) absorbance and are capable of fully dissociating back to original 5 nm particles that can be renally cleared.

Gold plasmonic nanoparticles are being used in various types of NIR optical biomedical imaging including photoacoustic imaging. This method can take advantage of cluster formation that can facilitate high NIR absorption for photoacoustic imaging. The clusters susequently can dissociate back to primary particles small enough for renal clearance thus reducing tissue accumulation concerns.

Yeager, Y.-S. Chen, S. Litovsky, S. Emelianov, “Intravascular photoacoustics for image-guidance and temperature monitoring during plasmonic photothermal therapy of atherosclerotic plaques: a feasibility study,” Theranostics, 4(1):36-46 (2014).

Summary: Intravascular ultrasound and photoacoustic imaging provides a platform for detection and temperature monitoring of atherosclerotic plaques through the selective heating of plasmonic gold nanoparticle contrast agents.

Intravascular ultrasound and photoacoustic (IVUS/IVPA) imaging can be used as a tool for localized temperature monitoring during laser heating. The temperature dependent change in IVPA signal intensity of silica-coated gold nanorod contrast agents absorbing within the near-infrared optical wavelength range has a linear relationship, with a slope greater than that of endogenous tissue. A continuous wave laser, when incorporated into the IVUS/IVPA integrated catheter, can be utilized to selectively heat the nanoparticles with simultaneous IVPA temperature monitoring. 

G.P. Luke, S.Y. Nam, S.Y. Emelianov, “Optical wavelength selection for improved spectroscopic photoacoustic imaging,” Photoacoustics, 1(2):36-42 (2013).

Summary: A developed algorithm can provide a versatile framework to select optical wavelengths and evaluate sets of absorbers for spectroscopic photoacoustic imaging.

Spectroscopic photoacoustic imaging has the potential to become a powerful tool that can estimate distributions of optically absorbing chromophores in the body.  A developed algorithm uses the smallest singular value of a matrix constructed from the absorption spectra as a criterion to remove extraneous wavelengths. This algorithm can be used to select imaging wavelengths for spectroscopic photoacoustics given the spectra of expected chromophores.

Wang, A. Karpiouk, D. Yeager, J. Amirian, S. Litovsky, R. Smalling, and S. Emelianov, “Intravascular photoacoustic imaging of lipid in atherosclerotic plaques in the presence of luminal blood,” Optics Letters, 37(7), 1244-1246 (2012).

Summary: It is possible to detect lipid in atherosclerotic plaques in vivo using combined intravascular ultrasound and photoacoustic imaging.

Intravascular photoacoustic (IVPA) imaging can characterize atherosclerotic plaque composition on the basis of the optical absorption contrast between different tissue types. Strong optical absorption of lipid combined with low background signal from other tissues provides a high-contrast, depth-resolved IVPA images.

Wang, A. Karpiouk, D. Yeager, J. Amirian, S. Litovsky, R. Smalling, and S. Emelianov, “In vivo intravascular ultrasound-guided photoacoustic imaging of lipid in plaques using an animal model of atherosclerosis,” Ultrasound in Medicine and Biology, 38(12):2098-103 (2012).

Summary: In vivo intravascular ultrasound-guided photoacoustic imaging can detect rupture-prone plaques

Both in vivo and ex vivo ultrasound-guided intravascular photoacoustic (IVPA) images clearly can show the distribution of lipid in atherosclerotic vessels. In vivo IVPA imaging is able to identify diffuse, lipid-rich plaques in a Watanabe heritable hyperlipidemic (WHHL) rabbit model of atherosclerosis. Furthermore, IVPA imaging at a single wavelength is able to identify the lipid core within the human right coronary artery ex vivo.  The images can obtained in presence of luminal blood, without the need for saline flush or balloon occlusion. Ultrasound-guided IVPA imaging can potentially be used for depth-resolved visualization of lipid deposits within the anatomical context of the vessel wall and lumen.

Karpiouk, B. Wang, J. Amirian, R. Smalling, and S. Emelianov, “Feasibility of in vivo intravascular photoacoustic imaging using integrated ultrasound and photoacoustic imaging catheter,” Journal of Biomedical Optics, 17(9), 096008,  doi:10.1117/1.JBO.17.9.096008 (2012).

Summary: In vivo intravascular photoacoustic imaging is feasible using the integrated ultrasound and photoacoustic imaging catheter.

A prototype of an integrated  intravascular ultrasound (IVUS) and intravascular photoacoustic (IVPA) imaging catheter consisting of a single-element ultrasound transducer and a light delivery system based on a single optical fiber can be adapted and used for in vivo imaging of a coronary stent deployed in a rabbit's thoracic aorta in the presence of luminal blood. Using the catheter, in vivo IVUS/IVPA imaging is feasible.

Yeager, A. Karpiouk, B. Wang, J. Amirian, K. Sokolov, R. Smalling, and S. Emelianov, “Intravascular photoacoustic imaging of exogenously labeled atherosclerotic plaque through luminal blood,” Journal of Biomedical Optics, 17(10), 106016,  doi: 10.1117/1.JBO.17.10.106016 (2012).

Summary: Gold nanorod detection within the arterial wall can be achieved using intravascular ultrasound and intravascular photoacoustic imaging, even in the case of imaging through luminal blood.

Combined intravascular ultrasound and intravascular photoacoustic (IVUS/IVPA) imaging is a viable mean for assessing atherosclerotic plaque morphological and compositional characteristics using both endogenous and exogenous contrast. Ex vivo imaging results imaging of atherosclerotic rabbit aortas following systemic injection of gold nanorods (AUNRs) reveal a high photoacoustic signal from localized AUNRs in regions with atherosclerotic plaques. Histological staining further confirms the preferential extravasation of AUNRs in atherosclerotic regions with compromised luminal endothelium and acute inflammation.

Kim, Y. S. Chen, G. P. Luke, and S. Y. Emelianov, "In vivo three-dimensional spectroscopic photoacoustic imaging for monitoring nanoparticle delivery," Biomedical Optics Express, vol. 2, pp. 2540-2550 (2011).

Summary: Three-dimensional ultrasound-guided spectroscopic PA imaging can monitor nanoparticle delivery in vivo.

In vivo monitoring of nanoparticle delivery is essential to better understand cellular and molecular interactions of nanoparticles with tissue and to better plan nanoparticle-mediated therapies. Three-dimensional ultrasound and photoacoustic (PA) imaging system and a spectroscopic PA imaging algorithm can be used to identify and quantify the presence of nanoparticles and other tissue constituents.

Qu, S. Mallidi, M. Mehrmohammadi, P. Joshi, K. Homan, Y. Chen, and S. Emelianov, “Magneto-photo-acoustic imaging,” Biomedical Optics Express, 2(2), 385–395 (2011).

Summary: Magneto-photo-acoustic imaging is capable of identifying the nanoparticle-labeled pathological regions from the normal tissue, providing a promising platform to noninvasively diagnose and characterize pathologies.

Hybrid nanoconstructs, liposomes encapsulating gold nanorods and iron oxide nanoparticles, can be used as a dual-contrast agent for magneto-photo-acoustic imaging. Magneto-photo-acoustic imaging is capable of visualizing the location of cells or tissues labeled with dual-contrast nanoparticles with sufficient contrast, excellent contrast resolution and high spatial resolution in the context of the anatomical structure of the surrounding tissues.

Mallidi, G. P. Luke, and S. Emelianov, "Photoacoustic imaging in cancer detection, diagnosis, and treatment guidance," Trends in biotechnology, vol. 29, pp. 213-21 (2011).

Summary: Photoacoustics and photoacoustic-augmented imaging play an important role in the clinical management of cancer, including screening, diagnosis, treatment planning and therapy monitoring.

Ultrasound-guided photoacoustics is able to provide in vivo morphological and functional information about the tumor within the surrounding tissue. With targeted contrast agents, photoacoustics is also capable of in vivo molecular imaging, thus facilitating further molecular and cellular characterization of cancer.

Su, B. Wang, K. Wilson, C. Bayer, Y-S. Chen, S. Kim, K. Homan, and S. Emelianov, “Advances in Clinical and Biomedical Applications of Photoacoustic Imaging,” Expert Opinion on Medical Diagnostics, 4(6), 497-510 (2010).

Summary: Photoacoustic imaging offers unique advantages over existing imaging modalities.

The imaging field is broad with many exciting applications for detecting and diagnosing diseased tissue or processes. Photoacoustics is also used in therapeutic applications to identify and characterize the pathology and then to monitor the treatment. Although the technology is still in its infancy, much work has been done in the pre-clinical arena, and photoacoustic imaging is fast approaching the clinical setting.

Homan, S. Kim, Y. Chen, B. Wang, S. Mallidi, and Stanislav Emelianov, “Prospects of molecular photoacoustic imaging at 1064 nm wavelength,” Optics Letters, 35(15), 2663-2665 (2010).

Summary: Contrast-enhanced photoacoustic imaging at 1064 nm enables high contrast when exogenous, molecularly targeted agents are employed.

Contrast-enhanced photoacoustic (PA) imaging at 1064 nm is advantageous because it provides a homogeneous signal from native tissue. Of all the wavelengths tested in a range from 710 to 1064 nm, the background PA signal from tissue in vivo was lowest and more homogeneous at 1064 nm. Furthermore, when plasmonic nanoparticles, such as silver nanoplates, were introduced in vivo as contrast agents, the contrast in PA images at 1064 nm increased 38% compared to 750 nm.

Sethuraman, S. R. Aglyamov, R. W. Smalling, and S. Y. Emelianov, "Remote temperature estimation in intravascular photoacoustic imaging," Ultrasound Med Biol, vol. 34, pp. 299-308 (2008).

Summary: Intravascular ultrasound-guided photoacoustic imaging can be used to estimate a laser-induced temperature increase in tissue.

Monitoring spatio-temporal temperature changes associated with laser-tissue interaction is important to address thermal safety of IVPA imaging, which can be done using IVUS-based strain measurements. Furthermore, analysis based on the Arrhenius thermal damage model indicates that intravascular photoacoustic (IVPA) imaging causes no thermal injury in the arterial tissue, suggesting the safety of IVPA imaging

Shah, S. R. Aglyamov, K. Sokolov, T. E. Milner, and S. Y. Emelianov, "Ultrasound imaging to monitor photothermal therapy - feasibility study," Opt Express, vol. 16, pp. 3776-85 (2008).

Summary: Ultrasound imaging is a candidate approach to remotely guide photothermal therapy.

Ultrasound imaging can be used to monitor temperature changes during photothermal treatment. Ultrasound thermal imaging, performed during laser heating on tissue-mimicking phantoms and ex-vivo animal tissue samples, shows that the temperature elevation is localized to a region of embedded or injected gold nanoparticles.

Shah, S. Park, S. Aglyamov, T. Larson, L. Ma, K. Sokolov, K. Johnston, T. Milner, and S. Y. Emelianov, "Photoacoustic imaging and temperature measurement for photothermal cancer therapy," J Biomed Opt, vol. 13, p. 034024 (2008).

Summary: Photoacoustic imaging, augmented by ultrasound imaging, is a viable candidate to guide photoabsorber-enhanced photothermal therapy

Photothermal therapy is a noninvasive, targeted, laser-based technique for cancer treatment. During photothermal therapy, light energy is converted to heat by tumor-specific photoabsorbers. The corresponding temperature rise causes localized cancer destruction. For effective treatment, however, the presence of photoabsorbers in the tumor must be ascertained before therapy and thermal imaging must be performed during therapy. Guiding photothermal therapy with photoacoustic imaging can be used to detect photoabsorbers and to monitor temperature elevation.

Sethuraman, S. R. Aglyamov, J. Amirian, R. Smalling, and S. Y. Emelianov, "Development of a combined intravascular ultrasound and photoacoustic imaging system," Proceedings of the SPIE Photonics West, vol. 6086, pp. 101-117 (2006).

Summary: Intravascular ultrasound and photoacoustic imaging can be used as an imaging system in interventional cardiology.

Intravascular ultrasound (IVUS) imaging has emerged as an imaging technique to evaluate coronary artery diseases including vulnerable plaques. However, in addition to the morphological characteristics provided by IVUS imaging, there is a need for functional imaging capability that could identify the composition of vulnerable plaques. Intravascular photoacoustic (IVPA) imaging, in conjunction with clinically available IVUS imaging, can be such a technique allowing vulnerable plaque characterization and differentiation.

Y. Emelianov, S. R. Aglyamov, J. Shah, S. Sethuraman, W. G. Scott, R. Schmitt, M. Motamedi, A. Karpiouk, and A. Oraevsky, "Combined ultrasound, optoacoustic, and elasticity imaging," Proceedings of the SPIE Photonics West, vol. 5320, pp. 101-112 (2004).

Summary: Monitoring cancer treatment and guidance of tissue biopsy is possible with a combined ultrasound, optoacoustic, and elasticity imaging system.

The combination of three complementary imaging technologies - ultrasound imaging, elastography, and optoacoustic imaging - can be used for the detection and diagnostics of tissue pathology including cancer. The fusion of these ultrasound-based techniques results in a novel imaging system capable of simultaneous imaging of the anatomy (ultrasound imaging), cancer-induced angiogenesis (optoacoustic imaging) and changes in mechanical properties (elasticity imaging) of tissue to uniquely identify and differentiate tissue pathology at different cancer stages.