Mohammad Mehrmohammadi

Photoacoustic Imaging for Cancer Detection and Staging

Cancer is one of the leading causes of death in the world. Diagnosing a cancer at its early stages of development can decrease the mortality rate significantly and reduce healthcare costs. Over the past two decades, photoacoustic imaging has seen steady growth and has demonstrated notable capabilities to detect cancerous cells and stage cancer. Furthermore, photoacoustic imaging combined with ultrasound imaging and augmented with molecular targeted contrast agents is capable of imaging cancer at the cellular and molecular level, thus opening diverse opportunities to improve diagnosis of tumors, detect circulating tumor cells and identify metastatic lymph nodes. In this paper we introduce the principles of photoacoustic imaging, and review recent developments in photoacoustic imagingas an emerging imaging modality for cancer diagnosis and staging.

Magneto-photo-acoustic imaging

Magneto-photo-acoustic imaging, a technique based on the synergy of magneto-motive ultrasound, photoacoustic and ultrasound imaging, is introduced. Hybrid nanoconstructs, liposomes encapsulating gold nanorods and iron oxide nanoparticles, were used as a dual-contrast agent for magneto-photo-acoustic imaging. Tissue-mimicking phantom and macrophage cells embedded in ex vivo porcine tissue were used to demonstrate that 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. Therefore, 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.

Pulsed Magneto-motive Ultrasound Imaging Using Ultrasmall Magnetic Nanoprobes

Nano-sized particles are widely regarded as a tool to study biologic events at the cellular and molecular levels. However, only some imaging modalities can visualize interaction between nanoparticles and living cells. We present a new technique, pulsed magnetomotive ultrasound imaging, which is capable of in vivo imaging of magnetic nanoparticles in real time and at sufficient depth. In pulsed magneto-motive ultrasound imaging, an external high-strength pulsed magnetic field is applied to induce the motion within the magnetically labeled tissue and ultrasound is used to detect the induced internal tissue motion. Our experiments demonstrated a sufficient contrast between normal and iron-laden cells labeled with ultrasmall magnetic nanoparticles. Therefore, pulsed magnetomotive ultrasound imaging could become an imaging tool capable of detecting magnetic nanoparticles and characterizing the cellular and molecular composition of deep-lying structures.

8B-2 Imaging of Iron Oxide Nanoparticles Using Magneto-Motive Ultrasound

Due to its excellent spatial resolution, fast and reliable performance, cost and wide availability, ultrasound should be considered the imaging modality of choice for many applications including molecular imaging. However, ultrasound imaging cannot image molecular content of tissue due to trade-off between spatial resolution and penetration depth. Consequently, contrast agents have been developed both to enhance the contrast of ultrasound images and to make the images molecularly specific. Most ultrasound contrast agents, however, are micrometer sized and may not be applicable to wide range of pathology-specific cellular and molecular imaging. We have developed an imaging technique - magneto-motive ultrasound (MMUS) imaging, capable of imaging magnetic nanoparticles subjected to time-varying magnetic field. The result of our studies indicate that magnetically excited nanoparticles can be used as contrast agents in magneto-motive ultrasound imaging thus expanding the role of ultrasound imaging to cellular scales and molecular sensitivity.

Pulsed magneto-acoustic imaging

Nanoparticles are attracting considerable interest as contrast agents for many different imaging modalities. Moreover, imaging the events at the cellular and molecular level is possible by using nanoparticles that have the desired targeting moiety. Unfortunately, ultrasound imaging cannot visualize the nano-structures directly due to its limited spatial resolution and contrast. We present a new technique, pulsed magneto-acoustic imaging, capable of imaging magnetic nanoparticles indirectly. In this method, a high-strength pulsed magnetic field is used to induce motion within the magnetically labeled tissue and ultrasound is used to detect internal tissue motion. Experiments on tissue-mimicking phantoms and ex-vivo animal tissues demonstrated a clear contrast between normal and iron-laden samples labeled with 5 nm magnetic nanoparticles. In addition, the sensitivity of this new imaging technique was investigated for different concentrations of magnetic agents. The results of the study suggest that magnetic nanoparticles can be used as contrast agents in pulsed magneto-acoustic imaging. Furthermore, PMA imaging could become an imaging tool capable of visualizing the cellular and molecular composition of deep-lying structures.

In vivo pulsed magneto-motive ultrasound imaging using high-performance magnetoactive contrast nanoagents

Previously, pulsed magneto-motive ultrasound (pMMUS) imaging has been introduced as a contrast-agent-assisted ultrasound-based imaging modality capable of visualizing biological events at the cellular and molecular level. In pMMUS imaging, a high intensity pulsed magnetic field is used to excite cells or tissue labeled with magnetic nanoparticles. Then, ultrasound (US) imaging is used to monitor the mechanical response of the tissue to an externally applied magnetic field (i.e., tissue displacement). Signal to noise ratio (SNR) in pMMUS imaging can be improved by using superparamagnetic nanoparticles with larger saturation magnetization. Metal-doped magnetic nanoparticles with enhanced tunable nanomagnetism are suitable candidates to improve the SNR and, therefore, sensitivity of pMMUS imaging, which is essential for in vivo pMMUS imaging. In this study, we demonstrate the capability of pMMUS imaging to identify the presence and distribution of zinc-doped iron oxide nanoparticles in live nude mice bearing A431 (human epithelial carcinoma) xenograft tumors.

Enhanced pulsed magneto-motive ultrasound imaging using superparamagnetic nanoclusters

Recently, pulsed magneto-motive ultrasound (pMMUS) imaging augmented with ultra-small magnetic nanoparticles has been introduced as a tool capable of imaging events at molecular and cellular levels. The sensitivity of a pMMUS system depends on several parameters, including the size, geometry and magnetic properties of the nanoparticles. Under the same magnetic field, larger magnetic nanostructures experience a stronger magnetic force and produce larger displacement, thus improving the sensitivity and signal-to-noise ratio (SNR) of pMMUS imaging. Unfortunately, large magnetic iron-oxide nanoparticles are typically ferromagnetic and thus are very difficult to stabilize against colloidal aggregation. In the current study we demonstrate improvement of pMMUS image quality by using large size superparamagnetic nanoclusters characterized by strong magnetization per particle. Water-soluble magnetic nanoclusters of two sizes (15 and 55 nm average size) were synthesized from 3 nm iron precursors in the presence of citrate capping ligand. The size distribution of synthesized nanoclusters and individual nanoparticles was characterized using dynamic light scattering (DLS) analysis and transmission electron microscopy (TEM). Tissue mimicking phantoms containing single nanoparticles and two sizes of nanoclusters were imaged using a custom-built pMMUS imaging system. While the magnetic properties of citrate-coated nanoclusters are identical to those of superparamagnetic nanoparticles, the magneto-motive signal detected from nanoclusters is larger, i.e. the same magnetic field produced larger magnetically induced displacement. Therefore, our study demonstrates that clusters of superparamagnetic nanoparticles result in pMMUS images with higher contrast and SNR.

Detection of Nanoparticle Endocytosis Using Magneto- Photoacoustic Imaging

and targeted therapy, [ 3 ] for their ubiquitous tissue accessibility, large surface-area-to-volume ratios, and functional versatility. [ 1–4 ] In biological applications, delivering nanoparticles to the tissues of interest is a fi rst critical step. [ 5 ] The delivered nanoparticles can then interact readily with living cells. Cellular endocytosis of nanoparticles—an important manifestation of the cell–nanoparticle interaction—can infl uence the associated diagnostic sensitivity and therapeutic effi ciency. [ 4 ]

Pulsed magneto-motive ultrasound imaging to detect intracellular accumulation of magnetic nanoparticles

As applications of nanoparticles in medical imaging and biomedicine rapidly expand, the interactions of nanoparticles with living cells have become an area of active interest. For example, intracellular accumulation of nanoparticles-an important part of cell-nanoparticle interaction-has been well studied using plasmonic nanoparticles and optical or optics-based techniques due to the change in optical properties of the nanoparticle aggregates. However, 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. In this study, we investigated the feasibility of a novel imaging technique-pulsed magneto-motive ultrasound (pMMUS)-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. We demonstrated previously that clusters of magnetic nanoparticles amplify the pMMUS signal in comparison to the signal from individual nanoparticles. Here we further demonstrate that pMMUS imaging can identify interaction between magnetic nanoparticles and living cells, i.e.xa0intracellular accumulation of nanoparticles within the cells. The results of our study suggest that pMMUS imaging can not only detect the presence of magnetic nanoparticles but also provides information about their intracellular accumulation non-invasively and in real-time.

Ultrasound-based imaging of nanoparticles: From molecular and cellular imaging to therapy guidance

The effectiveness of an imaging technique is often based on the ability to image quantitatively both morphological and physiological functions of the tissue. Here we present several ultrasound-based imaging techniques capable of visualizing both structural and functional properties of living tissue. Each imaging system utilizes custom-made, targeted nanoparticles developed to probe specific molecular events. Therefore, images of these nanoparticles display molecular processes in the body. Furthermore, the developed nanoparticle contrast agents can also be used for image-guided molecular therapy. For each imaging system, the basic physics and principles behind each approach are described. Experimental aspects of each imaging system including fabrication of integrated imaging probes and associated imaging hardware, and design of targeted contrast agents are discussed. Finally, biomedical and clinical applications of the developed imaging approaches ranging from microscopic to macroscopic imaging of cardiovascular diseases, cancer detection, diagnosis, therapy and therapy monitoring are demonstrated and discussed.