Emad S. Ebbini

Enhancement of tumor thermal therapy using gold nanoparticle–assisted tumor necrosis factor-α delivery

Tumor necrosis factor-α (TNF-α) is a potent cytokine with anticancer efficacy that can significantly enhance hyperthermic injury. However, TNF-α is systemically toxic, thereby creating a need for its selective tumor delivery. We used a newly developed nanoparticle delivery system consisting of 33-nm polyethylene glycol–coated colloidal gold nanoparticles (PT-cAu-TNF-α) with incorporated TNF-α payload (several hundred TNF-α molecules per nanoparticle) to maximize tumor damage and minimize systemic exposure to TNF-α. SCK mammary carcinomas grown in A/J mice were treated with 125 or 250 μg/kg PT-cAu-TNF-α alone or followed by local heating at 42.5°C using a water bath for 60 minutes, 4 hours after nanoparticle injection. Increases in tumor growth delay were observed for both PT-cAu-TNF-α alone and heat alone, although the most dramatic effect was found in the combination treatment. Tumor blood flow was significantly suppressed 4 hours after an i.v. injection of free TNF-α or PT-cAu-TNF-α. Tumor perfusion, imaged by contrast enhanced ultrasonography, on days 1 and 5 after treatment revealed perfusion defects after the injection of PT-cAu-TNF-α alone and, in many regions, complete flow inhibition in tumors treated with combination treatment. The combination treatment of SCK tumors in vivo reduced the in vivo/in vitro tumor cell survival to 0.05% immediately following heating and to 0.005% at 18 hours after heating, suggesting vascular damage–mediated tumor cell killing. Thermally induced tumor growth delay was enhanced by pretreatment with TNF-α-coated gold nanoparticles when given i.v. at the proper dosage and timing. [Mol Cancer Ther 2006;5(4):1014–20]

Real-Time 2-D Temperature Imaging Using Ultrasound

We have previously introduced methods for noninvasive estimation of temperature change using diagnostic ultrasound. The basic principle was validated both in vitro and in vivo by several groups worldwide. Some limitations remain, however, that have prevented these methods from being adopted in monitoring and guidance of minimally invasive thermal therapies, e.g., RF ablation and high-intensity-focused ultrasound (HIFU). In this letter, we present first results from a real-time system for 2-D imaging of temperature change using pulse-echo ultrasound. The front end of the system is a commercially available scanner equipped with a research interface, which allows the control of imaging sequence and access to the RF data in real time. A high-frame-rate 2-D RF acquisition mode, M2D, is used to capture the transients of tissue motion/deformations in response to pulsed HIFU. The M2D RF data is streamlined to the back end of the system, where a 2-D temperature imaging algorithm based on speckle tracking is implemented on a graphics processing unit. The real-time images of temperature change are computed on the same spatial and temporal grid of the M2D RF data, i.e., no decimation. Verification of the algorithm was performed by monitoring localized HIFU-induced heating of a tissue-mimicking elastography phantom. These results clearly demonstrate the repeatability and sensitivity of the algorithm. Furthermore, we present in vitro results demonstrating the possible use of this algorithm for imaging changes in tissue parameters due to HIFU-induced lesions. These results clearly demonstrate the value of the real-time data streaming and processing in monitoring, and guidance of minimally invasive thermotherapy.

Noninvasive estimation of tissue temperature via high-resolution spectral analysis techniques

We address the noninvasive temperature estimation from pulse-echo radio frequency signals from standard diagnostic ultrasound imaging equipment. In particular, we investigate the use of a high-resolution spectral estimation method for tracking frequency shifts at two or more harmonic frequencies associated with temperature change. The new approach, employing generalized second-order statistics, is shown to produce superior frequency shift estimates when compared to conventional high-resolution spectral estimation methods Seip and Ebbini (1995). Furthermore, temperature estimates from the new algorithm are compared with results from the more commonly used echo shift method described in Simon et al. (1998).

New piezoelectric transducers for therapeutic ultrasound

Therapeutic ultrasound (US) has been of increasing interest during the past few years. However, the development of this technique depends on the availability of high-performance transducers. These transducers have to be optimised for focusing and steering high-power ultrasonic energy within the target volume. Recently developed high-power 1-3 piezocomposite materials bring to therapeutic US the exceptional electroacoustical properties of piezocomposite technology: these are high efficiency, large bandwidth, predictable beam pattern, more flexibility in terms of shaping and definition of sampling in annular arrays, linear arrays or matrix arrays. The construction and evaluation of several prototypes illustrates the benefit of this new approach that opens the way to further progress in therapeutic US.

Dual-Mode Ultrasound Phased Arrays for Image-Guided Surgery

A 64-element, 1 MHz prototype dual-mode array (DMUA) with therapeutic and imaging capabilities is described. Simulation and experimental results for the characterization of the therapeutic operating field (ThxOF) and imaging field-of-view (IxFOV) for a DMUA are given. In addition, some of the special considerations for imaging with DMUAs are given and illustrated experimentally using wire-target arrays and commercial, quality-assurance phantoms. These results demonstrate what is potentially the most powerful advantage of the use of DMUAs in image-guided surgery; namely, inherent registration between the imaging and therapeutic coordinate systems. We also present imaging results before and after discrete and volumetric HIFU-induced lesions in freshly-excised tissues. DMUA images consistently show changes in echogenicity after lesion formation with shape and extent reflecting the actual shape of the lesion. While changes in echogenicity cannot be used as an indicator of irreversible HIFU-induced tissue damage, they provide important feedback on the location and extent of the expected lesion. Thus, together with the self-registration property of DMUAs, lesion images can be expected to provide immediate and spatially-accurate feedback on the tissue response to the therapeutic HIFU beams. Based on the results provided here, the imaging capabilities of DMUAs can add unique features to other forms of image guidance, e.g. MRI, CT and diagnostic ultrasound.

Performance analysis of cellular mobile systems with successive co-channel interference cancellation

This paper presents an analytical framework for the performance evaluation of cellular mobile radio systems equipped with smart antenna systems. In particular, the paper focuses on low-complexity systems which are able to successively suppress the strongest active interferers. The desired user fading statistics is assumed to be flat Rayleigh, Rician, or Nakagami, whereas the interfering signals are assumed to be independent and subject to slow flat Rayleigh fading. The paper starts by presenting generic closed-form expressions for the the carrier-to-interference ratio probability density function after interference cancellation. Based on that, exact closed-form expressions for the outage probability and average error rate formulas are derived. Finally, a comparison with a practical cancellation scheme and the impact of some practical considerations on the performance of successive interference cancellation are investigated. More specifically, the effect of traffic loading, the overall spectral efficiency gain, and the impact of time delay are studied.

Nanotherapeutics for enhancing thermal therapy of cancer

Purpose: The current work describes the synergistic enhancement of hyperthermic cancer therapy by selective thermal sensitization and induction of vascular injury at the tumor site. The specificity of this response was mediated by CYT-6091: a pegylated colloidal gold-based nanotherapeutic designed to selectively deliver an inflammatory cytokine, tumor necrosis factor alpha (TNF), to solid tumors. Materials and methods: FSaII murine fibrosarcoma-bearing C3H mice received an intravenous injection of either soluble TNF or CYT-6091 (50–250 µg/kg TNF). Four hours later the tumors were exposed to localized heating (42.5 or 43.5°C, 60 min). Tumor responses were assessed by growth delay and/or perfusion. Results: Both soluble TNF and CYT-6091 reduced tumor perfusion by 80% of control (no treatment), 4 hours post administration. However, soluble TNF was toxic to the tumor burdened mice and resulted in 40% mortality alone and 100% mortality when combined with hyperthermia. Conversely, no toxicities were noted with CYT-6091 alone or when combined with hyperthermia. Additionally, CYT-6091 combined with heat yielded significant tumor regression in vivo as compared to heat or CYT-6091 alone as demonstrated by tumor growth delay. Pretreatment with soluble TNF or CYT-6091 followed by heating reduced in vitro tumor and endothelial cell survival by 40–50% (TNF) and 70–75% (CYT-6091) of the control cell (i.e. tumor and endothelial) values, respectively. Conclusions: CYT-6091, by selectively delivering TNF to solid tumors, improves the safety of TNF treatment. In addition, the targeted delivery of TNF augments cancer thermal therapy efficacy possibly by inducing a tumor-localized inflammatory response.

Post-beamforming second-order Volterra filter for pulse-echo ultrasonic imaging

We present a new algorithm for deriving a second-order Volterra filter (SVF) capable of separating linear and quadratic components from echo signals. Images based on the quadratic components are shown to provide contrast enhancement between tissue and ultrasound contrast agents (UCAs) without loss in spatial resolution. It is also shown that the quadratic images preserve the low scattering regions due to their high dynamic range when compared with standard B-mode or harmonic images. A robust algorithm for deriving the filter has been developed and tested on real-time imaging data from contrast and tissue-mimicking media. Illustrative examples from image targets containing contrast agent and tissue-mimicking media are presented and discussed. Quantitative assessment of the contrast enhancement is performed on both the RF data and the envelope-detected log-compressed image data. It is shown that the quadratic images offer levels of enhancement comparable or exceeding those from harmonic filters while maintaining the visibility of low scattering regions of the image.

Viscoelastic property measurement in thin tissue constructs using ultrasound

A variety of imaging methods employing the principle of acoustic radiation force (ARF) have been proposed recently. It is now well accepted that ARF-based methods produce significant improvement in contrast compared to coventional ultrasound. However, interpretation of the ARF-induced displacements is rendered difficult in the presence of nearby boundary conditions, e.g. skin imaging. We present a dual-element ultrasound transducer system for generating and tracking of localized tissue displacements in thin tissue constructs on hard substrates. The system is comprised of a highly focused 5-MHz ARF transducer and a confocal 25-MHz PVDF imaging transducer. The ARF transducer produces a sharp focus with 200 mum diameter and 1 mm depth of field. This allows for the generation of measurable displacements in tissue samples on hard substrates with thickness values down to 500 mum. The ARF transducer is driven by an arbitrary waveform generator for modulating the 5-MHZ ARF carrier. Impulse-like and longer duration sine- modulated ARF pulses are possible with intermittent M-mode data acquisition for displacement tracking. Spatio-temporal maps of tissue displacements in response to a variety of modulated ARF beams are produced in tissue-mimicking elastography phantoms on a hard substrate. The frequency response was measured for phantoms with different stiffness and thickness values. The frequency response exhibits resonant behavior determined by the stiffness and the thickness of the samples. We have also used the extended Kalman filter (EKF) for tracking the apparent stiffness and viscosity of samples subjected to sinusoidaly-modulated ARF. Finally, C-mode imaging results of a soft phantom with a harder inclusion are shown to demonstrate the potential for significant contrast enhancement with ARF-based methods.

Ultrasound-guided therapeutic focused ultrasound: Current status and future directions

Abstract This paper reviews ultrasound imaging methods for the guidance of therapeutic focused ultrasound (USgFUS), with emphasis on real-time preclinical methods. Guidance is interpreted in the broadest sense to include pretreatment planning, siting of the FUS focus, real-time monitoring of FUS-tissue interactions, and real-time control of exposure and damage assessment. The paper begins with an overview and brief historical background of the early methods used for monitoring FUS-tissue interactions. Current imaging methods are described, and discussed in terms of sensitivity and specificity of the localisation of the FUS effects in both therapeutic and sub-therapeutic modes. Thermal and non-thermal effects are considered. These include cavitation-enhanced heating, tissue water boiling and cavitation. Where appropriate, USgFUS methods are compared with similar methods implemented using other guidance modalities, e.g. magnetic resonance imaging. Conclusions are drawn regarding the clinical potential of the various guidance methods, and the feasibility and current status of real-time implementation.