Laura Curiel

Experimental evaluation of lesion prediction modelling in the presence of cavitation bubbles: Intended for high-intensity focused ultrasound prostate treatment

The accuracy of high-intensity focused ultrasound (HIFU) lesion prediction modelling was evaluated for a truncated spherical transducer designed for prostate cancer treatment. The modelling adapted the bio heat transfer equation (BHTE) to take into account the activity of cavitation bubbles generated during HIFU exposure. This modelling was used to predict the lesions produced by three different transducer geometries: fixed-focus, concentric-ring and 1.5D phased-array. Lesions were predicted for different ultrasound exposure conditions close to those used in prostate cancer treatment. Twenty-onein vitro and ninein vitro experiments were performed on pig liver to validate the accuracy of the predictions. A good match was found between the predicted and experimental lesion shapes. Lesion dimensions (maximum depth and length, area at the centre of the lesion or central surface area) were measured on experimental and predicted lesions. The central surface area was predicted by the model with a range of error of 0.15–6.5% forin vitro tests and 0.97–9%in vivo. For comparison, BHTE without bubbles had a range of error of 0.4–55.5% (in vitro) and 9–25.5% (in vivo). The model should be accurate enough to predict HIFU lesions under ultrasound exposure conditions used in prostate cancer treatment.

1.5-D high intensity focused ultrasound array for non-invasive prostate cancer surgery

The aim of this study is to demonstrate the feasibility of a new spherically curved 1.5-D phased array for the treatment of localized prostatic cancer. The device is designed to conform to the Ablatherm(R) machine (EDAP-Technomed. France), a commercially available machine in which high intensity focused ultrasound (HIFU) treatment for prostate cancer is administered transrectally. It uses high intensity electronically focused ultrasound to steer a beam along two axes, allowing enough depth to be reached to treat large prostates and eliminating two degrees of mechanical movement. Through computer simulation, it was determined that a curved 1.5-D configuration offered the optimal design. Two configurations were then proposed, and their ability to steer a beam within a target volume centered on the geometric focus of the transducer was simulated. An eight-element prototype was constructed to test the piezo-composite material and its electro-acoustical efficiency. Then, an array was constructed, and a multichannel amplifier and control system were added, to permit remote operation. Acoustical and electrical measurements were made to verify performance. Finally, the 1.5-D array was tested in vitro on samples of pig liver to confirm the ability to induce lesions.

Synergistic inhibitory effect of high-intensity focused ultrasound combined with chemotherapy on Dunning adenocarcinoma

To evaluate the therapeutic effect of high‐intensity focused ultrasound (HIFU) combined with chemotherapy (paclitaxel + estramustine) on AT2 Dunning adenocarcinoma, as no satisfactory treatment for localized prostate cancer is available for patients with a poor prognosis, e.g. stage T3, a high Gleason score, or a prostate‐specific antigen level of >15 ng/mL.

High intensity focused ultrasound technology, its scope and applications in therapy and drug delivery.

Ultrasonography is a safe, inexpensive and wide-spread diagnostic tool capable of producing real-time non-invasive images without significant biological effects. However, the propagation of higher energy, intensity and frequency ultrasound waves through living tissues can induce thermal, mechanical and chemical effects useful for a variety of therapeutic applications. With the recent development of clinically approved High Intensity Focused Ultrasound (HIFU) systems, therapeutic ultrasound is now a medical reality. Indeed, HIFU has been used for the thermal ablation of pathological lesions; localized, minimally invasive ultrasound-mediated drug delivery through the transient formation of pores on cell membranes; the temporary disruption of skin and the blood brain barrier; the ultrasound induced break-down of blood clots; and the targeted release of drugs using ultrasound and temperature sensitive drug carriers. This review seeks to engage the pharmaceutical research community by providing an overview on the biological effects of ultrasound as well as highlighting important therapeutic applications, current deficiencies and future directions.

Sonoporation delivery of monoclonal antibodies against human papillomavirus 16 E6 restores p53 expression in transformed cervical keratinocytes.

High-risk types of human papillomavirus (HPV), such as HPV16, have been found in nearly all cases of cervical cancer. Therapies targeted at blocking the HPV16 E6 protein and its deleterious effects on the tumour suppressor pathways of the cell can reverse the malignant phenotype of affected keratinocytes while sparing uninfected cells. Through a strong interdisciplinary collaboration between engineering and biology, a novel, non-invasive intracellular delivery method for the HPV16 E6 antibody, F127-6G6, was developed. The method employs high intensity focused ultrasound (HIFU) in combination with microbubbles, in a process known as sonoporation. In this proof of principle study, it was first demonstrated that sonoporation antibody delivery into the HPV16 positive cervical carcinoma derived cell lines CaSki and SiHa was possible, using chemical transfection as a baseline for comparison. Delivery of the E6 antibody using sonoporation significantly restored p53 expression in these cells, indicating the antibody is able to enter the cells and remains active. This delivery method is targeted, non-cytotoxic, and non-invasive, making it more easily translatable for in vivo experiments than other transfection methods.

New integrated imaging high intensity focused ultrasound probe for transrectal prostate cancer treatment.

The present study proposes a new integrated imaging (II) high-intensity focused ultrasound (HIFU) probe intended as an improvement to the Ablatherm prostate cancer treatment. Because of a perforation in the center of the II probe, the expected lesion differs from the one obtained for the original Ablatherm probe. In this paper, the new geometry and the strategy followed to establish the treatment parameters are presented. The original probe has a 40-mm focal length, a 50-mm aperture and is truncated at 31 mm. The II probe has a 45-mm focal length, a 61-mm aperture, a central perforation of 25 mm and is truncated at 31 mm. Both probes operate at 3 MHz. A mathematical model for lesion prediction was used for setting the treatment parameters for the II probe. These parameters should ensure equivalence between the lesions obtained with the original and II probes. Simulation-obtained parameters were validated by in-vitro and in-vivo (on liver of 70 New Zealand rabbits) experiments. The new II probe was used clinically to treat 30 patients. The mean age was 70.9 +/- 5.3 years (SD), the mean prostate volume 26.9 +/- 7.7 mL and the mean serum prostate specific antigen (PSA) concentration before treatment was 9.2 +/- 5.5 ng/mL. Simulations showed that for the II probe acoustical power and duration when the transducer is inactive should be reduced of 14% and 1s. In-vitro and in-vivo experiments confirmed the equivalence between the lesions obtained with the two probes. The lesion volume obtained under in-vitro conditions (for a traversed tissue depth of 16 mm to the focus) was 5 +/- 0.4 cm(3) and 5.1 +/- 0.5 cm(3) for the original and II probes, respectively. Under in-vivo conditions, the lesion volume (for a traversed tissue depth of 18 mm) was 5.3 +/- 1.1 cm(3) and 5.1 +/- 1.1 cm(3) for the original and II probes, respectively. During the clinical trial, a correction of + 1s in the exposure time was required to recreate the same degree of efficacy observed with the original probe (p = 0.97): 66.7 % of negative biopsies and 75% of patients with PSA at 3 mo < or =1 ng/mL. The morbidity observed was minimal and identical to that observed with the original probe.

Influence of cell line and cell cycle phase on sonoporation transfection efficiency in cervical carcinoma cells under the same physical conditions

Using cervical-carcinoma-derived cells as a model, the present study investigates the effects cell line and cell cycle phase have on sonoporation transfection efficiency under the same physical conditions. A plasmid expressing green fluorescent protein (GFP) was used to measure transfection efficiency. To evaluate the effect of cell type, CaSki, HeLa, and SiHa cells were sonoporated using an acoustic pressure of 1 MPa for 30 s with a duty cycle of 4.8% in the presence of the GFP plasmid. To study the effect of cell cycle phase, SiHa cells were synchronized at S-phase using a double thymidine block and sonoporated at different time points after the block. Contrast agent microbubbles were used at a 0.33% volume concentration. Results indicated that both cell line and cell cycle phase impact the transfection efficiency obtained with sonoporation.

HIFU and Chemotherapy Synergistic Inhibitory Effect on Dunning AT2 Tumour‐Bearing Rats

Since there is no 100% satisfactory treatment for localized prostate cancer in patients presenting symptoms representing a poor prognosis (stage T3, high Gleason score, PSA level greater than 15 ng/ml, etc.), this study aimed to evaluate the therapeutic and synergistic inhibition effects of using High Intensity Focused Ultrasound (HIFU) in combination with chemotherapy (Taxane + Estramustine). Forty‐one Dunning AT2 tumour‐bearing Copenhagen rats receiving HIFU and/or chemotherapy were divided into four groups: control group; chemotherapy group; HIFU group; and HIFU‐chemotherapy combined group. Increase in the tumour volume was observed over 3 weeks and the tumour volume doubling time was evaluated. Growth curves for each group were then plotted and statistically evaluated. HIFU treatment combined with Taxane + Estramusine was found to have a significant synergistic effect; on day 30, the distribution of tumour volume relative to the treatment group was significantly different (p = 0.0007). The control gro...

1.5D multi-elements phased array applied to high intensity focused ultrasound

High Intensity Focused Ultrasound (HIFU) has been used successfully to treat localized prostate cancer. The systems currently used involve fixed-focus therapeutic probes. This study describes a new probe able to electronically focus the ultrasound beam in the prostates sagittal plane. Its form is that of a section of a spherical shell containing 126 elements, all with the same area and arranged in a 1.5D configuration. Initially, simulations of the acoustic beam were undertaken to determine the ideal configuration of the array for dynamic focusing in a sagittal plane of 2/spl times/2 cm/sup 2/ in area centered on the geometric focus of the shell. An array containing 210 elements (with an inter-element spacing of 0.97 mm) was then built using a piezocomposite material. The section consists of a central, 11 mm-wide strip with 4 lateral strips of 5.5 mm, each containing 42 elements. To limit the number of electrically independent elements to 126 in total, the lateral strip elements are connected in pairs symmetrically with respect to the central strip. The array elements are arranged on a piezocomposite spherical shell of the same dimensions and properties as those of previously used probes. Power is supplied to the transducer elements from a 126-channel amplifier (2 W per channel). Simulation results and acoustic measurements show that this 126-element 1.5D array can be electronically adjusted to steer the focal point around the predefined 2/spl times/2-cm/sup 2/ area. The electroacoustic efficiency of this 126-element array is 40.44%, i.e. relatively low for this kind of material (which usually yields between 70 and 80% with single-element probes).

Sonoporation of Cervical Carcinoma Cells Affected with E6‐Oncoprotein for the Treatment of Uterine Cancer

Cervical cancer has been identified as the third leading cause of average years of life lost per person dying of cancer. Since essentially all cervical cancers contain copies of human papillomavirus (HPV) DNA, we propose a treatment that targets HPV‐infected cells using strategies that re‐introduce normal functions into the infected cells while sparing healthy cells. We propose the use of focused ultrasound in combination with microbubbles as means to deliver antibodies against the E6 protein present only in HPV positive cells. We conducted in vitro studies with cell cultures of SiHa cervical carcinoma cells seeded into Opticell™ chambers. An in‐house ultrasound excitation apparatus was used to control and explore the optimal acoustic parameters in order to maximize delivery. We first validated the possibility of delivering the EX‐EGFP‐M02 vector (Genecopoeia) into the cells; 1.2 μL of activated microbubbles (Definity®) and 50 μg of the vector were mixed in media and then injected into the Opticell™ chamb...