The Journal of the Acoustical Society of America, 2012
ABSTRACT Encapsulating chemotherapeutic agents in liposomes improves targeting and efficacy of tr... more ABSTRACT Encapsulating chemotherapeutic agents in liposomes improves targeting and efficacy of treatments against some tumors. The present work aims at evaluating if sonosensitive liposomes combined with cavitation for drug delivery enhance efficacy and reduce toxicity. Two focused beams were combined for stabilizing the cavitation cloud and an imaging probe used for guidance. Each 1MHz focused transducer had a 5cm diameter and focal length. Exposure conditions were 10.8kW/cm(2) Isppa, 250Hz PRF and 1% duty cycle. Phosphatidylcholine-based nongaseous liposomes were loaded with Doxorubicin. To control for mechanical tissue damage, AT2 Dunning tumors on rats were first exposed to ultrasound only. Treatment induced temperature rose below 0.5° C. The tumor growth was not significantly slowed down by ultrasound, but histological examination of tumors evidenced large areas of necrosis which resorbed one week after ultrasound. The new liposomes were compared with conventional HSPC-based liposomes in terms of efficacy and toxicity on the same tumor model. Ultrasound led to equivalent efficacy when applied on HSPC-based liposomes, while the new liposomes were efficient only with concomitant cavitation. We present a confocal ultrasound set-up able to provide sufficient inertial cavitation for drug release from a nongaseous liposome with reduced systemic toxicity. Eureka-labelled project (E!4056) funded by NRC, FFN and OSEO.
The Journal of the Acoustical Society of America, 2008
ABSTRACT Drug release from liposomes can be activated by ultrasound and inertial cavitation is as... more ABSTRACT Drug release from liposomes can be activated by ultrasound and inertial cavitation is assumed to be the main involved mechanism. Broadband noise is known as a good indicator for such cavitation. The feasibility of assessing the extent of drug release by acoustic noise measurements has been investigated. A 1.17-MHz focused transducer (50-mm diameter and 50-mm focal length) was excited with tone-bursts (duty cycle: 10%-100%, PRF: 100 Hz-10 kHz, and Ispta < 800 Wcm(2)). Emitted noise was registered with a broadband needle hydrophone and bandpass filtered between the fundamental and the first harmonic frequency for assessing the instantaneous inertial cavitation activity. A cavitation index (CI) was computed by integrating the filtered signal over time. This index was validated experimentally using terephthalate oxidized to fluorescent hydroxyterephthalate under the action of free hydroxyl radicals generated by inertial cavitation. The hydroxyterephthalate fluorescence and the CI were well correlated (R(2) approximately 0.92). Experiments with liposomes were performed showing very good correlation between CI and drug release extent from liposomes. The definition of this CI allowed applying consistent doses of cavitation and performing comparative tests between different liposome formulations. [This work was funded by a grant from the Norwegian Research Council (NANOMAT programme). Epitarget AS, Norway is acknowledged for the supply of liposome samples.].
The Journal of the Acoustical Society of America, 2013
ABSTRACT Inertial cavitation has been shown to be useful in many therapeutic applications; thus, ... more ABSTRACT Inertial cavitation has been shown to be useful in many therapeutic applications; thus, controlling this phenomenon is of great therapeutic interest. However, the stochastic nature of cavitation often proves problematic for predicting its location and extent. Traditional solutions to this problem are the of use dedicated detection apparatuses, or to use injectable microbubbles (MBs), which act as nuclei for the initiation of cavitation. We hypothesize here that cavitation can be reliably controlled without the use of MBs using a confocal system, which produces a lobular focal zone due to acoustic interference. This interference pattern was studied both in simulation and hydrophone measurement. Cavitation extent was confirmed chemometrically with an assay for hydroxyl radical formation, and by passive cavitation detection with a hydrophone. A high speed camera was used to image the initiation of cavitation within the focal zone, the evolution of the bubble cloud, and the subsequent bubble rebound after pulse cessation. The experiments in this work confirm that cavitation is produced more reliably in the confocal setup as opposed to a single transducer, as well as illuminating the mechanisms for this enhancement. [Work supported by the European Union through the Eurostars program (project E!6173) and Caviskills SAS.].
The combination of liposomal doxorubicin (DXR) and confocal ultrasound (US) was investigated for ... more The combination of liposomal doxorubicin (DXR) and confocal ultrasound (US) was investigated for the enhancement of drug delivery in a rat tumour model. The liposomes, based on the unsaturated phospholipid dierucoylphosphocholine, were designed to be stable during blood circulation in order to maximize accumulation in tumour tissue and to release drug content upon US stimulation. A confocal US setup was developed for delivering inertial cavitation to tumours in a well-controlled and reproducible manner. In vitro studies confirm drug release from liposomes as a function of inertial cavitation dose, while in vivo pharmacokinetic studies show long blood circulation times and peak tumour accumulation at 24-48 h post intravenous administration. Animals injected 6 mg kg(-1) liposomal DXR exposed to US treatment 48 h after administration show significant tumour growth delay compared to control groups. A liposomal DXR dose of 3 mg kg(-1), however, did not induce any significant therapeutic response. This study demonstrates that inertial cavitation can be generated in such a fashion as to disrupt drug carrying liposomes which have accumulated in the tumour, and thereby increase therapeutic effect with a minimum direct effect on the tissue. Such an approach is an important step towards a therapeutic application of cavitation-induced drug delivery and reduced chemotherapy toxicity.
The Journal of the Acoustical Society of America, 2009
ABSTRACT Previous in vitro studies conducted in our group have shown the feasibility of monitorin... more ABSTRACT Previous in vitro studies conducted in our group have shown the feasibility of monitoring drug release from liposomes by an inertial acoustic cavitation index. We currently report in vivo experiments utilizing the cavitation index in combined treatment of AT2 Dunning tumor grafted rats with focused ultrasound and liposomal doxorubicin. Sixty-three rats were allocated into seven groups: control, low level ultrasound treatment, high level ultrasound treatment, free doxorubicin+high level ultrasound treatment, and liposomal doxorubicin, liposomal doxorubicin+low level ultrasound treatment, and liposomal doxorubicin+high level ultrasound treatment. Based on pharmacokinetic studies, it was decided to apply ultrasound to the tumor 48 h after drug injection. An experimental setup was built to perform repeatable and rapid sonications of tumors monitored by the cavitation index. Tumor growth was assessed for a period of 35 days after tumor inoculation. Results showed that liposomal doxorubicin significantly slowed down tumor growth. However, the synergy between ultrasound and liposomal doxorubicin could not be firmly demonstrated. The lack of synergy may be due to inefficient induction of drug delivery in vivo or too high liposome dosage hiding synergistic effects. [Work funded by the Norwegian Research Council (NANOMAT programme). Epitarget AS is acknowledged for the supply of liposomes.].
This work examines the use of lanthanide-based contrast agents and magnetic resonance imaging in ... more This work examines the use of lanthanide-based contrast agents and magnetic resonance imaging in monitoring liposomal behavior in vivo. Dysprosium (Dy) and gadolinium (Gd) chelates, Dy-diethylenetriaminepentaacetic acid bismethylamide (Dy-DTPA-BMA) and Gd-DTPA-BMA, were encapsulated in pegylated distearoylphosphatidylethanolamine-based (saturated) liposomes, and then intravenously injected into Copenhagen rats with subcutaneous Dunning AT2 xenografts. Liposome-encapsulated Dy chelate shortens transverse relaxation times (T(2) and T(2)*) of tissue; thus, liposomal accumulation in the tumor can be monitored by observing the decrease in T(2)* relaxation time over time. The tumor was treated at the time of maximum liposomal accumulation (48 h) with confocal, cavitating high-intensity focused ultrasound to induce liposomal payload release. Using liposome-encapsulated Gd chelate at high enough concentrations and saturated liposomal phospholipids induces an exchange-limited longitudinal (T(1)) relaxation when the liposomes are intact; when the liposomes are released, exchange limitation is relieved, thus allowing in vivo observation of payload release as a decrease in tumor T(1).
Acoustic cavitation is a way to improve local drug delivery in tumors. When no external nucleatio... more Acoustic cavitation is a way to improve local drug delivery in tumors. When no external nucleation agents are injected, high negative pressures are required for initiating inertial cavitation, which can lead to biological damages. In the present study, unseeded inertial cavitation was obtained in vivo using confocal beams and the effect of these exposure conditions was assessed on drug structure and activity, shallow tissues and growth of breast tumors. No change was observed on structure and cytotoxicity of doxorubicin after sonication. Experiments were conducted on healthy rats, exposing the thigh and abdomen. Histological analyses at 72 hours and 2 weeks post-treatment demonstrated only a modest impact on tissues, mainly resulting in mild skin damages. Finally, 4T1 breast tumors in mice were sonicated. Immunohistochemical analyses showed that the exposures of mammary tumors did not impact vascular density, proliferation, nor the proliferation and apoptosis of cancer cells. Moreover, ultrasound did not negatively impact on the spreading of cancer cells to the lungs and bone marrow. Thus, our study provides experimental evidence that these particular ultrasound parameters can be used safely for unseeded inertial cavitation in vivo.
OBJECT The blood-brain barrier (BBB) limits the intracerebral penetration of drugs and brain tumo... more OBJECT The blood-brain barrier (BBB) limits the intracerebral penetration of drugs and brain tumor treatment efficacy. The effect of ultrasound-induced BBB opening on the intracerebral concentration of temozolomide (TMZ) and irinotecan (CPT-11) was assessed. METHODS This study was performed using 34 healthy New Zealand rabbits. Half had unilateral BBB opening, and half served as controls. Sonications were performed by pulsing a 1.05-MHz planar ultrasound transducer with a duty cycle of 2.5% and an in situ acoustic pressure level of 0.6 MPa after injection of a microbubble ultrasound contrast agent. Drugs were injected either 5 minutes before (ChemoPreUS) or 15 minutes after (ChemoPostUS) the ultrasound sonication. The plasma and intracerebral concentrations of both drugs were quantified using ultra-performance liquid chromatography. RESULTS The mean intracerebral tissue-to-plasma drug concentration ratio in the control hemispheres was 34% for TMZ and 2% for CPT-11. After BBB opening, these values increased by up to 21% for TMZ and up to 178% for CPT-11. Intracerebral concentrations of drugs were enhanced in regions where the BBB was opened compared with the contralateral hemisphere (p < 0.01 and p < 0.0001 for CPT-11, p = 0.02 and p = 0.03 for TMZ, in ChemoPreUS and ChemoPostUS, respectively) and compared with the control group (p < 0.001 and p < 0.0001 for CPT-11, p < 0.01 and p = 0.02 for TMZ, in ChemoPreUS and ChemoPostUS, respectively). The intracerebral distribution of drugs was heterogeneous, depending on the distance from the ultrasound source. CONCLUSIONS Ultrasound-induced opening of the BBB significantly enhances the intracerebral concentration of both TMZ and CPT-11 in rabbits.
European Journal of Pharmaceutics and Biopharmaceutics, 2013
Dioeleoylphosphatidylethanolamine (DOPE)-based liposomes were recently reported as a new class of... more Dioeleoylphosphatidylethanolamine (DOPE)-based liposomes were recently reported as a new class of liposomes for ultrasound (US)-mediated drug delivery. The liposomes showed both high stability and in vitro US-mediated drug release (sonosensitivity). In the current study, in vivo proof-of-principle of US triggered release in tumoured mice was demonstrated using optical imaging. Confocal non-thermal US was used to deliver cavitation to tumours in a well-controlled manner. To detect in vivo release, the near infrared fluorochrome Al (III) Phthalocyanine Chloride Tetrasulphonic acid (AlPcS₄) was encapsulated into both DOPE-based liposomes and control liposomes based on hydrogenated soy phosphatidylcholine (HSPC). Encapsulation causes concentration dependent quenching of fluorescence that is recovered upon AlPcS₄ release from the liposomes. Exposure of tumours to US resulted in a significant increase in fluorescence in mice administered with DOPE-based liposomes, but no change in the mice treated with HSPC-based liposomes. Thus, DOPE-based liposomes showed superior sonosensitivity compared to HSPC-based liposomes in vivo.
Acoustic cavitation can improve local drug delivery in tumors. Without injected external nucleati... more Acoustic cavitation can improve local drug delivery in tumors. Without injected external nucleation agents, initiating inertial cavitation requires high negative pressures, which can lead to biological damage. In the present study, unseeded inertial cavitation was obtained in vivo using confocal beams, and the effect of these exposure conditions was assessed on drug structure and activity, shallow tissues and growth of breast tumors. No change was observed in the structure and cytotoxicity of doxorubicin. Experiments were conducted on healthy rats, exposing the thigh and abdomen. Histologic analyses at 72 h and 2 weeks post-treatment demonstrated a modest impact on tissues. Syngeneic 4 T1 breast tumors in mice were sonicated. Immunohistochemical analyses showed that ultrasound did not impact vascular density, proliferation and apoptosis of cancer cells. In addition, ultrasound did not negatively modify cancer cell spreading to the lungs and bone marrow. This provides evidence that these particular parameters can be used safely in vivo.
1999 IEEE Ultrasonics Symposium. Proceedings. International Symposium (Cat. No.99CH37027), 1999
The frequent late diagnosis and the poor efficiency of systemic therapy such as radiotherapy gene... more The frequent late diagnosis and the poor efficiency of systemic therapy such as radiotherapy generate huge difficulties in the treatment of ducts cancers. Palliative techniques of bilary debulking, either surgical or by endoscopic route, are actually performed. A light invasive local treatment would allow to fill up this therapeutic gap. Thus, the authors developed an ultrasound applicator for interstitial thermal
In contrast with most ultrasound modalities for medical applications, (especially ultrasound imag... more In contrast with most ultrasound modalities for medical applications, (especially ultrasound imaging), High Intensity Focused Ultrasound (HIFU) involves technologies and procedures which may present risk to the patient. These risks, resulting from the high power levels required for effective therapy, should be taken into account at the earliest stages in the design of a system dedicated to HIFU treatment. An understanding of these risks must thus be shared amongst the many players in the field of therapy using high power ultrasound. Moreover, since the number of applications of HIFU has increased appreciably over recent years and the technology is ready to move from the research to the industrial level, it is worth now considering solutions that should be put in place to guarantee the safety of the patient during HIFU treatment. This paper reports thoughts on this, and identifies some risks to the patient that must be taken into consideration in the design of HIFU transducers, and p...
Long lasting elevation is a key factor during endoscopic submucosal dissection (ESD) and can be o... more Long lasting elevation is a key factor during endoscopic submucosal dissection (ESD) and can be obtained by water jet injection of saline solution or by viscous macromolecular solutions. In a previous animal study, we assessed the Nestis Enki II system to combine jet injection and viscous solutions. In the present work, we used this combination in humans in different sites of the digestive tract. We retrospectively report all of the consecutive ESD procedures performed with jet injection of viscous solutions in four centers. Information was collected about the lesion, the procedure, the histological result, and the outcomes for the patient. In total, 45 resections were completed by six operators: five experts and one beginner with only one previous experience in human ESD. Lesions were located in the esophagus (10), the stomach (11), the duodenum (1), the colon (1) and the rectum (22). Average maximal lesion diameter was 4.8 cm (SD 2.4, range 2 - 11 cm), average lesion surface area was 19.8 cm(2) (SD 17.7, range 2.2 - 72 cm(2)), and average duration of procedure was 79.9 min (SD 50.3 min, range 19 - 225 min). ESD could be conducted while the endoscope was retroflexed at its maximum in 26 cases. Four adverse events were observed: two diminutive perforations and two delayed bleeding occurrences treated conservatively. The R0 resection rate was 91.1 %. The catheter was obstructed in six occurrences of bleeding. Endoscopic submucosal dissection using high pressure injection of viscous macromolecular solutions is safe and effective in different parts of the digestive tract. It does not impede working with the endoscope in the maximal retroflexed position.
ABSTRACT It has been shown that a very deep and selective interstitial thermal therapy can be per... more ABSTRACT It has been shown that a very deep and selective interstitial thermal therapy can be performed using a rotating flat miniature ultrasound transducer. This heating modality would be significantly improved by implementing imaging and monitoring. The space limitations in interstitial applications require combining imaging and therapy on the same transducer. In conventional endoscopic ultrasound imaging, a miniprobe can be positioned inside the lumen of an organ and fast rotation of a single element transducer enables real time peripheral imaging of the lumen. Based on this idea, we proposed an original therapeutic strategy. Imaging can be interrupted for a short period of time corresponding to an angle Deltaalpha in order to apply high intensity ultrasound for thermal ablation. First, theoretical simulations were conducted. A 1D thermal model of the transducer demonstrated that this operating mode is not critical for the transducer. Simulations using the BioHeat Transfer Equation showed that Deltaalpha=pi/4 induced efficient therapy. An applicator was built in order to test this treatment strategy. The active element consisted in a 2.5 times 7.5 mm2 dual mode single element transducer operating at a frequency of 11 MHz. The applicator was driven in rotation at 7-turns per second pace. Experiments were performed in vitro on porcine liver. Ultrasound images were reconstructed and the size of the -6 dB point spread function at focal distance was 0.55 mm times 0.25 mm. The electronics for performing the therapeutic strategy considered above was set up. Up to 8 millimeters-deep thermal lesions were obtained with Deltaalpha=pi/4 and peak intensity of 110 W/cm 2. This work demonstrated that thermal lesions can be performed with a fast-rotating dual mode transducer. This approach enabled real-time image-guided therapy
The Journal of the Acoustical Society of America, 2012
ABSTRACT Encapsulating chemotherapeutic agents in liposomes improves targeting and efficacy of tr... more ABSTRACT Encapsulating chemotherapeutic agents in liposomes improves targeting and efficacy of treatments against some tumors. The present work aims at evaluating if sonosensitive liposomes combined with cavitation for drug delivery enhance efficacy and reduce toxicity. Two focused beams were combined for stabilizing the cavitation cloud and an imaging probe used for guidance. Each 1MHz focused transducer had a 5cm diameter and focal length. Exposure conditions were 10.8kW/cm(2) Isppa, 250Hz PRF and 1% duty cycle. Phosphatidylcholine-based nongaseous liposomes were loaded with Doxorubicin. To control for mechanical tissue damage, AT2 Dunning tumors on rats were first exposed to ultrasound only. Treatment induced temperature rose below 0.5° C. The tumor growth was not significantly slowed down by ultrasound, but histological examination of tumors evidenced large areas of necrosis which resorbed one week after ultrasound. The new liposomes were compared with conventional HSPC-based liposomes in terms of efficacy and toxicity on the same tumor model. Ultrasound led to equivalent efficacy when applied on HSPC-based liposomes, while the new liposomes were efficient only with concomitant cavitation. We present a confocal ultrasound set-up able to provide sufficient inertial cavitation for drug release from a nongaseous liposome with reduced systemic toxicity. Eureka-labelled project (E!4056) funded by NRC, FFN and OSEO.
The Journal of the Acoustical Society of America, 2008
ABSTRACT Drug release from liposomes can be activated by ultrasound and inertial cavitation is as... more ABSTRACT Drug release from liposomes can be activated by ultrasound and inertial cavitation is assumed to be the main involved mechanism. Broadband noise is known as a good indicator for such cavitation. The feasibility of assessing the extent of drug release by acoustic noise measurements has been investigated. A 1.17-MHz focused transducer (50-mm diameter and 50-mm focal length) was excited with tone-bursts (duty cycle: 10%-100%, PRF: 100 Hz-10 kHz, and Ispta < 800 Wcm(2)). Emitted noise was registered with a broadband needle hydrophone and bandpass filtered between the fundamental and the first harmonic frequency for assessing the instantaneous inertial cavitation activity. A cavitation index (CI) was computed by integrating the filtered signal over time. This index was validated experimentally using terephthalate oxidized to fluorescent hydroxyterephthalate under the action of free hydroxyl radicals generated by inertial cavitation. The hydroxyterephthalate fluorescence and the CI were well correlated (R(2) approximately 0.92). Experiments with liposomes were performed showing very good correlation between CI and drug release extent from liposomes. The definition of this CI allowed applying consistent doses of cavitation and performing comparative tests between different liposome formulations. [This work was funded by a grant from the Norwegian Research Council (NANOMAT programme). Epitarget AS, Norway is acknowledged for the supply of liposome samples.].
The Journal of the Acoustical Society of America, 2013
ABSTRACT Inertial cavitation has been shown to be useful in many therapeutic applications; thus, ... more ABSTRACT Inertial cavitation has been shown to be useful in many therapeutic applications; thus, controlling this phenomenon is of great therapeutic interest. However, the stochastic nature of cavitation often proves problematic for predicting its location and extent. Traditional solutions to this problem are the of use dedicated detection apparatuses, or to use injectable microbubbles (MBs), which act as nuclei for the initiation of cavitation. We hypothesize here that cavitation can be reliably controlled without the use of MBs using a confocal system, which produces a lobular focal zone due to acoustic interference. This interference pattern was studied both in simulation and hydrophone measurement. Cavitation extent was confirmed chemometrically with an assay for hydroxyl radical formation, and by passive cavitation detection with a hydrophone. A high speed camera was used to image the initiation of cavitation within the focal zone, the evolution of the bubble cloud, and the subsequent bubble rebound after pulse cessation. The experiments in this work confirm that cavitation is produced more reliably in the confocal setup as opposed to a single transducer, as well as illuminating the mechanisms for this enhancement. [Work supported by the European Union through the Eurostars program (project E!6173) and Caviskills SAS.].
The combination of liposomal doxorubicin (DXR) and confocal ultrasound (US) was investigated for ... more The combination of liposomal doxorubicin (DXR) and confocal ultrasound (US) was investigated for the enhancement of drug delivery in a rat tumour model. The liposomes, based on the unsaturated phospholipid dierucoylphosphocholine, were designed to be stable during blood circulation in order to maximize accumulation in tumour tissue and to release drug content upon US stimulation. A confocal US setup was developed for delivering inertial cavitation to tumours in a well-controlled and reproducible manner. In vitro studies confirm drug release from liposomes as a function of inertial cavitation dose, while in vivo pharmacokinetic studies show long blood circulation times and peak tumour accumulation at 24-48 h post intravenous administration. Animals injected 6 mg kg(-1) liposomal DXR exposed to US treatment 48 h after administration show significant tumour growth delay compared to control groups. A liposomal DXR dose of 3 mg kg(-1), however, did not induce any significant therapeutic response. This study demonstrates that inertial cavitation can be generated in such a fashion as to disrupt drug carrying liposomes which have accumulated in the tumour, and thereby increase therapeutic effect with a minimum direct effect on the tissue. Such an approach is an important step towards a therapeutic application of cavitation-induced drug delivery and reduced chemotherapy toxicity.
The Journal of the Acoustical Society of America, 2009
ABSTRACT Previous in vitro studies conducted in our group have shown the feasibility of monitorin... more ABSTRACT Previous in vitro studies conducted in our group have shown the feasibility of monitoring drug release from liposomes by an inertial acoustic cavitation index. We currently report in vivo experiments utilizing the cavitation index in combined treatment of AT2 Dunning tumor grafted rats with focused ultrasound and liposomal doxorubicin. Sixty-three rats were allocated into seven groups: control, low level ultrasound treatment, high level ultrasound treatment, free doxorubicin+high level ultrasound treatment, and liposomal doxorubicin, liposomal doxorubicin+low level ultrasound treatment, and liposomal doxorubicin+high level ultrasound treatment. Based on pharmacokinetic studies, it was decided to apply ultrasound to the tumor 48 h after drug injection. An experimental setup was built to perform repeatable and rapid sonications of tumors monitored by the cavitation index. Tumor growth was assessed for a period of 35 days after tumor inoculation. Results showed that liposomal doxorubicin significantly slowed down tumor growth. However, the synergy between ultrasound and liposomal doxorubicin could not be firmly demonstrated. The lack of synergy may be due to inefficient induction of drug delivery in vivo or too high liposome dosage hiding synergistic effects. [Work funded by the Norwegian Research Council (NANOMAT programme). Epitarget AS is acknowledged for the supply of liposomes.].
This work examines the use of lanthanide-based contrast agents and magnetic resonance imaging in ... more This work examines the use of lanthanide-based contrast agents and magnetic resonance imaging in monitoring liposomal behavior in vivo. Dysprosium (Dy) and gadolinium (Gd) chelates, Dy-diethylenetriaminepentaacetic acid bismethylamide (Dy-DTPA-BMA) and Gd-DTPA-BMA, were encapsulated in pegylated distearoylphosphatidylethanolamine-based (saturated) liposomes, and then intravenously injected into Copenhagen rats with subcutaneous Dunning AT2 xenografts. Liposome-encapsulated Dy chelate shortens transverse relaxation times (T(2) and T(2)*) of tissue; thus, liposomal accumulation in the tumor can be monitored by observing the decrease in T(2)* relaxation time over time. The tumor was treated at the time of maximum liposomal accumulation (48 h) with confocal, cavitating high-intensity focused ultrasound to induce liposomal payload release. Using liposome-encapsulated Gd chelate at high enough concentrations and saturated liposomal phospholipids induces an exchange-limited longitudinal (T(1)) relaxation when the liposomes are intact; when the liposomes are released, exchange limitation is relieved, thus allowing in vivo observation of payload release as a decrease in tumor T(1).
Acoustic cavitation is a way to improve local drug delivery in tumors. When no external nucleatio... more Acoustic cavitation is a way to improve local drug delivery in tumors. When no external nucleation agents are injected, high negative pressures are required for initiating inertial cavitation, which can lead to biological damages. In the present study, unseeded inertial cavitation was obtained in vivo using confocal beams and the effect of these exposure conditions was assessed on drug structure and activity, shallow tissues and growth of breast tumors. No change was observed on structure and cytotoxicity of doxorubicin after sonication. Experiments were conducted on healthy rats, exposing the thigh and abdomen. Histological analyses at 72 hours and 2 weeks post-treatment demonstrated only a modest impact on tissues, mainly resulting in mild skin damages. Finally, 4T1 breast tumors in mice were sonicated. Immunohistochemical analyses showed that the exposures of mammary tumors did not impact vascular density, proliferation, nor the proliferation and apoptosis of cancer cells. Moreover, ultrasound did not negatively impact on the spreading of cancer cells to the lungs and bone marrow. Thus, our study provides experimental evidence that these particular ultrasound parameters can be used safely for unseeded inertial cavitation in vivo.
OBJECT The blood-brain barrier (BBB) limits the intracerebral penetration of drugs and brain tumo... more OBJECT The blood-brain barrier (BBB) limits the intracerebral penetration of drugs and brain tumor treatment efficacy. The effect of ultrasound-induced BBB opening on the intracerebral concentration of temozolomide (TMZ) and irinotecan (CPT-11) was assessed. METHODS This study was performed using 34 healthy New Zealand rabbits. Half had unilateral BBB opening, and half served as controls. Sonications were performed by pulsing a 1.05-MHz planar ultrasound transducer with a duty cycle of 2.5% and an in situ acoustic pressure level of 0.6 MPa after injection of a microbubble ultrasound contrast agent. Drugs were injected either 5 minutes before (ChemoPreUS) or 15 minutes after (ChemoPostUS) the ultrasound sonication. The plasma and intracerebral concentrations of both drugs were quantified using ultra-performance liquid chromatography. RESULTS The mean intracerebral tissue-to-plasma drug concentration ratio in the control hemispheres was 34% for TMZ and 2% for CPT-11. After BBB opening, these values increased by up to 21% for TMZ and up to 178% for CPT-11. Intracerebral concentrations of drugs were enhanced in regions where the BBB was opened compared with the contralateral hemisphere (p < 0.01 and p < 0.0001 for CPT-11, p = 0.02 and p = 0.03 for TMZ, in ChemoPreUS and ChemoPostUS, respectively) and compared with the control group (p < 0.001 and p < 0.0001 for CPT-11, p < 0.01 and p = 0.02 for TMZ, in ChemoPreUS and ChemoPostUS, respectively). The intracerebral distribution of drugs was heterogeneous, depending on the distance from the ultrasound source. CONCLUSIONS Ultrasound-induced opening of the BBB significantly enhances the intracerebral concentration of both TMZ and CPT-11 in rabbits.
European Journal of Pharmaceutics and Biopharmaceutics, 2013
Dioeleoylphosphatidylethanolamine (DOPE)-based liposomes were recently reported as a new class of... more Dioeleoylphosphatidylethanolamine (DOPE)-based liposomes were recently reported as a new class of liposomes for ultrasound (US)-mediated drug delivery. The liposomes showed both high stability and in vitro US-mediated drug release (sonosensitivity). In the current study, in vivo proof-of-principle of US triggered release in tumoured mice was demonstrated using optical imaging. Confocal non-thermal US was used to deliver cavitation to tumours in a well-controlled manner. To detect in vivo release, the near infrared fluorochrome Al (III) Phthalocyanine Chloride Tetrasulphonic acid (AlPcS₄) was encapsulated into both DOPE-based liposomes and control liposomes based on hydrogenated soy phosphatidylcholine (HSPC). Encapsulation causes concentration dependent quenching of fluorescence that is recovered upon AlPcS₄ release from the liposomes. Exposure of tumours to US resulted in a significant increase in fluorescence in mice administered with DOPE-based liposomes, but no change in the mice treated with HSPC-based liposomes. Thus, DOPE-based liposomes showed superior sonosensitivity compared to HSPC-based liposomes in vivo.
Acoustic cavitation can improve local drug delivery in tumors. Without injected external nucleati... more Acoustic cavitation can improve local drug delivery in tumors. Without injected external nucleation agents, initiating inertial cavitation requires high negative pressures, which can lead to biological damage. In the present study, unseeded inertial cavitation was obtained in vivo using confocal beams, and the effect of these exposure conditions was assessed on drug structure and activity, shallow tissues and growth of breast tumors. No change was observed in the structure and cytotoxicity of doxorubicin. Experiments were conducted on healthy rats, exposing the thigh and abdomen. Histologic analyses at 72 h and 2 weeks post-treatment demonstrated a modest impact on tissues. Syngeneic 4 T1 breast tumors in mice were sonicated. Immunohistochemical analyses showed that ultrasound did not impact vascular density, proliferation and apoptosis of cancer cells. In addition, ultrasound did not negatively modify cancer cell spreading to the lungs and bone marrow. This provides evidence that these particular parameters can be used safely in vivo.
1999 IEEE Ultrasonics Symposium. Proceedings. International Symposium (Cat. No.99CH37027), 1999
The frequent late diagnosis and the poor efficiency of systemic therapy such as radiotherapy gene... more The frequent late diagnosis and the poor efficiency of systemic therapy such as radiotherapy generate huge difficulties in the treatment of ducts cancers. Palliative techniques of bilary debulking, either surgical or by endoscopic route, are actually performed. A light invasive local treatment would allow to fill up this therapeutic gap. Thus, the authors developed an ultrasound applicator for interstitial thermal
In contrast with most ultrasound modalities for medical applications, (especially ultrasound imag... more In contrast with most ultrasound modalities for medical applications, (especially ultrasound imaging), High Intensity Focused Ultrasound (HIFU) involves technologies and procedures which may present risk to the patient. These risks, resulting from the high power levels required for effective therapy, should be taken into account at the earliest stages in the design of a system dedicated to HIFU treatment. An understanding of these risks must thus be shared amongst the many players in the field of therapy using high power ultrasound. Moreover, since the number of applications of HIFU has increased appreciably over recent years and the technology is ready to move from the research to the industrial level, it is worth now considering solutions that should be put in place to guarantee the safety of the patient during HIFU treatment. This paper reports thoughts on this, and identifies some risks to the patient that must be taken into consideration in the design of HIFU transducers, and p...
Long lasting elevation is a key factor during endoscopic submucosal dissection (ESD) and can be o... more Long lasting elevation is a key factor during endoscopic submucosal dissection (ESD) and can be obtained by water jet injection of saline solution or by viscous macromolecular solutions. In a previous animal study, we assessed the Nestis Enki II system to combine jet injection and viscous solutions. In the present work, we used this combination in humans in different sites of the digestive tract. We retrospectively report all of the consecutive ESD procedures performed with jet injection of viscous solutions in four centers. Information was collected about the lesion, the procedure, the histological result, and the outcomes for the patient. In total, 45 resections were completed by six operators: five experts and one beginner with only one previous experience in human ESD. Lesions were located in the esophagus (10), the stomach (11), the duodenum (1), the colon (1) and the rectum (22). Average maximal lesion diameter was 4.8 cm (SD 2.4, range 2 - 11 cm), average lesion surface area was 19.8 cm(2) (SD 17.7, range 2.2 - 72 cm(2)), and average duration of procedure was 79.9 min (SD 50.3 min, range 19 - 225 min). ESD could be conducted while the endoscope was retroflexed at its maximum in 26 cases. Four adverse events were observed: two diminutive perforations and two delayed bleeding occurrences treated conservatively. The R0 resection rate was 91.1 %. The catheter was obstructed in six occurrences of bleeding. Endoscopic submucosal dissection using high pressure injection of viscous macromolecular solutions is safe and effective in different parts of the digestive tract. It does not impede working with the endoscope in the maximal retroflexed position.
ABSTRACT It has been shown that a very deep and selective interstitial thermal therapy can be per... more ABSTRACT It has been shown that a very deep and selective interstitial thermal therapy can be performed using a rotating flat miniature ultrasound transducer. This heating modality would be significantly improved by implementing imaging and monitoring. The space limitations in interstitial applications require combining imaging and therapy on the same transducer. In conventional endoscopic ultrasound imaging, a miniprobe can be positioned inside the lumen of an organ and fast rotation of a single element transducer enables real time peripheral imaging of the lumen. Based on this idea, we proposed an original therapeutic strategy. Imaging can be interrupted for a short period of time corresponding to an angle Deltaalpha in order to apply high intensity ultrasound for thermal ablation. First, theoretical simulations were conducted. A 1D thermal model of the transducer demonstrated that this operating mode is not critical for the transducer. Simulations using the BioHeat Transfer Equation showed that Deltaalpha=pi/4 induced efficient therapy. An applicator was built in order to test this treatment strategy. The active element consisted in a 2.5 times 7.5 mm2 dual mode single element transducer operating at a frequency of 11 MHz. The applicator was driven in rotation at 7-turns per second pace. Experiments were performed in vitro on porcine liver. Ultrasound images were reconstructed and the size of the -6 dB point spread function at focal distance was 0.55 mm times 0.25 mm. The electronics for performing the therapeutic strategy considered above was set up. Up to 8 millimeters-deep thermal lesions were obtained with Deltaalpha=pi/4 and peak intensity of 110 W/cm 2. This work demonstrated that thermal lesions can be performed with a fast-rotating dual mode transducer. This approach enabled real-time image-guided therapy
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