Formulation and Pharmacokinetics of Thermosensitive Stealth® Liposomes Encapsulating 5-Fluorouracil

Sabbagh, Chantal Al; Tsapis, Nicolas; Novell, Anthony; Calleja-Gonzalez, Patricia; Escoffre, Jean‐Michel; Bouakaz, Ayache; Chacun, Hélène; Denis, Stéphanie; Vergnaud-Gauduchon, Juliette; Gueutin, Claire

doi:10.1007/s11095-014-1559-0

Cited by 27 publications

(11 citation statements)

References 44 publications

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“…In this study, a frequency of 1 MHz was chosen because of its use in numerous therapeutic treatments [5]. More precisely, sonoporation and the triggered release of thermosensitive liposomes (TSLs) [28] were targeted. Whereas sonoporation generally requires a relatively low peak negative pressure (PNP), the mild hyperthermia required to reach the melting phase transition temperature of the TSLs is more challenging to generate at 1 MHz: [29] showed that this temperature, typically approximately 42˚C, can be reached at 1 MHz, More detailed information about the design stage, the manufacturing process and the choice of the CMUT geometry are given by [27].…”

Section: Overview Of the Usgfus Cmut Probementioning

confidence: 99%

Evaluation of an Ultrasound-Guided Focused Ultrasound CMUT Probe for Targeted Therapy Applications

Gross¹,

Legros

Vince³

et al. 2018

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Capacitive Micromachined Ultrasonic Transducer (CMUT) technology, which has been widely studied in the field of medical imaging, possesses strong design flexibility due to its manufacturing process. Many applications could benefit from this unique feature, especially those that require different operating ultrasonic frequencies. This article reports on the characterization of the therapeutic low-frequency field provided by an ultrasound-guided focused ultrasound CMUT probe that is connected to a custom ultrasonic scanner for hyperthermia applications. The study begins by mapping the focused ultrasonic beam in the vicinity of the focal spot and a parametric analysis providing the maximum peak-to-peak (PTP) pressure delivered by the probe under different acoustic conditions. The measured maximum PTP pressure at the targeted operating frequency of 1 MHz is 3 MPa, with a maximum of 3.6 MPa at 1.25 MHz. Based on an in vitro setup found in the literature, the temperature elevation at the focal point was measured, showing results in agreement with the targeted applications (max. ∆T = 7.5˚C). The article concludes with a reliability study considering the delivered pressure and the self-heating of the CMUT probe: the results show the good stability of the pressure amplitude over 1.8 × 10 9 cycles at a duty cycle of 40%, with a moderate internal heating of 3˚C.

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Section: Overview Of the Usgfus Cmut Probementioning

confidence: 99%

Evaluation of an Ultrasound-Guided Focused Ultrasound CMUT Probe for Targeted Therapy Applications

Gross¹,

Legros

Vince³

et al. 2018

OJAppS

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“…Mild heating of a tumor (41 – 43°C for 10 – 60 min) may improve the therapeutic efficacy of drugs by acting on tumor hemodynamics ( Figure 3 ): (i) by increasing tumor perfusion, thus enhancing drug bioavailability in tumor tissue ( Song, 1984 ); (ii) by increasing vascular permeability ( Lefor et al, 1985 ; Kong et al, 2001 ) and reducing tumor interstitial pressure ( Vaupel and Kelleher, 2012 ), leading to better drug penetration within tumor tissue. In addition, local heating can act as an external trigger for drug release from a carrier, e.g., thermosensitive nanoparticles ( Yatvin et al, 1978 ; Lindner et al, 2004 ; Manzoor et al, 2012 ; Hijnen et al, 2014 ; Al Sabbagh et al, 2015 ). Ultrasound can also generate directional ARF on molecules along its propagation path ( Sarvazyan et al, 2010 ; Figure 3 ).…”

Section: Microbubble-assisted Ultrasoundmentioning

confidence: 99%

Sonochemotherapy: from bench to bedside

et al. 2015

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The combination of microbubbles and ultrasound has emerged as a promising method for local drug delivery. Microbubbles can be locally activated by a targeted ultrasound beam, which can result in several bio-effects. For drug delivery, microbubble-assisted ultrasound is used to increase vascular- and plasma membrane permeability for facilitating drug extravasation and the cellular uptake of drugs in the treated region, respectively. In the case of drug-loaded microbubbles, these two mechanisms can be combined with local release of the drug following destruction of the microbubble. The use of microbubble-assisted ultrasound to deliver chemotherapeutic agents is also referred to as sonochemotherapy. In this review, the basic principles of sonochemotherapy are discussed, including aspects such as the type of (drug-loaded) microbubbles used, the routes of administration used in vivo, ultrasound devices and parameters, treatment schedules and safety issues. Finally, the clinical translation of sonochemotherapy is discussed, including the first clinical study using sonochemotherapy.

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“…Currently DOX is only occasionally used in the clinic as a radiosensitizer in the treatment of soft tissue sarcomas, hence a soft tissue sarcoma cell line (HT1080) was used in this study. In contrast, other radiosensitizers, which are also chemotherapeutic agents, exist which are more commonly used in the clinic and are already encapsulated in a TSL, including cisplatin [ 46 ], pyrimidine analogue gemcitabine (dFdC) [ 47 ] and 5-FU [ 48 ]. However, the objective of these studies is to decrease the toxicity of the chemotherapeutic agent by TSL encapsulation, and as a consequence have not been tested as a radiosensitizer for triggered local release in combination with RT.…”

Section: Discussionmentioning

confidence: 99%

Triggered radiosensitizer delivery using thermosensitive liposomes and hyperthermia improves efficacy of radiotherapy: An in vitro proof of concept study

et al. 2018

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IntroductionTo increase the efficacy of chemoradiation and decrease its toxicity in normal tissue, a new concept is proposed, local radiosensitizer delivery, which combines triggered release of a radiosensitizer from thermosensitive liposomes with local hyperthermia and radiotherapy. Here, key aspects of this concept were investigated in vitro I) the effect of hyperthermia on the enhancement of radiotherapy by ThermoDox (thermosensitive liposome containing doxorubicin), II) the concentration dependence of the radiosensitizing effect of doxorubicin and III) the sequence of doxorubicin, hyperthermia and radiotherapy maximizing the radiosensitizing effect.MethodsSurvival of HT1080 (human fibrosarcoma) cells was measured after exposure to ThermoDox or doxorubicin for 60 minutes, at 37 or 43°C, with or without irradiation. Furthermore, cell survival was measured for cells exposed to different doxorubicin concentrations and radiation doses. Finally, cell survival was measured after applying doxorubicin and/or hyperthermia before or after irradiation. Cell survival was measured by clonogenic assay. In addition, DNA damage was assessed by γH2AX staining.ResultsExposure of cells to doxorubicin at 37°C resulted in cell death, but exposure to ThermoDox at 37°C did not. In contrast, ThermoDox and doxorubicin at 43°C resulted in similar cytotoxicity, and in combination with irradiation caused a similar enhancement of cell kill due to radiation. Doxorubicin enhanced the radiation effect in a small, but significant, concentration-dependent manner. Hyperthermia showed the strongest enhancement of radiation effect when applied after irradiation. In contrast, doxorubicin enhanced radiation effect only when applied before irradiation. Concurrent doxorubicin and hyperthermia immediately before or after irradiation showed equal enhancement of radiation effect.ConclusionIn vitro, ThermoDox resulted in cytotoxicity and enhancement of irradiation effect only in combination with hyperthermia. Therefore hyperthermia-triggered radiosensitizer release from thermosensitive liposomes may ultimately serve to limit toxicities due to the radiosensitizer in unheated normal tissue and result in enhanced efficacy in the heated tumor.

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Formulation and Pharmacokinetics of Thermosensitive Stealth® Liposomes Encapsulating 5-Fluorouracil

Abstract: Complexation of 5-FU with copper-polyethylenimine appears an interesting strategy to improve 5-FU retention into TSLs in vitro and in vivo. TSLs allow heat-triggered release of the drug within 10 min at 42°C, a reasonable time for future in vivo experiments.

Cited by 27 publications

References 44 publications

Evaluation of an Ultrasound-Guided Focused Ultrasound CMUT Probe for Targeted Therapy Applications

Evaluation of an Ultrasound-Guided Focused Ultrasound CMUT Probe for Targeted Therapy Applications

Sonochemotherapy: from bench to bedside

Triggered radiosensitizer delivery using thermosensitive liposomes and hyperthermia improves efficacy of radiotherapy: An in vitro proof of concept study

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