Effect of Ultrasound on the Permeability of Vascular Wall to Nano-emulsion Droplets

Thakkar, Dhaval; Gupta, Roohi; Monson, Kenneth L.; Rapoport, Natalya

doi:10.1016/j.ultrasmedbio.2013.04.008

Cited by 29 publications

(18 citation statements)

References 54 publications

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“…The data suggest that at the conditions studied, MRgFUS treatment did not noticeably enhance nanodroplet extravasation into the tumor tissue. The opposite was observed in a recent study where excised carotid arteries were inserted in PBS [ 50 ]. It appears reasonable to suggest that the ultrasound susceptibility of blood vessels inserted in solid matrices could differ from that of vessels inserted in liquid.…”

Section: Discussionmentioning

confidence: 68%

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Focused ultrasound-mediated drug delivery to pancreatic cancer in a mouse model

et al. 2013

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BackgroundMany aspects of the mechanisms involved in ultrasound-mediated therapy remain obscure. In particular, the relative roles of drug and ultrasound, the effect of the time of ultrasound application, and the effect of tissue heating are not yet clear. The current study was undertaken with the goal to clarify these aspects of the ultrasound-mediated drug delivery mechanism.MethodsFocused ultrasound-mediated drug delivery was performed under magnetic resonance imaging guidance (MRgFUS) in a pancreatic ductal adenocarcinoma (PDA) model grown subcutaneously in nu/nu mice. Paclitaxel (PTX) was used as a chemotherapeutic agent because it manifests high potency in the treatment of gemcitabine-resistant PDA. Poly(ethylene oxide)-co-poly(d,l-lactide) block copolymer stabilized perfluoro-15-crown-5-ether nanoemulsions were used as drug carriers. MRgFUS was applied at sub-ablative pressure levels in both continuous wave and pulsed modes, and only a fraction of the tumor was treated.ResultsPositive treatment effects and even complete tumor resolution were achieved by treating the tumor with MRgFUS after injection of nanodroplet encapsulated drug. The MRgFUS treatment enhanced the action of the drug presumably through enhanced tumor perfusion and blood vessel and cell membrane permeability that increased the drug supply to tumor cells. The effect of the pulsed MRgFUS treatment with PTX-loaded nanodroplets was clearly smaller than that of continuous wave MRgFUS treatment, supposedly due to significantly lower temperature increase as measured with MR thermometry and decreased extravasation. The time of the MRgFUS application after drug injection also proved to be an important factor with the best results observed when ultrasound was applied at least 6 h after the injection of drug-loaded nanodroplets. Some collateral damage was observed with particular ultrasound protocols supposedly associated with enhanced inflammation.ConclusionThis presented data suggest that there exists an optimal range of ultrasound application parameters and drug injection time. Decreased tumor growth, or complete resolution, was achieved with continuous wave ultrasound pressures below or equal to 3.1 MPa and drug injection times of at least 6 h prior to treatment. Increased acoustic pressure or ultrasound application before or shortly after drug injection gave increased tumor growth when compared to other protocols.

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Section: Discussionmentioning

confidence: 68%

“…The effect of the pulsed MRgFUS treatment with PTX-loaded nanodroplets was clearly smaller than that of CW MRgFUS treatment, which may be related to significantly lower temperature increase and/or decreased extravasation [ 50 ].…”

Section: Discussionmentioning

confidence: 99%

Focused ultrasound-mediated drug delivery to pancreatic cancer in a mouse model

et al. 2013

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“…Liquid fluorocarbons undergo liquid phase gas phase transition in response to external stimulation [18,19]. Natalya and colleagues developed a nano-emulsion containing liquid fluorocarbon that produced acoustic droplet vaporization (ADV) effects under low-intensity focused ultrasound (LIFU) [20][21][22]. The emulsions formed bubbles and simultaneously triggered drug release, thereby enabling tumor treatment.…”

Section: Introductionmentioning

confidence: 99%

pH- and acoustic-responsive platforms based on perfluoropentane-loaded protein nanoparticles for ovarian tumor-targeted ultrasound imaging and therapy

Jing

et al. 2020

Nanoscale Res Lett

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In this study, we developed a multifunctional ultrasound (US) therapeutic agent that encapsulates perfluoropentane (PFP) into ferritin (FRT) and conjugates the tumor-targeting molecule folic acid (FA) (FA-FRT-PFP). The prepared FA-FRT-PFP had an average particle diameter of 42.8 ± 2.5 nm, a zeta potential of − 41.1 ± 1.7 mV and shows good stability in physiological solution and temperatures. FRT is a pH-sensitive cage protein that, at pH 5.0, disassembles to form pores that can load PFP. The adjustment to neutral pH closes the pores and encapsulates the PFP inside the FRT to form nanoparticles. At pH 5.0, 3 min of low-intensity focused ultrasound (LIFU, 2 W/cm 2) significantly enhanced the US signal of FA-FRT-PFP through the acoustic droplet vaporization (ADV) effect. Under identical conditions, 4 min of LIFU irradiation caused the bubbles generated by FA-FRT-PFP to break. FA-FRT-PFP could be efficiently targeted into ovarian cancer cells and significantly enhanced the US contrast of FA-FRT-PFP after 3 min of LIFU irradiation. After 4 min of LIFU irradiation, cell viability significantly decreased due to necrosis, likely due to the FA-FRT-PFP mediated release of PFP in the acidic environment of lysosomes after entering the tumor cells. PFP is then transformed into bubbles that burst under LIFU irradiation, forming physical shock waves that lead to the destruction of the cell structure and necrosis, achieving tumor treatment. Taken together, this demonstrates that FA-FRT-PFP is both a novel and promising US theranostics agent for future clinic application.

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“…19 This increased circulation time could enhance therapeutic efficiency by extending treatment at a relatively low injected dose. [20][21][22][23] In considering applications involving solid tumors, PCCAs provide opportunities for extravasation into tissue via the cavitation-enhanced permeability and retention effect [24][25][26] due to the transit of a large population of nanoscale PCCAs with a size of~200 nm 27 through spaces of 200-1200 nm in the leaky vessel wall in tumors. 28 Phase change contrast agents have recently been demonstrated in several delivery applications including fibroblast growth factor to stimulate angiogenesis, 29 delivery of therapeutics to tumors [30][31][32] and neuromodulation in small animal models.…”

Section: Introductionmentioning

confidence: 99%

Transcranial activation and imaging of low boiling point phase‐change contrast agents through the temporal bone using an ultrafast interframe activation ultrasound sequence

2020

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Purpose: As a cavitation enhancer, low boiling point phase-change contrast agents (PCCA) offer potential for ultrasound-mediated drug delivery in applications including intracerebral hemorrhage or brain tumors. In addition to introducing cavitation, ultrasound imaging also has the ability to provide guidance and monitoring of the therapeutic process by localizing delivery events. However, the highly attenuating skull poses a challenge for achieving an image with useful contrast. In this study, the feasibility of transcranial activation and imaging of low boiling point PCCAs through the human temporal bone was investigated by using a low frequency ultrafast interframe activation ultrasound (UIAU) imaging sequence with singular value decomposition-based denoising. Methods: Lipid-shelled PCCAs filled with decafluorobutane were activated and imaged at 37°C in tissue-mimicking phantoms both without and with an ex vivo human skull using the new UIAU sequence and a low frequency diagnostic transducer array at frequencies from 1.5 to 3.5 MHz. A singular value decomposition-based denoising filter was developed and used to further enhance transcranial image contrast. The contrast-to-tissue ratio (CTR) and contrast enhancement (CE) of UIAU was quantitatively evaluated and compared with the amplitude modulation pulse inversion (AMPI) and vaporization detection imaging (VDI) approaches. Results: Image results demonstrate enhanced contrast in the phantom channel with suppressed background when the low boiling point PCCA was activated both without and with an ex vivo human skull using the UIAU sequence. Quantitative results show that without the skull, low frequency UIAU imaging provided significantly higher image contrast (CTR ≥ 18.56 dB and CE ≥ 18.66 dB) than that of AMPI and VDI (P < 0.05). Transcranial imaging results indicated that the CE of UIAU (≥18.80 dB) was significantly higher than AMPI for free-field activation pressures of 5 and 6 MPa. The CE of UIAU is also significantly higher than that of VDI when PCCAs were activated at 2.5 MHz and 3 MHz (P < 0.05). The CTR (23.30 [20.07-25.56] dB) of denoised UIAU increased by 12.58 dB relative to the non-denoised case and was significantly higher than that of AMPI at an activation pressure of 4 MPa (P < 0.05). Conclusions: Results indicate that low boiling point PCCAs can be activated and imaged at low frequencies including imaging through the temporal bone using the UIAU sequence. The UIAU imaging approach provides higher contrast than AMPI and VDI, especially at lower activation pressures with additional removal of electronic noise.

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Effect of Ultrasound on the Permeability of Vascular Wall to Nano-emulsion Droplets

Cited by 29 publications

References 54 publications

Focused ultrasound-mediated drug delivery to pancreatic cancer in a mouse model

Focused ultrasound-mediated drug delivery to pancreatic cancer in a mouse model

pH- and acoustic-responsive platforms based on perfluoropentane-loaded protein nanoparticles for ovarian tumor-targeted ultrasound imaging and therapy

Transcranial activation and imaging of low boiling point phase‐change contrast agents through the temporal bone using an ultrafast interframe activation ultrasound sequence

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