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10.3389%2Ffphar.2015.00138
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introduction
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Cancer presents the second leading cause of death in the European Union with 3.45 million new cases of cancer and 1.75 million deaths from cancer in 2012 (Ferlay et al., >>2013<<). Although a lot of progress has been made in the treatment of several cancers, many types of cancer are still lacking effective treatment options.
n3:mentions
n4:23485231
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In addition to challenges related to the physicochemical properties of drugs, tumors also possess physiological barriers (Jain, >>2001<<). Contrary to healthy tissues, tumor tissues have a high interstitial fluid pressure (IFP), which is related to the lack of functional lymphatics and the leaky tumor vasculature (Boucher et al., 1990). These high pressures establish an
n3:mentions
n4:11259838
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Contrary to healthy tissues, tumor tissues have a high interstitial fluid pressure (IFP), which is related to the lack of functional lymphatics and the leaky tumor vasculature (Boucher et al., >>1990<<). These high pressures establish an outward fluid motion from the core of the solid tumor to the periphery and reduce fluid infiltration across the vascular wall. Thus, even if the leaky vasculature permits drug extravasation,
n3:mentions
n4:2369726
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High tumor cell proliferation results in tumor cells forcing vessels apart, leading to a decrease in vascular density and a limitation in the access of drugs to distant tumor cells (Minchinton and Tannock, >>2006<<). In addition, the presence of high levels of extracellular matrix limits the interstitial transport of drugs (Weinberg, 2014). Altogether these barriers oppose sufficient and uniform distribution of drugs in solid tumors, thereby
n3:mentions
n4:16862189
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For several hydrophilic and charged drugs, e.g., bleomycin, this is a serious challenge and requires active uptake through plasma membrane transporters, which are not always present in the target cells (Pron et al., >>1999<<).
n3:mentions
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In order to improve the efficiency of anti-cancer chemotherapeutics, physical methods including electroporation, laser, and magnetic fields have been developed (Sersa et al., >>2008<<; Podaru et al., 2014; Sklar et al., 2014).
n3:mentions
n4:17614247
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In order to improve the efficiency of anti-cancer chemotherapeutics, physical methods including electroporation, laser, and magnetic fields have been developed (Sersa et al., 2008; Podaru et al., >>2014<<; Sklar et al., 2014).
n3:mentions
n4:25110807
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In order to improve the efficiency of anti-cancer chemotherapeutics, physical methods including electroporation, laser, and magnetic fields have been developed (Sersa et al., 2008; Podaru et al., 2014; Sklar et al., >>2014<<). The general principle of physical methods is based on the transient disruption of endothelial barrier and tumor cell membrane in order to facilitate the drug extravasation and the drug uptake into the endothelial and tumor cells.
n3:mentions
n4:24664987
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In recent years, research in the field of microbubble-assisted ultrasound (also known as sonoporation) aimed at delivering therapeutic molecules in vitro and in vivo has grown rapidly (Aryal et al., >>2014<<; Azagury et al., 2014; Kiessling et al., 2014; Rychak and Klibanov, 2014; Unga and Hashida, 2014; Unger et al., 2014).
n3:mentions
n4:24462453
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In recent years, research in the field of microbubble-assisted ultrasound (also known as sonoporation) aimed at delivering therapeutic molecules in vitro and in vivo has grown rapidly (Aryal et al., 2014; Azagury et al., >>2014<<; Kiessling et al., 2014; Rychak and Klibanov, 2014; Unga and Hashida, 2014; Unger et al., 2014).
n3:mentions
n4:24463344
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years, research in the field of microbubble-assisted ultrasound (also known as sonoporation) aimed at delivering therapeutic molecules in vitro and in vivo has grown rapidly (Aryal et al., 2014; Azagury et al., 2014; Kiessling et al., >>2014<<; Rychak and Klibanov, 2014; Unga and Hashida, 2014; Unger et al., 2014).
n3:mentions
n4:24316070
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of microbubble-assisted ultrasound (also known as sonoporation) aimed at delivering therapeutic molecules in vitro and in vivo has grown rapidly (Aryal et al., 2014; Azagury et al., 2014; Kiessling et al., 2014; Rychak and Klibanov, >>2014<<; Unga and Hashida, 2014; Unger et al., 2014).
n3:mentions
n4:24486388
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ultrasound (also known as sonoporation) aimed at delivering therapeutic molecules in vitro and in vivo has grown rapidly (Aryal et al., 2014; Azagury et al., 2014; Kiessling et al., 2014; Rychak and Klibanov, 2014; Unga and Hashida, >>2014<<; Unger et al., 2014).
n3:mentions
n4:24680708
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as sonoporation) aimed at delivering therapeutic molecules in vitro and in vivo has grown rapidly (Aryal et al., 2014; Azagury et al., 2014; Kiessling et al., 2014; Rychak and Klibanov, 2014; Unga and Hashida, 2014; Unger et al., >>2014<<). Microbubble-assisted ultrasound transiently increases the permeability of biological barriers, such as blood vessel walls (i.e., drug extravasation) and cellular membranes (i.e., cellular uptake of drugs), thus enhancing the local
n3:mentions
n4:24524934
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such as blood vessel walls (i.e., drug extravasation) and cellular membranes (i.e., cellular uptake of drugs), thus enhancing the local delivery of therapeutic molecules across these barriers in the targeted region (Lentacker et al., >>2014<<). Nowadays, the great potential of this modality for cancer therapy is clearly shown in an increasing number of publications on in vitro and in vivo drug delivery using microbubble-assisted ultrasound (Tables 1 and 2 respectively).
n3:mentions
n4:24270006
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that can be used to deliver a wide range of anticancer molecules including low molecular weight chemotherapeutic agents (sonochemotherapy), nucleic acids and monoclonal antibodies to a target site, e.g., tumor (Escoffre et al., 2013c; Ibsen et al., 2013; Unga and Hashida, 2014).
n3:mentions
n4:23157546
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of anticancer molecules including low molecular weight chemotherapeutic agents (sonochemotherapy), nucleic acids and monoclonal antibodies to a target site, e.g., tumor (Escoffre et al., 2013c; Ibsen et al., 2013; Unga and Hashida, >>2014<<). In addition, this method offers the possibility to treat superficial (e.g., skin) as well as deep organs (e.g., brain, liver, prostate), under the guidance of medical imaging modalities (magnetic resonance imaging, ultrasound imaging;
n3:mentions
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method offers the possibility to treat superficial (e.g., skin) as well as deep organs (e.g., brain, liver, prostate), under the guidance of medical imaging modalities (magnetic resonance imaging, ultrasound imaging; Kinoshita et al., >>2006<<; Deckers and Moonen, 2010; Lammers et al., 2015).
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to treat superficial (e.g., skin) as well as deep organs (e.g., brain, liver, prostate), under the guidance of medical imaging modalities (magnetic resonance imaging, ultrasound imaging; Kinoshita et al., 2006; Deckers and Moonen, >>2010<<; Lammers et al., 2015).
n3:mentions
n4:20709123
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(e.g., skin) as well as deep organs (e.g., brain, liver, prostate), under the guidance of medical imaging modalities (magnetic resonance imaging, ultrasound imaging; Kinoshita et al., 2006; Deckers and Moonen, 2010; Lammers et al., >>2015<<).
n3:mentions
n4:25729344
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MB-loaded)MicrobubbleUltrasound (US) parametersOutcome vs. drug aloneFrequencyIntensityDuty cycleTimeIwanaga et al. (>>2007<<)Ca9-22Free bleomycinOptison1 MHz1.0 W/cm210%20 s2.5-fold increase in apoptosisHeath et al. (2012)SCC-1, SCC-5, Cal27Free cisplatinDefinity1 MHz0.5 MI20%5 min≈50% increase in apoptosisEscoffre et al. (2011)U87MG, MDA-231Free doxorubicin
n3:mentions
n4:17273182
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drug aloneFrequencyIntensityDuty cycleTimeIwanaga et al. (2007)Ca9-22Free bleomycinOptison1 MHz1.0 W/cm210%20 s2.5-fold increase in apoptosisHeath et al. (>>2012<<)SCC-1, SCC-5, Cal27Free cisplatinDefinity1 MHz0.5 MI20%5 min≈50% increase in apoptosisEscoffre et al. (2011)U87MG, MDA-231Free doxorubicin (DOX)Vevo, BR14, SonoVue1 MHz400–800 kPa40%30 s30–40% decrease in viability, depending on cell
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n4:22323435
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cycleTimeIwanaga et al. (2007)Ca9-22Free bleomycinOptison1 MHz1.0 W/cm210%20 s2.5-fold increase in apoptosisHeath et al. (2012)SCC-1, SCC-5, Cal27Free cisplatinDefinity1 MHz0.5 MI20%5 min≈50% increase in apoptosisEscoffre et al. (>>2011<<)U87MG, MDA-231Free doxorubicin (DOX)Vevo, BR14, SonoVue1 MHz400–800 kPa40%30 s30–40% decrease in viability, depending on cell lineSorace et al. (2012)2LMPFree paclitaxel (PTX)Definity1 MHz1.0 MPa PNP20%5 min50% increase in cell deathHu et
n3:mentions
n4:21495672
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cisplatinDefinity1 MHz0.5 MI20%5 min≈50% increase in apoptosisEscoffre et al. (2011)U87MG, MDA-231Free doxorubicin (DOX)Vevo, BR14, SonoVue1 MHz400–800 kPa40%30 s30–40% decrease in viability, depending on cell lineSorace et al. (>>2012<<)2LMPFree paclitaxel (PTX)Definity1 MHz1.0 MPa PNP20%5 min50% increase in cell deathHu et al. (2012)BEL-7402Free 10-HCPT (free)Polymer3.5 MHz22.57 mW/cm2ND10 min20–30% decrease in viabilityRen et al. (2013)DLD-1Docetaxel-loaded MBLipid800
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doxorubicin (DOX)Vevo, BR14, SonoVue1 MHz400–800 kPa40%30 s30–40% decrease in viability, depending on cell lineSorace et al. (2012)2LMPFree paclitaxel (PTX)Definity1 MHz1.0 MPa PNP20%5 min50% increase in cell deathHu et al. (>>2012<<)BEL-7402Free 10-HCPT (free)Polymer3.5 MHz22.57 mW/cm2ND10 min20–30% decrease in viabilityRen et al. (2013)DLD-1Docetaxel-loaded MBLipid800 kHz2.56 W/cm250%10 min40% increase in inhibition rateTinkov et al. (2010)295/KDRDOX-loaded MBLipid1
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n4:22659591
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on cell lineSorace et al. (2012)2LMPFree paclitaxel (PTX)Definity1 MHz1.0 MPa PNP20%5 min50% increase in cell deathHu et al. (2012)BEL-7402Free 10-HCPT (free)Polymer3.5 MHz22.57 mW/cm2ND10 min20–30% decrease in viabilityRen et al. (>>2013<<)DLD-1Docetaxel-loaded MBLipid800 kHz2.56 W/cm250%10 min40% increase in inhibition rateTinkov et al. (2010)295/KDRDOX-loaded MBLipid1 MHz1 W/cm250%20 s40% decrease in cell viabilityYan et al. (2013)4T1PTX-liposome loaded MBLipid1 MHz1.0
n3:mentions
n4:23417512
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cell deathHu et al. (2012)BEL-7402Free 10-HCPT (free)Polymer3.5 MHz22.57 mW/cm2ND10 min20–30% decrease in viabilityRen et al. (2013)DLD-1Docetaxel-loaded MBLipid800 kHz2.56 W/cm250%10 min40% increase in inhibition rateTinkov et al. (>>2010<<)295/KDRDOX-loaded MBLipid1 MHz1 W/cm250%20 s40% decrease in cell viabilityYan et al. (2013)4T1PTX-liposome loaded MBLipid1 MHz1.0 MPa50%1 min20–30% decrease in viabilityDeng et al. (2014)MCF7/ADRDOX-liposome loaded MBLipid1 MHz1.65
n3:mentions
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decrease in viabilityRen et al. (2013)DLD-1Docetaxel-loaded MBLipid800 kHz2.56 W/cm250%10 min40% increase in inhibition rateTinkov et al. (2010)295/KDRDOX-loaded MBLipid1 MHz1 W/cm250%20 s40% decrease in cell viabilityYan et al. (>>2013<<)4T1PTX-liposome loaded MBLipid1 MHz1.0 MPa50%1 min20–30% decrease in viabilityDeng et al. (2014)MCF7/ADRDOX-liposome loaded MBLipid1 MHz1.65 W/cm220%15 sIncreased cellular accumulation and retention, 30% decrease in viability10-HCPT,
n3:mentions
n4:23306023
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_:vb42921903
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increase in inhibition rateTinkov et al. (2010)295/KDRDOX-loaded MBLipid1 MHz1 W/cm250%20 s40% decrease in cell viabilityYan et al. (2013)4T1PTX-liposome loaded MBLipid1 MHz1.0 MPa50%1 min20–30% decrease in viabilityDeng et al. (>>2014<<)MCF7/ADRDOX-liposome loaded MBLipid1 MHz1.65 W/cm220%15 sIncreased cellular accumulation and retention, 30% decrease in viability10-HCPT, 10-hydroxycamptothecin; ND, non-defined; PNP, peak-negative-pressure.
n3:mentions
n4:24287101
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ReferenceTumor (site, animal)DrugMicrobubbleAdministration routeUS parametersOutcome vs drug aloneFrequencyIntensityDuty cycleTimeYan et al. (>>2013<<)4T1 (s.c., mouse)PTX-liposome loaded MBLipidintravenous (i.v.)2.25 MHz1.9 MPa1%10 minFourfold increase it PTX accumulation, 2.5-fold decrease in tumor volume compared to PTX-loaded MB aloneBurke et al. (2014)C6 (s.
n3:mentions
n4:23306023
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2.25 MHz1.9 MPa1%10 minFourfold increase it PTX accumulation, 2.5-fold decrease in tumor volume compared to PTX-loaded MB aloneBurke et al. (>>2014<<)C6 (s.c., rat)5FU-NPs loaded MBAlbumini.v.1 MHz1.2 MPa (PNP)NDEvery 5 s for 60 minTwofold decrease in tumor volume, increase in median survival (34 days vs. 26 days) compared to free 5FUFan et al. (2013)C6 (i.c., rat)VEGFR2-BCNU- loaded
n3:mentions
n4:24172867
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26 days) compared to free 5FUFan et al. (>>2013<<)C6 (i.c., rat)VEGFR2-BCNU- loaded MBLipidi.
n3:mentions
n4:23246066
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<40 days) compared to untargeted BCNU-loaded MBIwanaga et al. (>>2007<<)Caco-9 (s.c., mouse)Free BleomycinOptisonIntratumoral (i.
n3:mentions
n4:17273182
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; co-injection)1 MHz2 W/cm250%2 minTwofold decrease in tumor volume compared to free BLMKang et al. (>>2010<<)VX2 (liver, rabbit)Docetaxel-loaded MBLipidi.
n3:mentions
n4:20040776
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(infusion)0.3 MHz2 W/cm250%6 minThreefold increase tumor inhibition, twofold increase in apoptosis, twofold decrease in proliferation compared to free DocetaxelLi et al. (>>2012<<)H22 (s.c., mouse)10-HCPT loaded MBLipidi.v.1 MHz2 W/cm250%6 minSixfold increase in it 10-HCPT accumulation, twofold decrease in tumor volume compared to free 10-HCPTPu et al. (2014)A2780/DDP (i.p. mouse)LHRHa-PTX loaded
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n4:22800580
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1 MHz2 W/cm250%6 minSixfold increase in it 10-HCPT accumulation, twofold decrease in tumor volume compared to free 10-HCPTPu et al. (>>2014<<)A2780/DDP (i.
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n4:24237050
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<40 days) compared to free PTXSonoda et al. (>>2007<<)B16 (s.c., mouse)Free BLMOptisoni.
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n4:17704642
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(co-injection)1 MHz2 W/cm250%4 minTumor eradication compared to free BLMTreat et al. (>>2012<<)9L (i.c., rat)Free DoxilDefinityi.v.1.7 MHz1.2 MPa1%1–2 min1.5-fold decrease in tumor volume and median survival compared to free DoxilEscoffre et al. (2013b)U-87 MG (s.c., mouse)Free IrinotecanMM1i.v.1 MHz0.4 MPa (PNP)40%3 minThreefold
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1.7 MHz1.2 MPa1%1–2 min1.5-fold decrease in tumor volume and median survival compared to free DoxilEscoffre et al. (2013b)U-87 MG (s.
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MHz0.4 MPa (PNP)40%3 minThreefold decrease in tumor volume, twofold decrease in tumor perfusion, threefold increase necrosis, 35% decrease in mitosis index, no acute liver toxicity compared to free irinotecanTing et al. (>>2012<<)C6 (i.c., rat)BCNU-loaded MBLipidi.v.
n3:mentions
n4:22019122
Subject Item
_:vb42921915
rdf:type
n3:Context
rdf:value
MHz0.5–0.7 MPa5%1 min / sonication siteFivefold increase in circulatory half-life of BCNU, fivefold decrease in liver accumulation, 13-fold decrease in tumor volume, 12% increase in median survival compared to free BCNUTinkov et al. (>>2010<<)DSL6A (s.c., rat)DOX-loaded MBLipidi.v. (perfusion)1.3 MHz1.2 MPaNDFour ultrasound frames every four cardiac cycles10-fold i.
n3:mentions
n4:20868711
Subject Item
_:vb42921916
rdf:type
n2:Section
dc:title
microbubble-assisted ultrasound
n2:contains
_:vb42921940 _:vb42921941 _:vb42921942 _:vb42921943 _:vb42921936 _:vb42921937 _:vb42921938 _:vb42921939 _:vb42921948 _:vb42921949 _:vb42921950 _:vb42921951 _:vb42921944 _:vb42921945 _:vb42921946 _:vb42921947 _:vb42921924 _:vb42921925 _:vb42921926 _:vb42921927 _:vb42921920 _:vb42921921 _:vb42921922 _:vb42921923 _:vb42921932 _:vb42921933 _:vb42921934 _:vb42921935 _:vb42921928 _:vb42921929 _:vb42921930 _:vb42921931 _:vb42921972 _:vb42921973 _:vb42921974 _:vb42921975 _:vb42921968 _:vb42921969 _:vb42921970 _:vb42921971 _:vb42921980 _:vb42921981 _:vb42921982 _:vb42921983 _:vb42921976 _:vb42921977 _:vb42921978 _:vb42921979 _:vb42921956 _:vb42921957 _:vb42921958 _:vb42921959 _:vb42921952 _:vb42921953 _:vb42921954 _:vb42921955 _:vb42921964 _:vb42921965 _:vb42921966 _:vb42921967 _:vb42921960 _:vb42921961 _:vb42921962 _:vb42921963 _:vb42921984 _:vb42921985 _:vb42921986 _:vb42921917 _:vb42921918 _:vb42921919
Subject Item
_:vb42921917
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contrast agents (i.e., consisting of gas microbubbles) was introduced as a promising method in improving the therapeutic efficacy of drugs by increasing local delivery, while minimizing side effects to healthy tissues (Price et al., >>1998<<). In this paper, we refer to this combination as microbubble-assisted ultrasound.
n3:mentions
n4:9751673
Subject Item
_:vb42921918
rdf:type
n3:Context
rdf:value
a second generation of microbubbles was developed, which were filled with heavy-weight hydrophobic gas (e.g., perfluorocarbon, sulfur hexafluoride) encapsulated by a biocompatible shell (e.g., lipids, polymer; Hernot and Klibanov, >>2008<<; Sirsi and Borden, 2014; Figure 1A). In studies on drug delivery by microbubble-assisted ultrasound, the bubbles are mixed with cells in vitro or injected in vivo intravascularly or directly into the tissue of interest.
n3:mentions
n4:18486268
Subject Item
_:vb42921919
rdf:type
n3:Context
rdf:value
of microbubbles was developed, which were filled with heavy-weight hydrophobic gas (e.g., perfluorocarbon, sulfur hexafluoride) encapsulated by a biocompatible shell (e.g., lipids, polymer; Hernot and Klibanov, 2008; Sirsi and Borden, >>2014<<; Figure 1A). In studies on drug delivery by microbubble-assisted ultrasound, the bubbles are mixed with cells in vitro or injected in vivo intravascularly or directly into the tissue of interest.
n3:mentions
n4:24389162
Subject Item
_:vb42921920
rdf:type
n3:Context
rdf:value
Microbubble behavior in an ultrasound field has been widely studied, which led to more understanding and subsequent control of the induced bio-effects that can be used for drug delivery (Kooiman et al., >>2014<<). The response of a microbubble to ultrasound waves depends on the acoustic parameters used, such as frequency, pressure levels, and pulse duration. In short, microbubbles stably oscillate over time upon exposure to a low acoustic
n3:mentions
n4:24667643
Subject Item
_:vb42921921
rdf:type
n3:Context
rdf:value
oscillations generate fluid flows surrounding the bubble, known as acoustic micro-streaming, and when in close contact with cells, result in shear stress on the cell membrane, leading to cellular uptake of drugs (Leighton, 1994; Wu, >>2002<<; Doinikov and Bouakaz, 2010). At higher acoustic pressures, microbubbles oscillate more rigorously, leading to their violent collapse and destruction, i.e., inertial cavitation (Figure 2).
n3:mentions
n4:11879959
Subject Item
_:vb42921922
rdf:type
n3:Context
rdf:value
flows surrounding the bubble, known as acoustic micro-streaming, and when in close contact with cells, result in shear stress on the cell membrane, leading to cellular uptake of drugs (Leighton, 1994; Wu, 2002; Doinikov and Bouakaz, >>2010<<). At higher acoustic pressures, microbubbles oscillate more rigorously, leading to their violent collapse and destruction, i.e., inertial cavitation (Figure 2).
n3:mentions
n4:20329820
Subject Item
_:vb42921923
rdf:type
n3:Context
rdf:value
Microbubble disruption can be accompanied by generation of shock waves in the medium close to the microbubbles (Junge et al., >>2003<<; Ohl and Wolfrum, 2003).
n3:mentions
n4:14698344
Subject Item
_:vb42921924
rdf:type
n3:Context
rdf:value
Microbubble disruption can be accompanied by generation of shock waves in the medium close to the microbubbles (Junge et al., 2003; Ohl and Wolfrum, >>2003<<). The ultrasound-induced collapse of the microbubble can be asymmetrical, leading to the formation of high velocity jets (Postema et al., 2005; Ohl et al., 2006). While shock waves induce shear stress to cells in close proximity,
n3:mentions
n4:14642823
Subject Item
_:vb42921925
rdf:type
n3:Context
rdf:value
The ultrasound-induced collapse of the microbubble can be asymmetrical, leading to the formation of high velocity jets (Postema et al., >>2005<<; Ohl et al., 2006).
n3:mentions
n4:16475770
Subject Item
_:vb42921926
rdf:type
n3:Context
rdf:value
The ultrasound-induced collapse of the microbubble can be asymmetrical, leading to the formation of high velocity jets (Postema et al., 2005; Ohl et al., >>2006<<). While shock waves induce shear stress to cells in close proximity, resulting in membrane permeability, the high velocity jets can pierce the cell membrane, and thereby create permeability. Stable and inertial cavitation are both
n3:mentions
n4:16950843
Subject Item
_:vb42921927
rdf:type
n3:Context
rdf:value
are both exploited to transiently increase the permeability of biological barriers, including the vascular endothelium and plasma membrane, and therefore enhance the extravasation and the cellular uptake of drugs (Lentacker et al., >>2014<<; Figure 2).
n3:mentions
n4:24270006
Subject Item
_:vb42921928
rdf:type
n3:Context
rdf:value
Microbubbles are intravascular contrast agents, which do not cross the vascular endothelium (Wilson and Burns, >>2010<<). Cavitating microbubbles close to the endothelial wall can result in several bio-effects including vascular disruption, vasoconstriction, or even shutdown of the vessels (Goertz, 2015).
n3:mentions
n4:20851938
Subject Item
_:vb42921929
rdf:type
n3:Context
rdf:value
Cavitating microbubbles close to the endothelial wall can result in several bio-effects including vascular disruption, vasoconstriction, or even shutdown of the vessels (Goertz, >>2015<<). Several studies observed that microbubble-assisted ultrasound increased (model-) drug extravasation by stimulating paracellular (i.e., disruption of tight junctions) and transcellular pathways (i.e., transcytosis), both in vitro as well
n3:mentions
n4:25716770
Subject Item
_:vb42921930
rdf:type
n3:Context
rdf:value
ultrasound increased (model-) drug extravasation by stimulating paracellular (i.e., disruption of tight junctions) and transcellular pathways (i.e., transcytosis), both in vitro as well as in vivo (Figure 2; Price et al., >>1998<<; Sheikov et al., 2008; Juffermans et al., 2009; Kooiman et al., 2010).
n3:mentions
n4:9751673
Subject Item
_:vb42921931
rdf:type
n3:Context
rdf:value
increased (model-) drug extravasation by stimulating paracellular (i.e., disruption of tight junctions) and transcellular pathways (i.e., transcytosis), both in vitro as well as in vivo (Figure 2; Price et al., 1998; Sheikov et al., >>2008<<; Juffermans et al., 2009; Kooiman et al., 2010).
n3:mentions
n4:18378064
Subject Item
_:vb42921932
rdf:type
n3:Context
rdf:value
extravasation by stimulating paracellular (i.e., disruption of tight junctions) and transcellular pathways (i.e., transcytosis), both in vitro as well as in vivo (Figure 2; Price et al., 1998; Sheikov et al., 2008; Juffermans et al., >>2009<<; Kooiman et al., 2010).
n3:mentions
n4:19766381
Subject Item
_:vb42921933
rdf:type
n3:Context
rdf:value
paracellular (i.e., disruption of tight junctions) and transcellular pathways (i.e., transcytosis), both in vitro as well as in vivo (Figure 2; Price et al., 1998; Sheikov et al., 2008; Juffermans et al., 2009; Kooiman et al., >>2010<<). In an in vitro endothelial barrier model, Kooiman et al. (2010) showed that microbubble-assisted ultrasound induced a 40% decrease in transendothelial electric resistance showing a loss of endothelial barrier integrity.
n3:mentions
n4:19709954
Subject Item
_:vb42921934
rdf:type
n3:Context
rdf:value
In an in vitro endothelial barrier model, Kooiman et al. (>>2010<<) showed that microbubble-assisted ultrasound induced a 40% decrease in transendothelial electric resistance showing a loss of endothelial barrier integrity.
n3:mentions
n4:19709954
Subject Item
_:vb42921935
rdf:type
n3:Context
rdf:value
In addition, Juffermans et al. (>>2009<<) showed that microbubble-assisted ultrasound significantly affected the integrity of in vitro endothelial monolayers by the destabilization of the tight junctions.
n3:mentions
n4:19766381
Subject Item
_:vb42921936
rdf:type
n3:Context
rdf:value
an acoustical pressure threshold ranging from 0.1 to 0.75 MPa was required to enhance the extravasation of intravascular agents (e.g., red blood cells, imaging tracers, fluorescent dyes, or drugs) in skeletal muscle (Price et al., >>1998<<), brain (Raymond et al., 2007; Sheikov et al., 2008), liver (Gao et al., 2012), and tumor (Bohmer et al., 2010; Hu et al., 2012) tissues.
n3:mentions
n4:9751673
Subject Item
_:vb42921937
rdf:type
n3:Context
rdf:value
ranging from 0.1 to 0.75 MPa was required to enhance the extravasation of intravascular agents (e.g., red blood cells, imaging tracers, fluorescent dyes, or drugs) in skeletal muscle (Price et al., 1998), brain (Raymond et al., >>2007<<; Sheikov et al., 2008), liver (Gao et al., 2012), and tumor (Bohmer et al., 2010; Hu et al., 2012) tissues.
n3:mentions
n4:16685254
Subject Item
_:vb42921938
rdf:type
n3:Context
rdf:value
to 0.75 MPa was required to enhance the extravasation of intravascular agents (e.g., red blood cells, imaging tracers, fluorescent dyes, or drugs) in skeletal muscle (Price et al., 1998), brain (Raymond et al., 2007; Sheikov et al., >>2008<<), liver (Gao et al., 2012), and tumor (Bohmer et al., 2010; Hu et al., 2012) tissues.
n3:mentions
n4:18378064
Subject Item
_:vb42921939
rdf:type
n3:Context
rdf:value
to enhance the extravasation of intravascular agents (e.g., red blood cells, imaging tracers, fluorescent dyes, or drugs) in skeletal muscle (Price et al., 1998), brain (Raymond et al., 2007; Sheikov et al., 2008), liver (Gao et al., >>2012<<), and tumor (Bohmer et al., 2010; Hu et al., 2012) tissues. This extravasation occurs through tight junctions between endothelial cells (0.2–200 μm; Price et al., 1998; Song et al., 2002; Stieger et al., 2007).
n3:mentions
n4:22104531
Subject Item
_:vb42921940
rdf:type
n3:Context
rdf:value
intravascular agents (e.g., red blood cells, imaging tracers, fluorescent dyes, or drugs) in skeletal muscle (Price et al., 1998), brain (Raymond et al., 2007; Sheikov et al., 2008), liver (Gao et al., 2012), and tumor (Bohmer et al., >>2010<<; Hu et al., 2012) tissues. This extravasation occurs through tight junctions between endothelial cells (0.2–200 μm; Price et al., 1998; Song et al., 2002; Stieger et al., 2007).
n3:mentions
n4:20600402
Subject Item
_:vb42921941
rdf:type
n3:Context
rdf:value
(e.g., red blood cells, imaging tracers, fluorescent dyes, or drugs) in skeletal muscle (Price et al., 1998), brain (Raymond et al., 2007; Sheikov et al., 2008), liver (Gao et al., 2012), and tumor (Bohmer et al., 2010; Hu et al., >>2012<<) tissues. This extravasation occurs through tight junctions between endothelial cells (0.2–200 μm; Price et al., 1998; Song et al., 2002; Stieger et al., 2007).
n3:mentions
n4:22659591
Subject Item
_:vb42921942
rdf:type
n3:Context
rdf:value
This extravasation occurs through tight junctions between endothelial cells (0.2–200 μm; Price et al., >>1998<<; Song et al., 2002; Stieger et al., 2007).
n3:mentions
n4:9751673
Subject Item
_:vb42921943
rdf:type
n3:Context
rdf:value
This extravasation occurs through tight junctions between endothelial cells (0.2–200 μm; Price et al., 1998; Song et al., >>2002<<; Stieger et al., 2007).
n3:mentions
n4:11849875
Subject Item
_:vb42921944
rdf:type
n3:Context
rdf:value
This extravasation occurs through tight junctions between endothelial cells (0.2–200 μm; Price et al., 1998; Song et al., 2002; Stieger et al., >>2007<<). In vivo, the integrity of the blood–brain barrier was restored within 1–4 h following ultrasound exposure (Sheikov et al., 2008; Ting et al., 2012). However, Marty et al. (2012) showed that the duration of extravasation after ultrasound
n3:mentions
n4:17392250
Subject Item
_:vb42921945
rdf:type
n3:Context
rdf:value
In vivo, the integrity of the blood–brain barrier was restored within 1–4 h following ultrasound exposure (Sheikov et al., >>2008<<; Ting et al., 2012).
n3:mentions
n4:18378064
Subject Item
_:vb42921946
rdf:type
n3:Context
rdf:value
In vivo, the integrity of the blood–brain barrier was restored within 1–4 h following ultrasound exposure (Sheikov et al., 2008; Ting et al., >>2012<<). However, Marty et al. (2012) showed that the duration of extravasation after ultrasound exposure depends on the particle size. The microbubble-assisted ultrasound enhanced transcellular pathways (e.g., transcytosis) have been mainly
n3:mentions
n4:22019122
Subject Item
_:vb42921947
rdf:type
n3:Context
rdf:value
However, Marty et al. (>>2012<<) showed that the duration of extravasation after ultrasound exposure depends on the particle size.
n3:mentions
n4:22805875
Subject Item
_:vb42921948
rdf:type
n3:Context
rdf:value
The microbubble-assisted ultrasound enhanced transcellular pathways (e.g., transcytosis) have been mainly investigated on the brain vasculature (Raymond et al., >>2007<<; Sheikov et al., 2008; Deng et al., 2012).
n3:mentions
n4:16685254
Subject Item
_:vb42921949
rdf:type
n3:Context
rdf:value
The microbubble-assisted ultrasound enhanced transcellular pathways (e.g., transcytosis) have been mainly investigated on the brain vasculature (Raymond et al., 2007; Sheikov et al., >>2008<<; Deng et al., 2012).
n3:mentions
n4:18378064
Subject Item
_:vb42921950
rdf:type
n3:Context
rdf:value
The microbubble-assisted ultrasound enhanced transcellular pathways (e.g., transcytosis) have been mainly investigated on the brain vasculature (Raymond et al., 2007; Sheikov et al., 2008; Deng et al., >>2012<<). They reported that low (1 MHz, 0.2 MPa) and high (1.63 MHz, 1-3 MPa) acoustic pressures increased the number of transcytotic vesicles on both the luminal and abluminal surface of the endothelium. Sheikov et al. (2004) hypothesized that
n3:mentions
n4:21861133
Subject Item
_:vb42921951
rdf:type
n3:Context
rdf:value
Sheikov et al. (>>2004<<) hypothesized that the transient vasoconstriction constitutes a potential cause for the increased transcytosis in vivo.
n3:mentions
n4:15313330
Subject Item
_:vb42921952
rdf:type
n3:Context
rdf:value
In addition, Hu et al. (>>2012<<) showed that the destruction of microbubbles with a high acoustic pressure (5 MHz, 2 MPa) decreased the tumor blood flow for 30 min before it returned back to normal, without an increase in hemorrhage.
n3:mentions
n4:22659591
Subject Item
_:vb42921953
rdf:type
n3:Context
rdf:value
Besides cavitation, ultrasound can also induce heating and acoustic radiation force (ARF) to improve the extravasation of drugs (Deckers and Moonen, >>2010<<). Heating can result from the absorbance of acoustic energy as the ultrasound beam propagates through tissue.
n3:mentions
n4:20709123
Subject Item
_:vb42921954
rdf:type
n3:Context
rdf:value
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.
n3:mentions
n4:6467226
Subject Item
_:vb42921955
rdf:type
n3:Context
rdf:value
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.
n3:mentions
n4:3982038
Subject Item
_:vb42921956
rdf:type
n3:Context
rdf:value
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.
n3:mentions
n4:11306483
Subject Item
_:vb42921957
rdf:type
n3:Context
rdf:value
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.
n3:mentions
n4:22838732
Subject Item
_:vb42921958
rdf:type
n3:Context
rdf:value
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).
n3:mentions
n4:364652
Subject Item
_:vb42921959
rdf:type
n3:Context
rdf:value
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).
n3:mentions
n4:15041738
Subject Item
_:vb42921960
rdf:type
n3:Context
rdf:value
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).
n3:mentions
n4:22952218
Subject Item
_:vb42921961
rdf:type
n3:Context
rdf:value
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).
n3:mentions
n4:24463345
Subject Item
_:vb42921962
rdf:type
n3:Context
rdf:value
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).
n3:mentions
n4:25416027
Subject Item
_:vb42921963
rdf:type
n3:Context
rdf:value
Ultrasound can also generate directional ARF on molecules along its propagation path (Sarvazyan et al., >>2010<<; Figure 3).
n3:mentions
n4:20800165
Subject Item
_:vb42921964
rdf:type
n3:Context
rdf:value
This enhances the extravasation of free drug or drug-loaded nanoparticles into tumor tissue by causing tissue shear stress and opening of endothelial tight junctions (Seidl et al., >>1994<<; Mesiwala et al., 2002).
n3:mentions
n4:8079400
Subject Item
_:vb42921965
rdf:type
n3:Context
rdf:value
This enhances the extravasation of free drug or drug-loaded nanoparticles into tumor tissue by causing tissue shear stress and opening of endothelial tight junctions (Seidl et al., 1994; Mesiwala et al., >>2002<<). ARF induces fluid streaming through the interstitium, thus improving biodistribution of intravascular dyes and drugs in the target tissue (Lum et al., 2006; Hancock et al., 2009). Using optical imaging, Shortencarier et al. (2004)
n3:mentions
n4:11978420
Subject Item
_:vb42921966
rdf:type
n3:Context
rdf:value
ARF induces fluid streaming through the interstitium, thus improving biodistribution of intravascular dyes and drugs in the target tissue (Lum et al., >>2006<<; Hancock et al., 2009).
n3:mentions
n4:16380187
Subject Item
_:vb42921967
rdf:type
n3:Context
rdf:value
ARF induces fluid streaming through the interstitium, thus improving biodistribution of intravascular dyes and drugs in the target tissue (Lum et al., 2006; Hancock et al., >>2009<<). Using optical imaging, Shortencarier et al. (2004) showed that the application of ARF induced visible aggregates of fluorescent dye-loaded gas lipospheres in the direction of the beam on the far vessel wall. The lipospheres disappeared
n3:mentions
n4:19616368
Subject Item
_:vb42921968
rdf:type
n3:Context
rdf:value
Using optical imaging, Shortencarier et al. (>>2004<<) showed that the application of ARF induced visible aggregates of fluorescent dye-loaded gas lipospheres in the direction of the beam on the far vessel wall.
n3:mentions
n4:15301001
Subject Item
_:vb42921969
rdf:type
n3:Context
rdf:value
The lipospheres disappeared when the ARF pulses were turned off (Shortencarier et al., >>2004<<). In addition to lipospheres, ARFs can push circulating microbubbles toward the endothelial wall, thereby improving microbubble–cell contact, which might enhance cavitation-mediated extravasation of intravascular compounds (Rychak et al.,
n3:mentions
n4:15301001
Subject Item
_:vb42921970
rdf:type
n3:Context
rdf:value
addition to lipospheres, ARFs can push circulating microbubbles toward the endothelial wall, thereby improving microbubble–cell contact, which might enhance cavitation-mediated extravasation of intravascular compounds (Rychak et al., >>2005<<; Wang et al., 2014).
n3:mentions
n4:15857050
Subject Item
_:vb42921971
rdf:type
n3:Context
rdf:value
ARFs can push circulating microbubbles toward the endothelial wall, thereby improving microbubble–cell contact, which might enhance cavitation-mediated extravasation of intravascular compounds (Rychak et al., 2005; Wang et al., >>2014<<). Using ultrasound imaging, Frinking et al. (2012) reported that ARF (38 kPa PNP, 95% DC) induced a sevenfold increase in the binding of VEGFR2-targeted microbubbles (also known as BR-55) on the endothelial wall in a prostate
n3:mentions
n4:24374866
Subject Item
_:vb42921972
rdf:type
n3:Context
rdf:value
Using ultrasound imaging, Frinking et al. (>>2012<<) reported that ARF (38 kPa PNP, 95% DC) induced a sevenfold increase in the binding of VEGFR2-targeted microbubbles (also known as BR-55) on the endothelial wall in a prostate adenocarcinoma rat model compared with the binding without ARF.
n3:mentions
n4:22579540
Subject Item
_:vb42921973
rdf:type
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rdf:value
Based on the uptake or release of non-permeant dyes (Meijering et al., >>2009<<; Kaddur et al., 2010) and by measuring changes in membrane electrophysiology (Tran et al., 2007; Juffermans et al., 2008), previous studies showed that microbubble-assisted ultrasound induced a transient increase in membrane permeability
n3:mentions
n4:19168443
Subject Item
_:vb42921974
rdf:type
n3:Context
rdf:value
Based on the uptake or release of non-permeant dyes (Meijering et al., 2009; Kaddur et al., >>2010<<) and by measuring changes in membrane electrophysiology (Tran et al., 2007; Juffermans et al., 2008), previous studies showed that microbubble-assisted ultrasound induced a transient increase in membrane permeability through the
n3:mentions
n4:20639150
Subject Item
_:vb42921975
rdf:type
n3:Context
rdf:value
Based on the uptake or release of non-permeant dyes (Meijering et al., 2009; Kaddur et al., 2010) and by measuring changes in membrane electrophysiology (Tran et al., >>2007<<; Juffermans et al., 2008), previous studies showed that microbubble-assisted ultrasound induced a transient increase in membrane permeability through the generation of transient hydrophilic pores.
n3:mentions
n4:17189059
Subject Item
_:vb42921976
rdf:type
n3:Context
rdf:value
Based on the uptake or release of non-permeant dyes (Meijering et al., 2009; Kaddur et al., 2010) and by measuring changes in membrane electrophysiology (Tran et al., 2007; Juffermans et al., >>2008<<), previous studies showed that microbubble-assisted ultrasound induced a transient increase in membrane permeability through the generation of transient hydrophilic pores.
n3:mentions
n4:17993242
Subject Item
_:vb42921977
rdf:type
n3:Context
rdf:value
The intracellular delivery of molecules through membrane pores is likely governed by passive diffusion or by ultrasound-mediated propulsion (i.e., microstreaming, ARF; Shortencarier et al., >>2004<<; Lum et al., 2006).
n3:mentions
n4:15301001
Subject Item
_:vb42921978
rdf:type
n3:Context
rdf:value
The intracellular delivery of molecules through membrane pores is likely governed by passive diffusion or by ultrasound-mediated propulsion (i.e., microstreaming, ARF; Shortencarier et al., 2004; Lum et al., >>2006<<). The size of these ultrasound induced pores depend on the acoustic parameters used, ranging from 1 to 94 nm at 0.19 MPa PSP and from 2 to 4 μm at 0.48 MPa PSP (Yang et al., 2008).
n3:mentions
n4:16380187
Subject Item
_:vb42921979
rdf:type
n3:Context
rdf:value
The size of these ultrasound induced pores depend on the acoustic parameters used, ranging from 1 to 94 nm at 0.19 MPa PSP and from 2 to 4 μm at 0.48 MPa PSP (Yang et al., >>2008<<).
n3:mentions
n4:18727944
Subject Item
_:vb42921980
rdf:type
n3:Context
rdf:value
In addition to hydrophilic pore formation, enhancement of endocytosis has also been demonstrated following microbubble-assisted ultrasound exposure (Meijering et al., >>2009<<). Electrophysiological studies reported that microbubble-assisted ultrasound induced an influx of Ca2+, followed by an activation of BKCa channels that results in local hyperpolarization of the cell membrane (Tran et al., 2007; Juffermans
n3:mentions
n4:19168443
Subject Item
_:vb42921981
rdf:type
n3:Context
rdf:value
Electrophysiological studies reported that microbubble-assisted ultrasound induced an influx of Ca2+, followed by an activation of BKCa channels that results in local hyperpolarization of the cell membrane (Tran et al., >>2007<<; Juffermans et al., 2008).
n3:mentions
n4:17189059
Subject Item
_:vb42921982
rdf:type
n3:Context
rdf:value
studies reported that microbubble-assisted ultrasound induced an influx of Ca2+, followed by an activation of BKCa channels that results in local hyperpolarization of the cell membrane (Tran et al., 2007; Juffermans et al., >>2008<<). At moderate ultrasound conditions (1 MHz, 0.15–0.3 MPa), the membrane hyperpolarization facilitates the molecular uptake through endocytosis and macropinocytosis.
n3:mentions
n4:17993242
Subject Item
_:vb42921983
rdf:type
n3:Context
rdf:value
Similar to pore formation, the contribution of endocytosis processes depends strongly on the marker size and the acoustic pressures. Meijering et al. (>>2009<<) reported that low acoustic pressures (1 MHz, 0.22 MPa PNP) resulted in the cellular uptake of 4.4 and 70 kDa fluorescent dextrans through membrane pores while the entrance of 155 and 500 kDa fluorescent dextrans is dominated by
n3:mentions
n4:19168443
Subject Item
_:vb42921984
rdf:type
n3:Context
rdf:value
However, De Cock et al. (>>2015<<) showed that increasing the acoustic pressures (1 MHz, 0.5 MPa, PNP) induced the intracellular delivery of large fluorescent dextrans (2 MDa) to shift from uptake by endocytosis to uptake via the membrane pores.
n3:mentions
n4:25449801
Subject Item
_:vb42921985
rdf:type
n3:Context
rdf:value
Regardless of the mechanism of uptake, the duration of microbubble-assisted ultrasound-mediated uptake is dependent on the plasma membrane recovery time, which is a few seconds to a few hours (van Wamel et al., >>2006<<; Lammertink et al., 2015).
n3:mentions
n4:16556469
Subject Item
_:vb42921986
rdf:type
n3:Context
rdf:value
of the mechanism of uptake, the duration of microbubble-assisted ultrasound-mediated uptake is dependent on the plasma membrane recovery time, which is a few seconds to a few hours (van Wamel et al., 2006; Lammertink et al., >>2015<<). The different kinetics depends on the ultrasound conditions, the model drug size and the cell physiology.
n3:mentions
n4:25497443
Subject Item
_:vb42921987
rdf:type
n2:Section
dc:title
anti-cancer drug delivery protocols
n2:contains
_:vb42922048 _:vb42922049 _:vb42922050 _:vb42922051 _:vb42922024 _:vb42922025 _:vb42922026 _:vb42922027 _:vb42922028 _:vb42922029 _:vb42922030 _:vb42922031 _:vb42922016 _:vb42922017 _:vb42922018 _:vb42922019 _:vb42922020 _:vb42922021 _:vb42922022 _:vb42922023 _:vb42922040 _:vb42922041 _:vb42922042 _:vb42922043 _:vb42922044 _:vb42922045 _:vb42922046 _:vb42922047 _:vb42922032 _:vb42922033 _:vb42922034 _:vb42922035 _:vb42922036 _:vb42922037 _:vb42922038 _:vb42922039 _:vb42921992 _:vb42921993 _:vb42921994 _:vb42921995 _:vb42921996 _:vb42921997 _:vb42921998 _:vb42921999 _:vb42921988 _:vb42921989 _:vb42921990 _:vb42921991 _:vb42922008 _:vb42922009 _:vb42922010 _:vb42922011 _:vb42922012 _:vb42922013 _:vb42922014 _:vb42922015 _:vb42922000 _:vb42922001 _:vb42922002 _:vb42922003 _:vb42922004 _:vb42922005 _:vb42922006 _:vb42922007
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_:vb42921988
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to the specific properties of each tumor tissue, such as differences in tissue organization, extracellular matrix, presence of necrosis and hypoxia, cell density, and the endothelial lining of the tumor vasculature (Chauhan et al., >>2011<<). To the best of our knowledge, no comparative study between tumor tissues with different properties has been reported using microbubble-assisted ultrasound for drug delivery.
n3:mentions
n4:22432620
Subject Item
_:vb42921989
rdf:type
n3:Context
rdf:value
unlike many other drug delivery strategies, sonochemotherapy does not depend on the enhanced permeability and retention (EPR) effect, which is very heterogeneous between or within tumors, and often overestimated (Lammers et al., >>2012<<). Interestingly, you could argue that the largest effect of sonochemotherapy can be expected in tissues with ‘non-leaky’ vessels, such as the brain (Ting et al., 2012), since the potential of increasing extravasation is highest.
n3:mentions
n4:21945285
Subject Item
_:vb42921990
rdf:type
n3:Context
rdf:value
Interestingly, you could argue that the largest effect of sonochemotherapy can be expected in tissues with ‘non-leaky’ vessels, such as the brain (Ting et al., >>2012<<), since the potential of increasing extravasation is highest.
n3:mentions
n4:22019122
Subject Item
_:vb42921991
rdf:type
n3:Context
rdf:value
The simplest method for drug delivery using microbubble-assisted ultrasound is to use coadministration (Heath et al., >>2012<<; Unga and Hashida, 2014). This approach includes drugs that are administered in patients anyway in current clinical practice, with the addition of an injection of (clinically approved) microbubbles.
n3:mentions
n4:22323435
Subject Item
_:vb42921992
rdf:type
n3:Context
rdf:value
The simplest method for drug delivery using microbubble-assisted ultrasound is to use coadministration (Heath et al., 2012; Unga and Hashida, >>2014<<). This approach includes drugs that are administered in patients anyway in current clinical practice, with the addition of an injection of (clinically approved) microbubbles.
n3:mentions
n4:24680708
Subject Item
_:vb42921993
rdf:type
n3:Context
rdf:value
(ii) instead of mixing microbubbles and drug before injection, two separate injections of the constituents can also be performed, thus allowing drugs to reach plasma peak levels before injecting microbubbles (Escoffre et al., 2013b). Microbubbles have a short circulation time and therefore need to be exposed to ultrasound within minutes after injection, otherwise they will be degraded and unable to induce bio-effects.
n3:mentions
n4:23675982
Subject Item
_:vb42921994
rdf:type
n3:Context
rdf:value
The coadministration approach seems to be the best strategy for in vitro purposes (Escoffre et al., >>2011<<; Sorace et al., 2012) or, in vivo, i.
n3:mentions
n4:21495672
Subject Item
_:vb42921995
rdf:type
n3:Context
rdf:value
The coadministration approach seems to be the best strategy for in vitro purposes (Escoffre et al., 2011; Sorace et al., >>2012<<) or, in vivo, i.
n3:mentions
n4:21981609
Subject Item
_:vb42921996
rdf:type
n3:Context
rdf:value
Iwanaga et al. (>>2007<<) showed that the in vitro delivery of bleomycin using microbubble-assisted ultrasound induced twofold decrease in cell viability compared to the bleomycin treatment alone (Table 1).
n3:mentions
n4:17273182
Subject Item
_:vb42921997
rdf:type
n3:Context
rdf:value
co-injection of microbubbles and bleomycin also resulted in a twofold decrease in tumor volume (Iwanaga et al., >>2007<<). Kotopoulis et al. (2014) coadministered commercially available microbubbles and gemcitabine i.v. in a pancreatic cancer model in mice. They showed that ultrasound exposure (1 MHz, 0.2 MPa PNP) decreased the tumor volume twofold compared
n3:mentions
n4:17273182
Subject Item
_:vb42921998
rdf:type
n3:Context
rdf:value
Kotopoulis et al. (>>2014<<) coadministered commercially available microbubbles and gemcitabine i.
n3:mentions
n4:23877869
Subject Item
_:vb42921999
rdf:type
n3:Context
rdf:value
They showed that ultrasound exposure (1 MHz, 0.2 MPa PNP) decreased the tumor volume twofold compared to gemcitabine alone (Kotopoulis et al., >>2014<<). Opposed to the advantages of coadministration using clinically approved microbubbles and drugs that allow clinical translation, there are also disadvantages. The main limitations of the i.v. injection of microbubble/drug mixture
n3:mentions
n4:23877869
Subject Item
_:vb42922000
rdf:type
n3:Context
rdf:value
By applying this approach, Burke et al. (>>2014<<) found that the application of ultrasound (1 MHz, 1.2 MPa, every 5 s for 60 min) on subcutaneous C6 glioma tumor following the i.
n3:mentions
n4:24172867
Subject Item
_:vb42922001
rdf:type
n3:Context
rdf:value
injection of 5-FU-loaded microbubbles (1 × 105 microbubbles/g body weight) led to twofold decrease in tumor volume compared to 5-FU treatment alone (Burke et al., >>2014<<). While these approaches seem to be promising, the low drug loading capacity of microbubbles is a major drawback. Consequently, the use of drug-loaded microbubbles requires either enhancement of the drug loading efficiency, administration
n3:mentions
n4:24172867
Subject Item
_:vb42922002
rdf:type
n3:Context
rdf:value
Recent publications reported that the binding of drug-loaded nanoparticles on the microbubble’s surface could increase the amount of loaded drug (Geers et al., >>2011<<). The loading efficiency can be further improved by applying multiple layers of drug-loaded nanoparticles around the microbubble shell. The binding of drug-loaded nanoparticles on microbubbles may not be necessary for polymer-based
n3:mentions
n4:21362448
Subject Item
_:vb42922003
rdf:type
n3:Context
rdf:value
The binding of drug-loaded nanoparticles on microbubbles may not be necessary for polymer-based microbubbles, as significant amounts of (model) drug can be loaded into the polymer-based shell (Fokong et al., >>2012<<). Cochran et al. (2011) showed that the loading capacity is higher for hydrophobic drugs compared to hydrophilic drugs, and that the acoustic properties of the microbubbles were unaffected (Cochran et al., 2011).
n3:mentions
n4:22580225
Subject Item
_:vb42922004
rdf:type
n3:Context
rdf:value
Cochran et al. (>>2011<<) showed that the loading capacity is higher for hydrophobic drugs compared to hydrophilic drugs, and that the acoustic properties of the microbubbles were unaffected (Cochran et al., 2011).
n3:mentions
n4:21609756
Subject Item
_:vb42922005
rdf:type
n3:Context
rdf:value
Cochran et al. (2011) showed that the loading capacity is higher for hydrophobic drugs compared to hydrophilic drugs, and that the acoustic properties of the microbubbles were unaffected (Cochran et al., >>2011<<).
n3:mentions
n4:21609756
Subject Item
_:vb42922006
rdf:type
n3:Context
rdf:value
However, the recommended diagnostic doses of microbubbles currently approved for contrast-enhanced ultrasound imaging (e.g., SonoVue®, Definity®) are between 109 and 1010 microbubbles for an 80-kg adult (Wilson and Burns, >>2010<<). Nevertheless, preclinical and clinical studies have reported a good tolerance with 100- and 1000-fold higher doses of these microbubbles in non-human primates and patients (Grauer et al., 1996; Bokor et al., 2001).
n3:mentions
n4:20851938
Subject Item
_:vb42922007
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n3:Context
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Nevertheless, preclinical and clinical studies have reported a good tolerance with 100- and 1000-fold higher doses of these microbubbles in non-human primates and patients (Grauer et al., 1996; Bokor et al., >>2001<<). Consequently, the injection of a high dose of drug-loaded microbubbles may not be a limitation for clinical use, but further preclinical studies might be necessary to identify any potential toxicity of high concentrations of liposome
n3:mentions
n4:11224758
Subject Item
_:vb42922008
rdf:type
n3:Context
rdf:value
Finally, several preclinical studies reported the use of repeated sonochemotherapy treatments (Kang et al., >>2010<<; Tinkov et al., 2010; Li et al., 2012; Ting et al., 2012).
n3:mentions
n4:20040776
Subject Item
_:vb42922009
rdf:type
n3:Context
rdf:value
Finally, several preclinical studies reported the use of repeated sonochemotherapy treatments (Kang et al., 2010; Tinkov et al., >>2010<<; Li et al., 2012; Ting et al., 2012).
n3:mentions
n4:20868711
Subject Item
_:vb42922010
rdf:type
n3:Context
rdf:value
Finally, several preclinical studies reported the use of repeated sonochemotherapy treatments (Kang et al., 2010; Tinkov et al., 2010; Li et al., >>2012<<; Ting et al., 2012).
n3:mentions
n4:22800580
Subject Item
_:vb42922011
rdf:type
n3:Context
rdf:value
Finally, several preclinical studies reported the use of repeated sonochemotherapy treatments (Kang et al., 2010; Tinkov et al., 2010; Li et al., 2012; Ting et al., >>2012<<). For example, Li et al. (2012) reported that the repetitive treatment (i.e., once a day for seven consecutive days) of subcutaneous hepatic tumor using 10-hydroxycamptothecin-loaded microbubbles (4 mg/kg) induced twofold stronger
n3:mentions
n4:22019122
Subject Item
_:vb42922012
rdf:type
n3:Context
rdf:value
For example, Li et al. (>>2012<<) reported that the repetitive treatment (i.e., once a day for seven consecutive days) of subcutaneous hepatic tumor using 10-hydroxycamptothecin-loaded microbubbles (4 mg/kg) induced twofold stronger decrease in tumor volume in a
n3:mentions
n4:22800580
Subject Item
_:vb42922013
rdf:type
n3:Context
rdf:value
microbubbles (4 mg/kg) induced twofold stronger decrease in tumor volume in a subcutaneous hepatic tumor model (1 MHz, 2 W/cm2, 6 min) compared to the 10-hydroxycamptothecin-based chemotherapy alone (Li et al., >>2012<<).
n3:mentions
n4:22800580
Subject Item
_:vb42922014
rdf:type
n3:Context
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antigen; LHR, luteinizing hormone receptor) or tumor microvasculature (VEGF-R2, vascular endothelial growth factor receptor -2) through attachment of targeting ligands or antibodies onto the microbubble’s shell (Kiessling et al., >>2012<<, 2014; Novell et al., 2013). This may lead to enhanced accumulation of the microbubbles in the target tumor cells or tissues.
n3:mentions
n4:22393225
Subject Item
_:vb42922015
rdf:type
n3:Context
rdf:value
LHR, luteinizing hormone receptor) or tumor microvasculature (VEGF-R2, vascular endothelial growth factor receptor -2) through attachment of targeting ligands or antibodies onto the microbubble’s shell (Kiessling et al., 2012, >>2014<<; Novell et al., 2013). This may lead to enhanced accumulation of the microbubbles in the target tumor cells or tissues.
n3:mentions
n4:24316070
Subject Item
_:vb42922016
rdf:type
n3:Context
rdf:value
For example, Fan et al. (>>2013<<) designed targeted BCNU-loaded microbubbles, which bind the VEGF-R2 overexpressed on tumor microvasculature (VEGFR2-BCNU-loaded microbubbles; Figure 4A).
n3:mentions
n4:23246066
Subject Item
_:vb42922017
rdf:type
n3:Context
rdf:value
injection of VEGFR2-BCNU-loaded microbubbles (1.25 mg BCNU) resulted in 1.75-fold decrease in tumor volume compared to the untargeted BCNU-loaded microbubbles (Figure 4B; Fan et al., >>2013<<). The use of microbubbles targeting overexpressed markers on the tumor cells themselves is limited to in vitro drug delivery, i.t. or intraperitoneal (i.p.) injection of microbubbles and drugs, primarily because the microbubbles, when
n3:mentions
n4:23246066
Subject Item
_:vb42922018
rdf:type
n3:Context
rdf:value
injection of microbubbles and drugs, primarily because the microbubbles, when administrated intravenously, cannot extravasate due to the size (Cavalieri et al., >>2010<<). For imaging, several groups have reported on the in vivo accumulation of targeted microbubbles in the tumor microvasculature by binding inflammation markers overexpressed on tumor endothelial cells (Deshpande et al., 2010). Although
n3:mentions
n4:20388108
Subject Item
_:vb42922019
rdf:type
n3:Context
rdf:value
For imaging, several groups have reported on the in vivo accumulation of targeted microbubbles in the tumor microvasculature by binding inflammation markers overexpressed on tumor endothelial cells (Deshpande et al., >>2010<<). Although these microbubbles were designed as ultrasound contrast agents for molecular imaging, it might be possible to develop optimal tissue- or organ-selective drug delivery agents by combining targeting capacities and drug loading of
n3:mentions
n4:20541656
Subject Item
_:vb42922020
rdf:type
n3:Context
rdf:value
as ultrasound contrast agents for molecular imaging, it might be possible to develop optimal tissue- or organ-selective drug delivery agents by combining targeting capacities and drug loading of microbubbles (Kiessling et al., >>2012<<). However, no evidence of their use for drug delivery has been reported yet.
n3:mentions
n4:22393225
Subject Item
_:vb42922021
rdf:type
n3:Context
rdf:value
Intracerebral BCNU delivery using VEGFR2-targeted and BCNU-loaded microbubbles with focused ultrasound for the glioma treatment (Adapted with permission from Fan et al., >>2013<< – Copyright © 2012 Elsevier Ltd.). (A) Antiangiogenic-targeting BCNU-loaded microbubbles combined with focused ultrasound for glioma treatment.
n3:mentions
n4:23246066
Subject Item
_:vb42922022
rdf:type
n3:Context
rdf:value
t. injection (Sonoda et al., >>2007<<; Sasaki et al., 2014). The advantages of i.t. administration over systemic injection include the circumvention of the transvascular barrier and the generation of transient interstitial pressure gradients.
n3:mentions
n4:17704642
Subject Item
_:vb42922023
rdf:type
n3:Context
rdf:value
The latter can induce convection and tissue deformation, which can decrease the connectedness of the extracellular matrix and size of pores in the tumor interstitial space (Frenkel, >>2008<<). By using i.t. administration, a high drug dose can be directly delivered into the target tumor while minimizing its side effects toward healthy tissues. This administration route overcomes the drawback related to the short plasma
n3:mentions
n4:18474406
Subject Item
_:vb42922024
rdf:type
n3:Context
rdf:value
For deep-seated tumors, most protocols recommend injection of drugs and microbubbles via blood flow, providing better access to deeper tumors (Treat et al., >>2012<<; Yan et al., 2013; Burke et al., 2014). The i.v. route is a relatively easy and safe way to be used in the clinic for the administration of therapeutics and microbubbles.
n3:mentions
n4:22818878
Subject Item
_:vb42922025
rdf:type
n3:Context
rdf:value
For deep-seated tumors, most protocols recommend injection of drugs and microbubbles via blood flow, providing better access to deeper tumors (Treat et al., 2012; Yan et al., >>2013<<; Burke et al., 2014). The i.v. route is a relatively easy and safe way to be used in the clinic for the administration of therapeutics and microbubbles.
n3:mentions
n4:23306023
Subject Item
_:vb42922026
rdf:type
n3:Context
rdf:value
For deep-seated tumors, most protocols recommend injection of drugs and microbubbles via blood flow, providing better access to deeper tumors (Treat et al., 2012; Yan et al., 2013; Burke et al., >>2014<<). The i.v. route is a relatively easy and safe way to be used in the clinic for the administration of therapeutics and microbubbles.
n3:mentions
n4:24172867
Subject Item
_:vb42922027
rdf:type
n3:Context
rdf:value
Therefore, drugs can be loaded on microbubbles to overcome these shortcomings (Ting et al., >>2012<<; Sirsi and Borden, 2014).
n3:mentions
n4:22019122
Subject Item
_:vb42922028
rdf:type
n3:Context
rdf:value
Therefore, drugs can be loaded on microbubbles to overcome these shortcomings (Ting et al., 2012; Sirsi and Borden, >>2014<<). The success of i.v. drug delivery relies on sufficient tumor vascularization, thus restricting the application of this administration route to hypervascularized tumors. Next to extravasation, microbubble-assisted ultrasound can also
n3:mentions
n4:24389162
Subject Item
_:vb42922029
rdf:type
n3:Context
rdf:value
injection may be useful for drug delivery using microbubble-assisted ultrasound for the treatments of primary peritoneal cancers or cancers with i.p. metastases. Pu et al. (>>2014<<) investigated the i.p.
n3:mentions
n4:24237050
Subject Item
_:vb42922030
rdf:type
n3:Context
rdf:value
This therapeutic protocol led to a twofold increase in apoptotic index and a 2.5-fold decrease in vessel number compared to the single injection of free PTX or PTX delivery using ultrasound alone (Pu et al., >>2014<<). Due to the microbubble size, penetration of the microbubbles by convection throughout the tumor is hindered, thereby limiting the tumor cell binding to the peripheral rim of the tumor. Nevertheless, the targeted microbubbles in this
n3:mentions
n4:24237050
Subject Item
_:vb42922031
rdf:type
n3:Context
rdf:value
Among these studies, clinical ultrasound scanners have been used to deliver drugs using microbubble-assisted ultrasound (Tinkov et al., >>2010<<; Sasaki et al., 2014), which has the advantage of enabling both imaging of- and drug delivery to the targeted tumor.
n3:mentions
n4:20868711
Subject Item
_:vb42922032
rdf:type
n3:Context
rdf:value
Hence, home-made and commercial therapeutic ultrasound devices have been designed to control many ultrasound parameters, which can subsequently be optimized for drug delivery (Zhao et al., >>2011<<; Lin et al., 2012; Escoffre et al., 2013a).
n3:mentions
n4:20429773
Subject Item
_:vb42922033
rdf:type
n3:Context
rdf:value
Hence, home-made and commercial therapeutic ultrasound devices have been designed to control many ultrasound parameters, which can subsequently be optimized for drug delivery (Zhao et al., 2011; Lin et al., >>2012<<; Escoffre et al., 2013a).
n3:mentions
n4:22619550
Subject Item
_:vb42922034
rdf:type
n3:Context
rdf:value
Hence, home-made and commercial therapeutic ultrasound devices have been designed to control many ultrasound parameters, which can subsequently be optimized for drug delivery (Zhao et al., 2011; Lin et al., 2012; Escoffre et al., 2013a). Ultrasound transducers used in the literature can be focused or unfocused (Sanches et al., 2011).
n3:mentions
n4:23287915
Subject Item
_:vb42922035
rdf:type
n3:Context
rdf:value
Ultrasound transducers used in the literature can be focused or unfocused (Sanches et al., >>2011<<). Focused beams are created using spherically curved transducers, which greatly increase the ultrasound intensity in a small region of interest, e.g., a tumor. Due to a lack of standardized calibration methods concerning the applied
n3:mentions
n4:22833903
Subject Item
_:vb42922036
rdf:type
n3:Context
rdf:value
Due to a lack of standardized calibration methods concerning the applied ultrasound parameters and the heterogeneity in equipment used, it is not straightforward to compare the results of most studies directly (ter Haar et al., >>2011<<).
n3:mentions
n4:21257086
Subject Item
_:vb42922037
rdf:type
n3:Context
rdf:value
b., ISPTA 0.0003 – 0.9 W/cm2 for ultrasound-based diagnostics) have been applied in recent studies to deliver drugs in tumor tissue without injuries (Kang et al., >>2010<<; Lu et al., 2011).
n3:mentions
n4:20040776
Subject Item
_:vb42922038
rdf:type
n3:Context
rdf:value
b., ISPTA 0.0003 – 0.9 W/cm2 for ultrasound-based diagnostics) have been applied in recent studies to deliver drugs in tumor tissue without injuries (Kang et al., 2010; Lu et al., >>2011<<). The MI used for in vivo drug delivery ranges from 0.2 to 2 (n.b., MI threshold for clinical diagnosis is 1.9). Drug delivery requires a minimum MI known as the permeabilization threshold, which is typically lower than 1 (Choi et al.,
n3:mentions
n4:20978763
Subject Item
_:vb42922039
rdf:type
n3:Context
rdf:value
Drug delivery requires a minimum MI known as the permeabilization threshold, which is typically lower than 1 (Choi et al., >>2007<<). Exposure of tumor tissues above, but near the cavitation threshold has so far yielded the most promising results of drug delivery without significant side effects. Increasing the ultrasound dose further enhanced drug delivery in the
n3:mentions
n4:17804879
Subject Item
_:vb42922040
rdf:type
n3:Context
rdf:value
Increasing the ultrasound dose further enhanced drug delivery in the target tissue but was also accompanied by hemorrhage and tissue injuries (Kang et al., >>2010<<; Lu et al., 2011).
n3:mentions
n4:20040776
Subject Item
_:vb42922041
rdf:type
n3:Context
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Increasing the ultrasound dose further enhanced drug delivery in the target tissue but was also accompanied by hemorrhage and tissue injuries (Kang et al., 2010; Lu et al., >>2011<<).
n3:mentions
n4:20978763
Subject Item
_:vb42922042
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n3:Context
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To prevent thermal tissue damage, low duty cycles are used when high ultrasound intensities are applied and vice versa (Lin et al., >>2012<<; Wei et al., 2013).
n3:mentions
n4:22619550
Subject Item
_:vb42922043
rdf:type
n3:Context
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However, exposure times of 1–5 min are recommended to prevent tissue injuries (e.g., hemorrhages; Mei et al., >>2009<<; Yan et al., 2013).
n3:mentions
n4:19546329
Subject Item
_:vb42922044
rdf:type
n3:Context
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However, exposure times of 1–5 min are recommended to prevent tissue injuries (e.g., hemorrhages; Mei et al., 2009; Yan et al., >>2013<<).
n3:mentions
n4:23306023
Subject Item
_:vb42922045
rdf:type
n3:Context
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drug administration at different time points following the exposure of tumor to microbubble-assisted ultrasound to assess the duration of enhanced permeability (few seconds – few hours, depending on the particle size; Marty et al., >>2012<<; Tzu-Yin et al., 2014; Lammertink et al., 2015). Other investigations recommend waiting for the peak concentration of drug in the blood before the administration of microbubbles and the subsequent exposure of tumors to ultrasound.
n3:mentions
n4:22805875
Subject Item
_:vb42922046
rdf:type
n3:Context
rdf:value
at different time points following the exposure of tumor to microbubble-assisted ultrasound to assess the duration of enhanced permeability (few seconds – few hours, depending on the particle size; Marty et al., 2012; Tzu-Yin et al., >>2014<<; Lammertink et al., 2015). Other investigations recommend waiting for the peak concentration of drug in the blood before the administration of microbubbles and the subsequent exposure of tumors to ultrasound.
n3:mentions
n4:24372231
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following the exposure of tumor to microbubble-assisted ultrasound to assess the duration of enhanced permeability (few seconds – few hours, depending on the particle size; Marty et al., 2012; Tzu-Yin et al., 2014; Lammertink et al., >>2015<<). Other investigations recommend waiting for the peak concentration of drug in the blood before the administration of microbubbles and the subsequent exposure of tumors to ultrasound.
n3:mentions
n4:25497443
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For example, Escoffre et al. (2013b) succeeded to optimize therapeutic efficacy of irinotecan using microbubble-assisted ultrasound in subcutaneous glioblastoma.
n3:mentions
n4:23675982
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administration of microbubbles (Escoffre et al., 2013b). This delay is required to reach the maximal systemic concentration of SN-38, the active metabolite of irinotecan, in the blood.
n3:mentions
n4:23675982
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In most therapeutic protocols using the coadministration approach or drug-loaded microbubbles, ultrasound was applied to the tumors immediately (5–10 s) after microbubble injection (Sonoda et al., >>2007<<; Matsuo et al., 2011). This strategy supposes that drugs and microbubbles are sufficiently accumulated in the target tissue during the few seconds following their administration.
n3:mentions
n4:17704642
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In most therapeutic protocols using the coadministration approach or drug-loaded microbubbles, ultrasound was applied to the tumors immediately (5–10 s) after microbubble injection (Sonoda et al., 2007; Matsuo et al., >>2011<<). This strategy supposes that drugs and microbubbles are sufficiently accumulated in the target tissue during the few seconds following their administration.
n3:mentions
n4:21459032
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n2:Section
dc:title
therapeutic efficacy vs. safety: from in vitro to preclinical studies
n2:contains
_:vb42922064 _:vb42922065 _:vb42922066 _:vb42922067 _:vb42922053 _:vb42922054 _:vb42922055 _:vb42922060 _:vb42922061 _:vb42922062 _:vb42922063 _:vb42922056 _:vb42922057 _:vb42922058 _:vb42922059
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benefit of drug delivery using microbubble-assisted ultrasound relies on enhancing accumulation of drugs in tumor cells or tissues and on decreasing their deposition in healthy tissues, thus reducing their side effects (Tinkov et al., >>2010<<; Li et al., 2012; Fan et al., 2013; Burke et al., 2014).
n3:mentions
n4:20868711
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using microbubble-assisted ultrasound relies on enhancing accumulation of drugs in tumor cells or tissues and on decreasing their deposition in healthy tissues, thus reducing their side effects (Tinkov et al., 2010; Li et al., >>2012<<; Fan et al., 2013; Burke et al., 2014).
n3:mentions
n4:22800580
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ultrasound relies on enhancing accumulation of drugs in tumor cells or tissues and on decreasing their deposition in healthy tissues, thus reducing their side effects (Tinkov et al., 2010; Li et al., 2012; Fan et al., >>2013<<; Burke et al., 2014).
n3:mentions
n4:23246066
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relies on enhancing accumulation of drugs in tumor cells or tissues and on decreasing their deposition in healthy tissues, thus reducing their side effects (Tinkov et al., 2010; Li et al., 2012; Fan et al., 2013; Burke et al., >>2014<<). Using the coadministration approach or drug-loaded microbubbles, microbubble-assisted ultrasound enhances in vitro the therapeutic efficacy of clinically approved chemotherapeutics including doxorubicin (Dox), cisplatin, bleomycin, PTX,
n3:mentions
n4:24172867
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For example, Deng et al. (>>2014<<) showed enhanced intracellular Dox levels (Figure 5A) and increased retention due to a down-regulation of P-glycoprotein following ultrasound exposure in the presence of Dox-liposome loaded microbubbles.
n3:mentions
n4:24287101
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∗p < 0.05, ∗∗p < 0.01 (Adapted with permission from Deng et al., >>2014<< – Copyright © 2014 Elsevier Ltd.
n3:mentions
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For example, Tinkov et al. (>>2010<<) demonstrated that the exposure of pancreas carcinoma in rats to ultrasound (1.3 MHz, 1.2 MPa PNP, four frames of ultrasound every four cardiac cycles) after i.
n3:mentions
n4:20868711
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DOX accumulation compared to DOX-loaded microbubble injection alone (Tinkov et al., >>2010<<). This therapeutic protocol led to a twofold decrease in tumor volume.
n3:mentions
n4:20868711
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Among the studies that do measure this, Yan et al. (>>2013<<) reported that the application of ultrasound (2.25 MHz, 1.9 MPa, 10 min, three treatments:
n3:mentions
n4:23306023
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administration of the PTX-loaded microbubbles and ultrasound exposure (Yan et al., >>2013<<). The PTX biodistribution in heart, spleen, and lung was not significantly different between mice that received PTX-loaded microbubbles treatment alone or combined with ultrasound (Figure 6A). However, the PTX delivery using
n3:mentions
n4:23306023
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Moreover, Ting et al. (>>2012<<) designed a therapeutic protocol based on BCNU-loaded microbubbles (0.8 mg – 1 × 1010) with focused ultrasound (1 MHz, 0.5–0.7 MPa, 2 sonications, 1 min/sonication) to improve BCNU-based chemotherapy for glioblastoma treatment.
n3:mentions
n4:22019122
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encapsulation of BCNU in microbubbles prolonged its circulatory half-life fivefold and intrahepatic accumulation of BCNU was reduced fivefold due to the slow reticuloendothelial system uptake of BCNU-loaded microbubbles (Ting et al., >>2012<<). These microbubbles alone or in combination with focused ultrasound were associated with lower levels of aspartate- and alanine-aminotransferases compared to free BCNU, suggesting that these microbubbles may effectively reduce liver
n3:mentions
n4:22019122
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Paclitaxel (PTX) delivery by PTX-loaded microbubble with ultrasound for breast cancer treatment (Adapted with permission from Yan et al., >>2013<< – Copyright © 2013 Elsevier Ltd.).
n3:mentions
n4:23306023
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For example, Burke et al. (>>2011<<) demonstrated that the mechanical effect of low duty cycle ultrasound (1 MHz, 1 MPa PNP) in combination with microbubbles could inhibit glioma growth by blocking tumor perfusion.
n3:mentions
n4:21214331
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The anti-vascular action of microbubble-assisted ultrasound (1 MHz, 1.6 MPa PNP) was also adopted by Todorova et al. (>>2013<<) who subsequently injected an anti-angiogenic agent to prevent the formation of new vessels.
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