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WIREs Nanomed Nanobiotechnol
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Phase‐shift, stimuli‐responsive perfluorocarbon nanodroplets for drug delivery to cancer

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Abstract This review focuses on phase‐shift perfluorocarbon nanoemulsions whose action depends on an ultrasound‐triggered phase shift from a liquid to gas state. For drug‐loaded perfluorocarbon nanoemulsions, microbubbles are formed under the action of tumor‐directed ultrasound and drug is released locally into tumor volume in this process. This review covers in detail mechanisms involved in the droplet‐to‐bubble transition as well as mechanisms of ultrasound‐mediated drug delivery. WIREs Nanomed Nanobiotechnol 2012, 4:492–510. doi: 10.1002/wnan.1176 This article is categorized under: Therapeutic Approaches and Drug Discovery > Emerging Technologies Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease

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Dodecafluoropentane/poly(ethylene oxide)‐co‐poly(l‐ lactide) (DDFP/PEG‐PLLA) microbubbles inserted into a plasma clot (a) before; (b) and (c) after 1‐min sonication at room temperature; ultrasound parameters: (b) 1 MHz, 3.4 W/cm2 nominal power density; (c) 90 kHz, 2.8 W/cm2.

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Schematic representation of the generation of lipid‐encapsulated decafluorobutane (DFB) nanodroplets based upon condensation of preformed DFB microbubbles. (Reprinted with permission from Ref 176. Copyright 2011 ACS Publications)

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| Ultrasound contrast enhancement in vitro. (a) Depiction of the gas phase of a photoacoustic nanodroplets (PAnD) after laser triggered vaporization has occurred. These microbubbles provide significant acoustic impedance mismatch between the perfluorocarbon (PFC) gas and the surrounding environment. (b) Optical images of a hydrogel with PAnDs before laser exposure and after laser exposure. Individual droplets are expected to create bubbles approximately 5 times the diameter of the original droplet. The larger bubbles are due to rapid coalescence of smaller bubbles. Scale bars represent 50 µm. (c) Sequential US frames captured as the laser irradiation produced desired pattern in the phantom. The image before laser irradiation illustrates that the ultrasound field alone does not activate PAnDs (i.e., does not initiate the liquid‐to‐gas transfer of the PFC). As PAnDs are irradiated with laser beam at corresponding positions, the microbubbles are locally triggered, resulting in ultrasound contrast enhancement. Each individual spot is approximately 1 mm, with the final letters standing 1.2 cm tall and 0.5 cm wide. Images are in 20 dB scale. (Reprinted with permission from Ref 175. Copyright 2012 Nature Publishing Group)

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Photoacoustic nanodroplets (PAnD) concept and mechanisms. (a) Diagram depicting the dual‐contrast agent concept—photoacoustic droplet consisting of plasmonic nanoparticles suspended in encapsulated perfluorocarbon (PFC; a superheated liquid at body temperature) and capped with a BSA (bovine serum albumin) shell. PAnDs may further contain therapeutic cargo and be surface functionalized for molecular targeting and cell‐particle interactions. (b) Step‐by‐step diagram of remote activation of PAnDs, providing photoacoustic signal via two mechanisms: vaporization of PAnDs (steps 2–3) and thermal expansion caused by plasmonic nanoparticles (steps 4–5). The resulting gas microbubble of PFC (step 6) provides ultrasound contrast due to acoustic impedance mismatch between gas and the surround environment. (Reprinted with permission from Ref 175. Copyright 2012 Nature Publishing Group)

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Intravital fluorescence images of subcutaneous pancreatic tumors before (a) and 3 days after focused ultrasound treatment (b). A mouse was injected with paclitaxel (PTX)‐loaded droplets 1% perfluoro‐15‐crown‐5‐ether (PFCE)/5% poly(ethylene oxide)‐co‐poly(l‐lactide) (PEG‐PDLA) droplets 6 h before ultrasound treatment; doxorubicin (DOX) dose was 40 mg/kg. Conditions of ultrasound treatment: Ultrasound beam was steered for 50 seconds in a circle of 4 mm diameter (8 ‘points’, 200 milliseconds/point, 30 circles/treatment resulting in a total 6‐second sonication of each ‘point’ with a maximum power density in the focal zone of 54 W/cm2). MRI thermometry showed tumor heating by about 10°C. (Reprinted with permission from Ref 123. Copyright 2011 Elsevier)

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A mouse bearing bilateral ovarian carcinoma tumors was treated by four systemic injections of nanodroplet encapsulated paclitaxel (PTX; 20 mg/kg) given twice weekly; only one (the right) tumor was sonicated by1‐MHz ultrasound at a nominal output power density 3.4 W/cm2, exposure duration 1 min; ultrasound was delivered 4.5 h after the injection of the drug formulation. The left tumor grew at the same rate as untreated controls tumors while the right tumor appeared completely resolved. (Reprinted with permission from Ref 124. Copyright 2009 Elsevier)

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(a) The doxorubicin‐derived fluorescence (red) of the microbubbles was clearly localized in the bubble walls formed by the bubble‐stabilizing copolymer. (b) upon a 30‐second exposure to 3‐MHz ultrasound at 2 W/cm2 power density, the cells incubated with doxorubicin (DOX)‐loaded microbubbles acquired strong fluorescence while bubbles lost fluorescence or were popped. (Reprinted with permission from Ref 56. Copyright 2007 Oxford University Press)

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Schematic illustration of drug transfer from droplets to bubbles to cells under the action of ultrasound. (Reprinted with permission from Ref 124. Copyright 2009 Elsevier)

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(a) The scheme of the nanodroplet structure. In nanodroplets, perfluorocarbon compounds form droplet cores while amphiphilic block copolymers form droplet shells that contain two layers. The inner layer is formed by the hydrophobic block of the block copolymer (e.g., polylactide or polycaprolactone) while the outer layer is formed by the hydrophilic block, poly(ethylene oxide) (PEG). Lipophilic drugs are encapsulated in the hydrophobic inner layer. (b) Laser confocal images of the dodecafluoropentane/poly(ethylene oxide)‐co‐poly(l‐lactide) (DDFP/PEG‐PLLA) droplets with encapsulated doxorubicin (DOX). Some micrometer‐scale droplets presented in panel (b) have been specially generated for better visualization of DOX distribution. DOX localization on the droplet surface is manifested by fluorescence.

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Schematic representation of the phase diagram of perfluorocarbon (PFC)/copolymer formulation in aqueous environment: points—micelles; circles—droplets. The dotted line corresponds to critical micelle concentration of copolymer below which neither micelles nor droplets can be formed. Zone 1 corresponds to micellar solutions with PFC dissolved in micelle cores; zone 2 corresponds to micelle/droplet mixtures; finally, zone 3 corresponds to droplets only. At a fixed copolymer concentration, transition proceeds from zone 1 to zone 2 to zone 3 upon increasing PFC concentration. (Reprinted with permission from Ref 56. Copyright 2007 Oxford University Press)

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Calculated dependence of the dodecafluoropentane (DDFP) vaporization temperature on the droplet size for two values of the surface tension, 30 and 50 mN/m.

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Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease
Therapeutic Approaches and Drug Discovery > Emerging Technologies

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