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Pharmaceutics
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Micro/Nano-Bubbles as a New Ultrasound Imaging and Drug Delivery Tool
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Micro/Nano-Bubbles as a New Ultrasound Imaging and Drug Delivery Tool

A special issue of Pharmaceutics (ISSN 1999-4923).

Deadline for manuscript submissions: closed (15 April 2019) | Viewed by 29486

Special Issue Editor

Prof. Katsuro Tachibana

E-Mail Website
Guest Editor
Department of Anatomy, Fukuoka University Faculty of Medicine, Fukuoka, Japan
Interests: ultrasound; sonoporation; micro/nanobubbles; sonothrombolysis; sonodynamic therapy

Special Issue Information

Dear Colleagues,

Recently, various types of microbubbles ("fine bubbles" larger than 1 µm) and smaller nanobubbles ("ultrafine bubbles" less than 1 µm diameter) for ultrasound contrast imaging have been under development. The advantage of small bubbles is their capability to easily perfuse into the capillaries, resulting in detailed images of biological tissues, such as tumors and normal organs. These bubbles can become a superior ultrasound contrast agent compared to larger bubbles. Other than their size, shelled and non-shelled bubbles have shown different acoustic characters, ultrasound images, and biological reactions. Utilizing bubble-shell material may permit molecular targeting and imaging. Another exciting aspect of bubbles is their ability to carry and delivery drugs to a specific location within the body. The collapse of bubbles due to high intensity-focused ultrasound in a localized area can induce or boost the sonoporation phenomenon, resulting in the opening of a hard-to-penetrate blood–brain barrier or increasing cell membrane permeability. Although the mechanism of sonoporation and imaging of nanobubbles are not known, combining ultrasound and bubbles may prove to be an ideal, non-invasive therapy/diagnosis (theranositcs) modality. This Special Issue invites manuscripts on subjects relating to ultrasound imaging and drug-delivery systems by means of micro and nano-bubbles.

Prof. Katsuro Tachibana
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Pharmaceutics is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • microbubbles/nanobubbles
  • sonoporation
  • ultrasound contrast agent
  • molecular targeting and imaging
  • drug delivery system
  • high-intensity-focused ultrasound
  • sonothrombolysis
  • sonodynamic therapy
  • gene therapy

Published Papers (7 papers)

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Research

13 pages, 1695 KiB  
Article
Theoretical and Experimental Gas Volume Quantification of Micro- and Nanobubble Ultrasound Contrast Agents
by Eric C. Abenojar, Ilya Bederman, Al C. de Leon, Jinle Zhu, Judith Hadley, Michael C. Kolios and Agata A. Exner
Pharmaceutics 2020, 12(3), 208; https://doi.org/10.3390/pharmaceutics12030208 - 01 Mar 2020
Cited by 25 | Viewed by 3413
Abstract
The amount of gas in ultrasound contrast agents is related to their acoustic activity. Because of this relationship, gas volume has been used as a key variable in normalizing the in vitro and in vivo acoustic behavior of lipid shell-stabilized bubbles with different [...] Read more.
The amount of gas in ultrasound contrast agents is related to their acoustic activity. Because of this relationship, gas volume has been used as a key variable in normalizing the in vitro and in vivo acoustic behavior of lipid shell-stabilized bubbles with different sizes and shell components. Despite its importance, bubble gas volume has typically only been theoretically calculated based on bubble size and concentration that is typically measured using the Coulter counter for microbubbles and nanoparticle tracking analysis (NTA) for nanoscale bubbles. However, while these methods have been validated for the analysis of liquid or solid particles, their application in bubble analysis has not been rigorously studied. We have previously shown that resonant mass measurement (RMM) may be a better-suited technique for sub-micron bubble analysis, as it can measure both buoyant and non-buoyant particle size and concentration. Here, we provide validation of RMM bubble analysis by using headspace gas chromatography/mass spectrometry (GC/MS) to experimentally measure the gas volume of the bubble samples. This measurement was then used as ground truth to test the accuracy of theoretical gas volume predictions based on RMM, NTA (for nanobubbles), and Coulter counter (for microbubbles) measurements. The results show that the headspace GC/MS gas volume measurements agreed well with the theoretical predictions for the RMM of nanobubbles but not NTA. For nanobubbles, the theoretical gas volume using RMM was 10% lower than the experimental GC/MS measurements; meanwhile, using NTA resulted in an 82% lower predicted gas volume. For microbubbles, the experimental gas volume from the GC/MS measurements was 27% lower compared to RMM and 72% less compared to the Coulter counter results. This study demonstrates that the gas volume of nanobubbles and microbubbles can be reliably measured using headspace GC/MS to validate bubble size measurement techniques. We also conclude that the accuracy of theoretical predictions is highly dependent on proper size and concentration measurements. Full article
(This article belongs to the Special Issue Micro/Nano-Bubbles as a New Ultrasound Imaging and Drug Delivery Tool)
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13 pages, 3280 KiB  
Article
Shelf-Life Evaluation and Lyophilization of PBCA-Based Polymeric Microbubbles
by Tarun Ojha, Vertika Pathak, Natascha Drude, Marek Weiler, Dirk Rommel, Stephan Rütten, Bertram Geinitz, Mies J. van Steenbergen, Gert Storm, Fabian Kiessling and Twan Lammers
Pharmaceutics 2019, 11(9), 433; https://doi.org/10.3390/pharmaceutics11090433 - 26 Aug 2019
Cited by 16 | Viewed by 6158
Abstract
Poly(n-butyl cyanoacrylate) microbubbles (PBCA-MB) are extensively employed for functional and molecular ultrasound (US) imaging, as well as for US-mediated drug delivery. To facilitate the use of PBCA-MB as a commercial platform for biomedical applications, it is important to systematically study and [...] Read more.
Poly(n-butyl cyanoacrylate) microbubbles (PBCA-MB) are extensively employed for functional and molecular ultrasound (US) imaging, as well as for US-mediated drug delivery. To facilitate the use of PBCA-MB as a commercial platform for biomedical applications, it is important to systematically study and improve their stability and shelf-life. In this context, lyophilization (freeze drying) is widely used to increase shelf-life and promote product development. Here, we set out to analyze the stability of standard and rhodamine-B loaded PBCA-MB at three different temperatures (4 °C, 25 °C, and 37 °C), for a period of time of up to 20 weeks. In addition, using sucrose, glucose, polyvinylpyrrolidone (PVP), and polyethylene glycol (PEG) as cryoprotectants, we investigated if PBCA-MB can be lyophilized without affecting their size, concentration, US signal generation properties, and dye retention. Stability assessment showed that PBCA-MB remain largely intact for three and four weeks at 4 °C and 25 °C, respectively, while they disintegrate within one to two weeks at 37 °C, thereby compromising their acoustic properties. Lyophilization analyses demonstrated that PBCA-MB can be efficiently freeze-dried with 5% sucrose and 5% PVP, without changing their size, concentration, and US signal generation properties. Experiments involving rhodamine-B loaded MB indicated that significant dye leakage from the polymeric shell takes place within two to four weeks in case of non-lyophilized PBCA-MB. Lyophilization of rhodamine-loaded PBCA-MB with sucrose and PVP showed that the presence of the dye does not affect the efficiency of freeze-drying, and that the dye is efficiently retained upon MB lyophilization. These findings contribute to the development of PBCA-MB as pharmaceutical products for preclinical and clinical applications. Full article
(This article belongs to the Special Issue Micro/Nano-Bubbles as a New Ultrasound Imaging and Drug Delivery Tool)
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Graphical abstract

17 pages, 8803 KiB  
Article
Intracellular Signaling in Key Pathways Is Induced by Treatment with Ultrasound and Microbubbles in a Leukemia Cell Line, but Not in Healthy Peripheral Blood Mononuclear Cells
by Ragnhild Haugse, Anika Langer, Stein-Erik Gullaksen, Silje Maria Sundøy, Bjørn Tore Gjertsen, Spiros Kotopoulis and Emmet McCormack
Pharmaceutics 2019, 11(7), 319; https://doi.org/10.3390/pharmaceutics11070319 - 06 Jul 2019
Cited by 11 | Viewed by 3253
Abstract
Treatment with ultrasound and microbubbles (sonoporation) to enhance therapeutic efficacy in cancer therapy is rapidly expanding, but there is still very little consensus as to why it works. Despite the original assumption that pore formation in the cell membrane is responsible for increased [...] Read more.
Treatment with ultrasound and microbubbles (sonoporation) to enhance therapeutic efficacy in cancer therapy is rapidly expanding, but there is still very little consensus as to why it works. Despite the original assumption that pore formation in the cell membrane is responsible for increased uptake of drugs, the molecular mechanisms behind this phenomenon are largely unknown. We treated cancer cells (MOLM-13) and healthy peripheral blood mononuclear cells (PBMCs) with ultrasound at three acoustic intensities (74, 501, 2079 mW/cm2) ± microbubbles. We subsequently monitored the intracellular response of a number of key signaling pathways using flow cytometry or western blotting 5 min, 30 min and 2 h post-treatment. This was complemented by studies on uptake of a cell impermeable dye (calcein) and investigations of cell viability (cell count, Hoechst staining and colony forming assay). Ultrasound + microbubbles resulted in both early changes (p38 (Arcsinh ratio at high ultrasound + microbubbles: +0.5), ERK1/2 (+0.7), CREB (+1.3), STAT3 (+0.7) and AKT (+0.5)) and late changes (ribosomal protein S6 (Arcsinh ratio at low ultrasound: +0.6) and eIF2α in protein phosphorylation). Observed changes in protein phosphorylation corresponded to changes in sonoporation efficiency and in viability, predominantly in cancer cells. Sonoporation induced protein phosphorylation in healthy cells was pronounced (p38 (+0.03), ERK1/2 (−0.03), CREB (+0.0), STAT3 (−0.1) and AKT (+0.04) and S6 (+0.2)). This supports the hypothesis that sonoporation may enhance therapeutic efficacy of cancer treatment, without causing damage to healthy cells. Full article
(This article belongs to the Special Issue Micro/Nano-Bubbles as a New Ultrasound Imaging and Drug Delivery Tool)
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Graphical abstract

10 pages, 2069 KiB  
Article
Development of Antibody-Modified Nanobubbles Using Fc-Region-Binding Polypeptides for Ultrasound Imaging
by Nobuhito Hamano, Sho Kamoshida, Yamato Kikkawa, Yusuke Yano, Tomomi Kobayashi, Yoko Endo-Takahashi, Ryo Suzuki, Kazuo Maruyama, Yuji Ito, Motoyoshi Nomizu and Yoichi Negishi
Pharmaceutics 2019, 11(6), 283; https://doi.org/10.3390/pharmaceutics11060283 - 15 Jun 2019
Cited by 20 | Viewed by 4378
Abstract
Ultrasound (US) imaging is a widely used imaging technique. The use of US contrast agents such as microbubbles, which consist of phospholipids and are filled with perfluorocarbon gases, has become an indispensable component of clinical US imaging, while molecular US imaging has recently [...] Read more.
Ultrasound (US) imaging is a widely used imaging technique. The use of US contrast agents such as microbubbles, which consist of phospholipids and are filled with perfluorocarbon gases, has become an indispensable component of clinical US imaging, while molecular US imaging has recently attracted significant attention in combination with efficient diagnostics. The avidin–biotin interaction method is frequently used to tether antibodies to microbubbles, leading to the development of a molecular targeting US imaging agent. However, avidin still has limitations such as immunogenicity. We previously reported that lipid-based nanobubbles (NBs) containing perfluorocarbon gas are suitable for US imaging and gene delivery. In this paper, we report on the development of a novel antibody modification method for NBs using Fc-region-binding polypeptides derived from protein A/G. First, we prepared anti-CD146 antibody-modified NBs using this polypeptide, resulting in high levels of attachment to human umbilical vein endothelial cells expressing CD146. To examine their targeting ability and US imaging capability, the NBs were administered to tumor-bearing mice. The contrast imaging of antibody-modified NBs was shown to be prolonged compared with that of non-labeled NBs. Thus, this antibody modification method using an Fc-binding polypeptide may be a feasible tool for developing a next-generation antibody-modified US imaging agent. Full article
(This article belongs to the Special Issue Micro/Nano-Bubbles as a New Ultrasound Imaging and Drug Delivery Tool)
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Graphical abstract

16 pages, 9840 KiB  
Article
Synchronized Optical and Acoustic Droplet Vaporization for Effective Sonoporation
by Wei-Wen Liu, Sy-Han Huang and Pai-Chi Li
Pharmaceutics 2019, 11(6), 279; https://doi.org/10.3390/pharmaceutics11060279 - 14 Jun 2019
Cited by 10 | Viewed by 3506
Abstract
Inertial cavitation-based sonoporation has been utilized to enhance treatment delivery efficacy. In our previous study, we demonstrated that tumor therapeutic efficacy can be enhanced through vaporization-assisted sonoporation with gold nanodroplets (AuNDs). Specifically, the AuNDs were vaporized both acoustically (i.e., acoustic droplet vaporization, ADV) [...] Read more.
Inertial cavitation-based sonoporation has been utilized to enhance treatment delivery efficacy. In our previous study, we demonstrated that tumor therapeutic efficacy can be enhanced through vaporization-assisted sonoporation with gold nanodroplets (AuNDs). Specifically, the AuNDs were vaporized both acoustically (i.e., acoustic droplet vaporization, ADV) and optically (i.e., optical droplet vaporization, ODV). A continuous wave (CW) laser was used for ODV in combination with an ultrasound pulse for ADV. Although effective for vaporization, the use of a CW laser is not energy efficient and may create unwanted heating and concomitant tissue damage. In this study, we propose the use of a pulsed wave (PW) laser to replace the CW laser. In addition, the PW laser was applied at the rarefaction phase of the ultrasound pulse so that the synergistic effects of ADV and ODV can be expected. Therefore, a significantly lower laser average power can be expected to achieve the vaporization threshold. Compared to the CW laser power at 2 W/cm2 from the previous approach, the PW laser power was reduced to only 0.2404 W/cm2. Furthermore, we also demonstrate in vitro that the sonoporation rate was increased when the PW laser was applied at the rarefaction phase. Specifically, the vaporization signal, the inertial cavitation signal, and the sonoporation rate all displayed a 1-µs period, which corresponded to the period of the 1-MHz acoustic wave used for ADV, as a function of the relative laser delay. The increased sonoporation rate indicates that this technique has the potential to enhance sonoporation-directed drug delivery and tumor therapy with a lower laser power while keeping the cell death rate at the minimum. Photoacoustic imaging can also be performed at the same time since a PW laser is used for the ODV. Full article
(This article belongs to the Special Issue Micro/Nano-Bubbles as a New Ultrasound Imaging and Drug Delivery Tool)
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Graphical abstract

13 pages, 3387 KiB  
Article
Application of Direct Sonoporation from a Defined Surface Area of the Peritoneum: Evaluation of Transfection Characteristics in Mice
by Koyo Nishimura, Keita Yonezawa, Shintaro Fumoto, Yusuke Miura, Masayori Hagimori, Koyo Nishida and Shigeru Kawakami
Pharmaceutics 2019, 11(5), 244; https://doi.org/10.3390/pharmaceutics11050244 - 22 May 2019
Cited by 12 | Viewed by 3888
Abstract
In the present study, we developed a sonoporation system, namely “direct sonoporation”, for transfecting the peritoneum from a defined surface area to avoid systematic side effects. Here, the transfection characteristics are explained because there is less information about direct sonoporation. Naked pDNA and [...] Read more.
In the present study, we developed a sonoporation system, namely “direct sonoporation”, for transfecting the peritoneum from a defined surface area to avoid systematic side effects. Here, the transfection characteristics are explained because there is less information about direct sonoporation. Naked pDNA and nanobubbles were administered to diffusion cell attached to the visceral and parietal peritoneum from the liver and peritoneal wall surface, respectively. Then, ultrasound was irradiated. Direct sonoporation showed a higher transfection efficacy at the applied peritoneum site from the liver surface while other sites were not detected. Moreover, transgene expression was observed in the peritoneal mesothelial cells (PMCs) at the applied peritoneum site. No abnormality was observed in the inner part of the liver. Although transgene expression of the visceral peritoneum was tenfold higher than that of the parietal peritoneum, transgene expression was observed in the PMCs on both the applied peritoneum sites. These results suggest that direct sonoporation is a site-specific transfection method of the PMCs on the applied peritoneum site without transgene expression at other sites and show little toxicity in the inner tissues at the applied site via cavitation energy. This information is valuable for the development of an intraperitoneal sonoporation device for treatment of peritoneal diseases such as peritoneal fibrosis. Full article
(This article belongs to the Special Issue Micro/Nano-Bubbles as a New Ultrasound Imaging and Drug Delivery Tool)
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14 pages, 3017 KiB  
Article
Concurrent Osteosarcoma Theranostic Strategy Using Contrast-Enhanced Ultrasound and Drug-Loaded Bubbles
by Tai-Tzung Kuo, Chung-Hsin Wang, Jir-You Wang, Hong-Jen Chiou, Ching-Hsiang Fan and Chih-Kuang Yeh
Pharmaceutics 2019, 11(5), 223; https://doi.org/10.3390/pharmaceutics11050223 - 08 May 2019
Cited by 17 | Viewed by 3472
Abstract
Osteosarcoma (OS) is the most common bone tumor in children and teenagers. The multidrug resistant property of OS produces a major obstacle to chemotherapy, since the effective drug dose cannot be achieved via conventional drug delivery routes without serious systemic cytotoxicity. Microbubbles in [...] Read more.
Osteosarcoma (OS) is the most common bone tumor in children and teenagers. The multidrug resistant property of OS produces a major obstacle to chemotherapy, since the effective drug dose cannot be achieved via conventional drug delivery routes without serious systemic cytotoxicity. Microbubbles in conjunction with ultrasound (US) has recently been shown to spatially and temporally permeabilize the cellular membrane, promoting drug penetration into tumors. Here, we investigated whether drug (doxorubicin, DOX)-loaded bubbles (DOX-bubbles) can serve as drug-loaded carriers in combination with US in order to facilitate tumor drug delivery. The proposed bubbles have a high payload capacity (efficiency of 69.4 ± 9.1%, payload of 1.4 mg/mL) for DOX. In vitro data revealed that when used in combination with US (1-MHz), these DOX-bubbles facilitate DOX entering into tumor cells. In tumor-bearing animals, DOX-bubbles + US could provide 3.7-fold suppression of tumor growth compared with the group without insonation (1.8 ± 0.9 cm3 vs. 8.5 ± 2.2 cm3) because of the acceleration of DOX-induced tumor necrosis. In the meantime, the tumor perfusion and volume can be monitored by DOX-bubbles with contrast-enhanced ultrasound imaging. Our data provide useful information in support of translating the use of theranostic US-responsive bubbles for regulated tumor drug delivery into clinical use. Full article
(This article belongs to the Special Issue Micro/Nano-Bubbles as a New Ultrasound Imaging and Drug Delivery Tool)
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