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Pharmaceutics
Special Issues
Ultrasound-Aided Drug Delivery
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Ultrasound-Aided Drug Delivery

A special issue of Pharmaceutics (ISSN 1999-4923). This special issue belongs to the section "Drug Delivery and Controlled Release".

Deadline for manuscript submissions: closed (31 January 2022) | Viewed by 11897

Special Issue Editor

Dr. Jongbum Seo

E-Mail Website
Guest Editor
Department of Biomedical Engineering, College of Health Sciences, Yonsei University, Seoul, Korea
Interests: drug delivery; ultrasound therapy; transdermal delivery

Special Issue Information

Dear Colleagues,

Ultrasound-induced cavitation could cause a disruptive effect within a limited area. When a cavitation event occurs close to a biological barrier, such as cell membrane, blood–brain barrier or skin, their barrier function can be temporally disturbed and drug molecules could be transported by mechanical force. Accordingly, ultrasound has become an attractive means of drug delivery although sub-millimeter level spatial selectivity from ultrasound is not as ideal as cell level selectivity in smart drug delivery. An intriguing aspect of ultrasound-aided drug delivery is that a single predominant mechanism, a cavitation, appears to explain permeability changes from the cell membrane level (sonoporation) to organ level, such as skin (sonophoresis), even though there exists a physical penetration depth difference to, at least, the order of two . Various cavitation seeds have been tried to induce cavitation in a more controllable manner while also providing enhanced stability and target selectivity. Additionally, a wide range of applications have been tried, from brain disease to skin disorders. Although individual target of ultrasound-aided drug delivery presents completely different constraints to still overcome, this method could provide a valuable means in medicine. This Special Issue invites manuscripts on subjects relating to various aspects of ultrasound-aided drug delivery, including new findings in mechanism, preclinical/clinical application works and breakthroughs in cavitation seeds. 

Dr. Jongbum Seo
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

  • sonoporation
  • sonophoresis
  • ultrasound-induced cavitation
  • therapeutic ultrasound
  • blood–brain barrier

Published Papers (5 papers)

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Research

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11 pages, 14006 KiB  
Communication
A Single Short ‘Tone Burst’ Results in Optimal Drug Delivery to Tumours Using Ultrasound-Triggered Therapeutic Microbubbles
by Nicola Ingram, Laura E. McVeigh, Radwa H. Abou-Saleh, Damien V. B. Batchelor, Paul M. Loadman, James R. McLaughlan, Alexander F. Markham, Stephen D. Evans and P. Louise Coletta
Pharmaceutics 2022, 14(3), 622; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics14030622 - 11 Mar 2022
Cited by 7 | Viewed by 2281
Abstract
Advanced drug delivery systems, such as ultrasound-mediated drug delivery, show great promise for increasing the therapeutic index. Improvements in delivery by altering the ultrasound parameters have been studied heavily in vitro but relatively little in vivo. Here, the same therapeutic microbubble and tumour [...] Read more.
Advanced drug delivery systems, such as ultrasound-mediated drug delivery, show great promise for increasing the therapeutic index. Improvements in delivery by altering the ultrasound parameters have been studied heavily in vitro but relatively little in vivo. Here, the same therapeutic microbubble and tumour type are used to determine whether altering ultrasound parameters can improve drug delivery. Liposomes were loaded with SN38 and attached via avidin: biotin linkages to microbubbles. The whole structure was targeted to the tumour vasculature by the addition of anti-vascular endothelial growth factor receptor 2 antibodies. Tumour drug delivery and metabolism were quantified in SW480 xenografts after application of an ultrasound trigger to the tumour region. Increasing the trigger duration from 5 s to 2 min or increasing the number of 5 s triggers did not improve drug delivery, nor did changing to a chirp trigger designed to stimulate a greater proportion of the microbubble population, although this did show that the short tone trigger resulted in greater release of free SN38. Examination of ultrasound triggers in vivo to improve drug delivery is justified as there are multiple mechanisms at play that may not allow direct translation from in vitro findings. In this setting, a short tone burst gives the best ultrasound parameters for tumoural drug delivery. Full article
(This article belongs to the Special Issue Ultrasound-Aided Drug Delivery)
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32 pages, 6168 KiB  
Article
SonoVue® vs. Sonazoid™ vs. Optison™: Which Bubble Is Best for Low-Intensity Sonoporation of Pancreatic Ductal Adenocarcinoma?
by Spiros Kotopoulis, Mihaela Popa, Mireia Mayoral Safont, Elisa Murvold, Ragnhild Haugse, Anika Langer, Georg Dimcevski, Christina Lam, Tormod Bjånes, Odd Helge Gilja and Emmet Mc Cormack
Pharmaceutics 2022, 14(1), 98; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics14010098 - 01 Jan 2022
Cited by 13 | Viewed by 2992
Abstract
The use of ultrasound and microbubbles to enhance therapeutic efficacy (sonoporation) has shown great promise in cancer therapy from in vitro to ongoing clinical studies. The fastest bench-to-bedside translation involves the use of ultrasound contrast agents (microbubbles) and clinical diagnostic scanners. Despite substantial [...] Read more.
The use of ultrasound and microbubbles to enhance therapeutic efficacy (sonoporation) has shown great promise in cancer therapy from in vitro to ongoing clinical studies. The fastest bench-to-bedside translation involves the use of ultrasound contrast agents (microbubbles) and clinical diagnostic scanners. Despite substantial research in this field, it is currently not known which of these microbubbles result in the greatest enhancement of therapy within the applied conditions. Three microbubble formulations—SonoVue®, Sonazoid™, and Optison™—were physiochemically and acoustically characterized. The microbubble response to the ultrasound pulses used in vivo was simulated via a Rayleigh–Plesset type equation. The three formulations were compared in vitro for permeabilization efficacy in three different pancreatic cancer cell lines, and in vivo, using an orthotopic pancreatic cancer (PDAC) murine model. The mice were treated using one of the three formulations exposed to ultrasound from a GE Logiq E9 and C1-5 ultrasound transducer. Characterisation of the microbubbles showed a rapid degradation in concentration, shape, and/or size for both SonoVue® and Optison™ within 30 min of reconstitution/opening. Sonazoid™ showed no degradation after 1 h. Attenuation measurements indicated that SonoVue® was the softest bubble followed by Sonazoid™ then Optison™. Sonazoid™ emitted nonlinear ultrasound at the lowest MIs followed by Optison™, then SonoVue®. Simulations indicated that SonoVue® would be the most effective bubble using the evaluated ultrasound conditions. This was verified in the pre-clinical PDAC model demonstrated by improved survival and largest tumor growth inhibition. In vitro results indicated that the best microbubble formulation depends on the ultrasound parameters and concentration used, with SonoVue® being best at lower intensities and Sonazoid™ at higher intensities. Full article
(This article belongs to the Special Issue Ultrasound-Aided Drug Delivery)
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15 pages, 5009 KiB  
Article
The Impact of Surface Drug Distribution on the Acoustic Behavior of DOX-Loaded Microbubbles
by Chia-Wei Lin, Ching-Hsiang Fan and Chih-Kuang Yeh
Pharmaceutics 2021, 13(12), 2080; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics13122080 - 04 Dec 2021
Cited by 4 | Viewed by 1676
Abstract
Previous studies have reported substantial improvement of microbubble (MB)-mediated drug delivery with ultrasound when drugs are loaded onto the MB shell compared with a physical mixture. However, drug loading may affect shell properties that determine the acoustic responsiveness of MBs, producing unpredictable outcomes. [...] Read more.
Previous studies have reported substantial improvement of microbubble (MB)-mediated drug delivery with ultrasound when drugs are loaded onto the MB shell compared with a physical mixture. However, drug loading may affect shell properties that determine the acoustic responsiveness of MBs, producing unpredictable outcomes. The aim of this study is to reveal how the surface loaded drug (doxorubicin, DOX) affects the acoustic properties of MBs. A suitable formulation of MBs for DOX loading was first identified by regulating the proportion of two lipid materials (1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC) and 1,2-distearoyl-sn-glycero-3-phospho-rac-glycerol sodium salt (DSPG)) with distinct electrostatic properties. We found that the DOX loading capacity of MBs was determined by the proportion of DSPG, since there was an electrostatic interaction with DOX. The DOX payload reduced the lipid fluidity of MBs, although this effect was dependent on the spatial uniformity of DOX on the MB shell surface. Loading DOX onto MBs enhanced acoustic stability 1.5-fold, decreased the resonance frequency from 12–14 MHz to 5–7 MHz, and reduced stable cavitation dose by 1.5-fold, but did not affect the stable cavitation threshold (300 kPa). Our study demonstrated that the DOX reduces lipid fluidity and decreases the elasticity of the MB shell, thereby influencing the acoustic properties of MBs. Full article
(This article belongs to the Special Issue Ultrasound-Aided Drug Delivery)
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10 pages, 3247 KiB  
Article
PMP(Porphyrin–Micelle–PSMA) Nanoparticles for Photoacoustic and Ultrasound Signal Amplification in Mouse Prostate Cancer Xenografts
by Daehyun Kim, Wonkook Han, Jin Ho Chang and Hak Jong Lee
Pharmaceutics 2021, 13(10), 1636; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics13101636 - 07 Oct 2021
Cited by 3 | Viewed by 1591
Abstract
Photoacoustic (PA) imaging is used widely in cancer diagnosis. However, the availability of PA agents has not made great progress due to the limitations of the one currently in use, porphyrin. Porphyrin–Micelle (PM), developed by synthesizing porphyrin and PEG-3.5k, confirmed the amplification of [...] Read more.
Photoacoustic (PA) imaging is used widely in cancer diagnosis. However, the availability of PA agents has not made great progress due to the limitations of the one currently in use, porphyrin. Porphyrin–Micelle (PM), developed by synthesizing porphyrin and PEG-3.5k, confirmed the amplification of the PA agent signal, and added binding affinity in an LNCaP model by attaching prostate-specific membrane antigen PSMA. Compared to the previously used porphyrin, a superior signal was confirmed, and the potential of PMP was confirmed when it showed a signal superior to that of hemoglobin at the same concentration. In addition, in the in vivo mouse experiment, it was confirmed that the signal in the LNCaP xenograft model was stronger than that in the PC-3 xenograft model, and the PMP signal was about three times higher than that of PM and porphyrin. Full article
(This article belongs to the Special Issue Ultrasound-Aided Drug Delivery)
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Review

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21 pages, 5562 KiB  
Review
Mechanistic Insights and Therapeutic Delivery through Micro/Nanobubble-Assisted Ultrasound
by Shirui Lu, Pengxuan Zhao, Youbin Deng and Yani Liu
Pharmaceutics 2022, 14(3), 480; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics14030480 - 22 Feb 2022
Cited by 16 | Viewed by 2516
Abstract
Ultrasound with low frequency (20–100 kHz) assisted drug delivery has been widely investigated as a non-invasive method to enhance the permeability and retention effect of drugs. The functional micro/nanobubble loaded with drugs could provide an unprecedented opportunity for targeted delivery. Then, ultrasound with [...] Read more.
Ultrasound with low frequency (20–100 kHz) assisted drug delivery has been widely investigated as a non-invasive method to enhance the permeability and retention effect of drugs. The functional micro/nanobubble loaded with drugs could provide an unprecedented opportunity for targeted delivery. Then, ultrasound with higher intensity would locally burst bubbles and release agents, thus avoiding side effects associated with systemic administration. Furthermore, ultrasound-mediated destruction of micro/nanobubbles can effectively increase the permeability of vascular membranes and cell membranes, thereby not only increasing the distribution concentration of drugs in the interstitial space of target tissues but also promoting the penetration of drugs through cell membranes into the cytoplasm. These advancements have transformed ultrasound from a purely diagnostic utility into a promising theragnostic tool. In this review, we first discuss the structure and generation of micro/nanobubbles. Second, ultrasound parameters and mechanisms of therapeutic delivery are discussed. Third, potential biomedical applications of micro/nanobubble-assisted ultrasound are summarized. Finally, we discuss the challenges and future directions of ultrasound combined with micro/nanobubbles. Full article
(This article belongs to the Special Issue Ultrasound-Aided Drug Delivery)
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