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Pharmaceutics
Special Issues
Ultrasound-Mediated Delivery of Nanopharmaceuticals
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Ultrasound-Mediated Delivery of Nanopharmaceuticals

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 December 2021) | Viewed by 17997

Special Issue Editors

Dr. Antonios N. Pouliopoulos

E-Mail Website
Guest Editor
Department of Biomedical Engineering, Columbia University, New York, NY, USA
Interests: targeted drug delivery using ultrasound; microbubble dynamics in ultrasound therapy; ultrasound therapy monitoring
Dr. Sophie V. Morse

E-Mail Website
Guest Editor
Department of Bioengineering, Faculty of Engineering, Imperial College London, London, UK
Interests: focused ultrasound; drug delivery; blood-brain barrier; brain disorders; microbubbles
Dr. Natasha D. Sheybani

E-Mail Website
Guest Editor
School of Medicine, Stanford University, Stanford, CA, USA
Interests: focused ultrasound; cancer immunotherapy; image-guided therapy; drug delivery; molecular imaging; image genomics (radiogenomics)

Special Issue Information

Dear Colleagues,

A whole class of nanopharmaceuticals such as theranostic nanoparticles, liposomes, monoclonal antibodies, and viral vectors, are not able to effectively reach their targets due to the presence of biological barriers. Ultrasound-mediated drug delivery shows great potential in overcoming the blood–brain or blood–tumor barrier, enabling non-invasive and localized increase of the delivered dose, thereby enlarging the therapeutic window.

In this Special Issue, we invite contributions focused on both preclinical and clinical research on ultrasound-mediated delivery of nanopharmaceuticals. We also welcome numerical and experimental work on ultrasound- or heat-responsive theranostic agents, designed for concurrent imaging and therapy of neurodegenerative diseases, cancer, etc. Potential applications include but are not limited to targeted immunotherapies, neuromodulation, neurorestoration and neuroprotection, chemotherapeutic delivery, tumor tagging, and targeted micro-/nanobubbles.

Submitted manuscripts should highlight the translational potential of ultrasound-mediated drug delivery and should be within the wider scope of Pharmaceutics.

Dr. Antonios N. Pouliopoulos
Dr. Sophie V. Morse
Dr. Natasha D. Sheybani
Guest Editors

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

  • therapeutic ultrasound
  • nanomedicine
  • biological barriers
  • targeted drug delivery
  • theranostics
  • immunotherapy
  • micro-/nanobubbles

Published Papers (5 papers)

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Research

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17 pages, 3616 KiB  
Communication
Ultrasound-Mediated Blood-Brain Barrier Opening Improves Whole Brain Gene Delivery in Mice
by Marie-Solenne Felix, Emilie Borloz, Khaled Metwally, Ambre Dauba, Benoit Larrat, Valerie Matagne, Yann Ehinger, Laurent Villard, Anthony Novell, Serge Mensah and Jean-Christophe Roux
Pharmaceutics 2021, 13(8), 1245; https://doi.org/10.3390/pharmaceutics13081245 - 12 Aug 2021
Cited by 17 | Viewed by 3227
Abstract
Gene therapy represents a powerful therapeutic tool to treat diseased tissues and provide a durable and effective correction. The central nervous system (CNS) is the target of many gene therapy protocols, but its high complexity makes it one of the most difficult organs [...] Read more.
Gene therapy represents a powerful therapeutic tool to treat diseased tissues and provide a durable and effective correction. The central nervous system (CNS) is the target of many gene therapy protocols, but its high complexity makes it one of the most difficult organs to reach, in part due to the blood-brain barrier that protects it from external threats. Focused ultrasound (FUS) coupled with microbubbles appears as a technological breakthrough to deliver therapeutic agents into the CNS. While most studies focus on a specific targeted area of the brain, the present work proposes to permeabilize the entire brain for gene therapy in several pathologies. Our results show that, after i.v. administration and FUS sonication in a raster scan manner, a self-complementary AAV9-CMV-GFP vector strongly and safely infected the whole brain of mice. An increase in vector DNA (19.8 times), GFP mRNA (16.4 times), and GFP protein levels (17.4 times) was measured in whole brain extracts of FUS-treated GFP injected mice compared to non-FUS GFP injected mice. In addition to this increase in GFP levels, on average, a 7.3-fold increase of infected cells in the cortex, hippocampus, and striatum was observed. No side effects were detected in the brain of treated mice. The combining of FUS and AAV-based gene delivery represents a significant improvement in the treatment of neurological genetic diseases. Full article
(This article belongs to the Special Issue Ultrasound-Mediated Delivery of Nanopharmaceuticals)
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14 pages, 2206 KiB  
Article
Ultrasound-Triggered Release of 5-Fluorouracil from Soy Lecithin Echogenic Liposomes
by Charles Izuchukwu Ezekiel, Alain Murhimalika Bapolisi, Roderick Bryan Walker and Rui Werner Maçedo Krause
Pharmaceutics 2021, 13(6), 821; https://doi.org/10.3390/pharmaceutics13060821 - 01 Jun 2021
Cited by 14 | Viewed by 2750
Abstract
Colorectal cancer is the third most diagnosed cancer and the second leading cause of death. The use of 5-fluorouracil (5-FU) has been the major chemotherapeutic treatment for colorectal cancer patients. However, the efficacy of 5-FU is limited by drug resistance, and bone marrow [...] Read more.
Colorectal cancer is the third most diagnosed cancer and the second leading cause of death. The use of 5-fluorouracil (5-FU) has been the major chemotherapeutic treatment for colorectal cancer patients. However, the efficacy of 5-FU is limited by drug resistance, and bone marrow toxicity through high-level expression of thymidylate synthase, justifying the need for improvement of the therapeutic index. In this study, the effects of ultrasound on echogenic 5-FU encapsulated crude soy liposomes were investigated for their potential to address these challenges. Liposomes were prepared by thin-film hydration using crude soy lecithin and cholesterol. Argon gas was entrapped in the liposomes for sonosensitivity (that is, responsiveness to ultrasound). The nanoparticles were characterized for particle size and morphology. The physicochemical properties were also evaluated using differential scanning calorimetry, Fourier transform infrared and X-ray diffraction. The release profile of 5-FU was assessed with and without 20 kHz low-frequency ultrasound waves at various amplitudes and exposure times. The result reveal that 5-FU-loaded liposomes were spherical with an encapsulation efficiency of approximately 60%. Approximately 65% of 5-FU was released at the highest amplitude and exposure time was investigated. The results are encouraging for the stimulated and controlled release of 5-FU for the management of colorectal cancer. Full article
(This article belongs to the Special Issue Ultrasound-Mediated Delivery of Nanopharmaceuticals)
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20 pages, 3461 KiB  
Article
Improving Release of Liposome-Encapsulated Drugs with Focused Ultrasound and Vaporizable Droplet-Liposome Nanoclusters
by Arvin Honari, Darrah A. Merillat, Aditi Bellary, Mohammadaref Ghaderi and Shashank R. Sirsi
Pharmaceutics 2021, 13(5), 609; https://doi.org/10.3390/pharmaceutics13050609 - 22 Apr 2021
Cited by 12 | Viewed by 4045
Abstract
Active targeted delivery of small molecule drugs is becoming increasingly important in personalized therapies, especially in cancer, brain disorders, and a wide variety of other diseases. However, effective means of spatial targeting and delivering high drug payloads in vivo are still lacking. Focused [...] Read more.
Active targeted delivery of small molecule drugs is becoming increasingly important in personalized therapies, especially in cancer, brain disorders, and a wide variety of other diseases. However, effective means of spatial targeting and delivering high drug payloads in vivo are still lacking. Focused ultrasound combined with superheated phase-shift nanodroplets, which vaporize into microbubbles using heat and sound, are rapidly becoming a popular strategy for targeted drug delivery. Focused ultrasound can target deep tissue with excellent spatial precision and without using ionizing energy, thus can activate nanodroplets in circulation. One of the main limitations of this technology has been poor drug loading in the droplet core or the shell material. To address this need, we have developed a strategy to combine low-boiling point decafluorabutane and octafluoropropane (DFB and OFP) nanodroplets with drug-loaded liposomes, creating phase-changeable droplet-liposome clusters (PDLCs). We demonstrate a facile method of assembling submicron PDLCs with high drug-loading capacity on the droplet surface. Furthermore, we demonstrate that chemical tethering of liposomes in PDLCs enables a rapid release of their encapsulated cargo upon acoustic activation (>60% using OFP-based PDLCs). Rapid uncaging of small molecule drugs would make them immediately bioavailable in target tissue or promote better penetration in local tissue following intravascular release. PDLCs developed in this study can be used to deliver a wide variety of liposome-encapsulated therapeutics or imaging agents for multi-modal imaging applications. We also outline a strategy to deliver a surrogate encapsulated drug, fluorescein, to tumors in vivo using focused ultrasound energy and PDLCs. Full article
(This article belongs to the Special Issue Ultrasound-Mediated Delivery of Nanopharmaceuticals)
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Review

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22 pages, 774 KiB  
Review
Focused Ultrasound Combined with Microbubbles in Central Nervous System Applications
by Ko-Ting Chen, Kuo-Chen Wei and Hao-Li Liu
Pharmaceutics 2021, 13(7), 1084; https://doi.org/10.3390/pharmaceutics13071084 - 15 Jul 2021
Cited by 25 | Viewed by 3352
Abstract
The blood–brain barrier (BBB) protects the central nervous system (CNS) from invasive pathogens and maintains the homeostasis of the brain. Penetrating the BBB has been a major challenge in the delivery of therapeutic agents for treating CNS diseases. Through a physical acoustic cavitation [...] Read more.
The blood–brain barrier (BBB) protects the central nervous system (CNS) from invasive pathogens and maintains the homeostasis of the brain. Penetrating the BBB has been a major challenge in the delivery of therapeutic agents for treating CNS diseases. Through a physical acoustic cavitation effect, focused ultrasound (FUS) combined with microbubbles achieves the local detachment of tight junctions of capillary endothelial cells without inducing neuronal damage. The bioavailability of therapeutic agents is increased only in the area targeted by FUS energy. FUS with circulating microbubbles is currently the only method for inducing precise, transient, reversible, and noninvasive BBB opening (BBBO). Over the past decade, FUS-induced BBBO (FUS-BBBO) has been preclinically confirmed to not only enhance the penetration of therapeutic agents in the CNS, but also modulate focal immunity and neuronal activity. Several recent clinical human trials have demonstrated both the feasibility and potential advantages of using FUS-BBBO in diseased patients. The promising results support adding FUS-BBBO as a multimodal therapeutic strategy in modern CNS disease management. This review article explores this technology by describing its physical mechanisms and the preclinical findings, including biological effects, therapeutic concepts, and translational design of human medical devices, and summarizes completed and ongoing clinical trials. Full article
(This article belongs to the Special Issue Ultrasound-Mediated Delivery of Nanopharmaceuticals)
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16 pages, 2275 KiB  
Review
Therapeutic Ultrasound as a Treatment Modality for Physiological and Pathological Ageing Including Alzheimer’s Disease
by Jürgen Götz, Gina Richter-Stretton and Esteban Cruz
Pharmaceutics 2021, 13(7), 1002; https://doi.org/10.3390/pharmaceutics13071002 - 01 Jul 2021
Cited by 3 | Viewed by 3588
Abstract
Physiological and pathological ageing (as exemplified by Alzheimer’s disease, AD) are characterized by a progressive decline that also includes cognition. How this decline can be slowed or even reversed is a critical question. Here, we discuss therapeutic ultrasound as a novel modality to [...] Read more.
Physiological and pathological ageing (as exemplified by Alzheimer’s disease, AD) are characterized by a progressive decline that also includes cognition. How this decline can be slowed or even reversed is a critical question. Here, we discuss therapeutic ultrasound as a novel modality to achieve this goal. In our studies, we explored three fundamental strategies, (i) scanning ultrasound on its own (SUSonly), (ii) therapeutic ultrasound in concert with intravenously injected microbubbles (which transiently opens the blood–brain barrier, SUS+MB), and (iii) SUS+MB in combination with therapeutic antibodies (SUS+MB+mAb). These studies show SUS+MB effectively clears amyloid and restores memory in amyloid-depositing mice and partially clears Tau and ameliorates memory impairments in Tau transgenic mice, with additional improvements found in combination trials (SUS+MB+mAb). Interestingly, both SUSonly and SUS+MB restored the induction of long-term potentiation (LTP, electrophysiological correlate of memory) in senescent wild-type mice. Both lead to increased neurogenesis, and SUSonly, in particular, resulted in improved spatial memory. We discuss these findings side-by-side with our findings obtained in AD mouse models. We conclude that therapeutic ultrasound is a non-invasive, pleiotropic modality that may present a treatment option not only for AD but also for enhancing cognition in physiological ageing. Full article
(This article belongs to the Special Issue Ultrasound-Mediated Delivery of Nanopharmaceuticals)
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