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Pharmaceutics
Special Issues
Ultrasonic Technologies in Imaging and Drug Delivery
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Ultrasonic Technologies in Imaging and 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 (20 December 2022) | Viewed by 15056

Special Issue Editors

Prof. Dr. Haoli Liu

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Guest Editor
Department of Biomedical Engineering, National Taiwan University, Da’an, Taipei 106, Taiwan
Interests: biosystem control; medical electronics; medical imaging; therapeutic ultrasound
Prof. Dr. Chih-Kuang Yeh

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Guest Editor
Department of Biomedical Engineering and Environmental Sciences, National Tsing Hua University, Hsinchu 30013, Taiwan
Interests: ultrasound image processing; biomedical signal processing; biomedical engineering
Dr. Ching-Hsiang Fan

E-Mail Website
Guest Editor
Department of Biomedical Engineering, National Cheng Kung University, Tainan 701, Taiwan
Interests: therapeutic ultrasound; drug delivery; ultrasound responsible contrast agent design; ultrasound imaging processing

Special Issue Information

Dear Colleagues,

The development of ultrasound technologies that allow non-invasively scrutinizing and interfering the body’s deep areas holds promise for the diagnosis, disease treatment, and even the study of probing intrinsic functional connection. Recently, several landmark breakthroughs of ultrasonic technology have been proposed and considered as a great potential for addressing human diseases. The evolution of high framerate and super-resolution ultrasound imaging allows mapping of the body’s interior vascular network and haemodynamics, which are related to diseases. Therapeutic ultrasound provides opportunities in permeating drugs, improving thrombolysis, and modulating neurons. In addition, with the recent great progress of developing novel ultrasound-responsible theranostic agents, the application of ultrasound can be further widened to achieve remotely controlled drug release under monitoring by single or multiple imaging modalities for disease treatment, gene delivery, and anaesthetization. Combining diagnostic and therapeutic ultrasound with ultrasonic drug carriers can even provide more emerging routes and multidisciplinary methods in enabling real-time mage-guided therapy for deep living tissue, improving drug concentrations in diseased tissues.

This Special Issue will cover these exciting ultrasonic technologies in imaging and drug delivery, including novel ultrasound theranostic agents, ultrasound molecular imaging, ultrasound-assisted drugs or nucleic acid delivery, biomedical applications, etc. We expect this Special Issue to inspire more research innovations via revealing previous used ultrasonic technologies in the search for methods that effectively treat diseases.

Prof. Dr. Haoli Liu
Prof. Dr. Chih-Kuang Yeh
Dr. Ching-Hsiang Fan
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

  • ultrasound
  • drug delivery
  • ultrasound imaging
  • ultrasound
  • theranostic agent
  • cavitation

Published Papers (7 papers)

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Research

14 pages, 1691 KiB  
Article
Cavitation Feedback Control of Focused Ultrasound Blood-Brain Barrier Opening for Drug Delivery in Patients with Parkinson’s Disease
by Yuexi Huang, Ying Meng, Christopher B. Pople, Allison Bethune, Ryan M. Jones, Agessandro Abrahao, Clement Hamani, Suneil K. Kalia, Lorraine V. Kalia, Nir Lipsman and Kullervo Hynynen
Pharmaceutics 2022, 14(12), 2607; https://doi.org/10.3390/pharmaceutics14122607 - 26 Nov 2022
Cited by 9 | Viewed by 2189
Abstract
Magnetic resonance-guided focused ultrasound (MRgFUS), in conjunction with circulating microbubbles, is an emerging technology that can transiently enhance the permeability of the blood-brain barrier (BBB) locally and non-invasively to facilitate targeted drug delivery to the brain. In this clinical trial, the feasibility and [...] Read more.
Magnetic resonance-guided focused ultrasound (MRgFUS), in conjunction with circulating microbubbles, is an emerging technology that can transiently enhance the permeability of the blood-brain barrier (BBB) locally and non-invasively to facilitate targeted drug delivery to the brain. In this clinical trial, the feasibility and safety of BBB modulation in the putamen were evaluated for biweekly therapeutic agent delivery in patients with Parkinson’s disease. The performance of the clinical MRgFUS system’s cavitation feedback controller for active power modulation throughout the exposures was examined. The putamen was targeted unilaterally by an ExAblate Neuro MRgFUS system operating at 220 kHz. Definity microbubbles were infused via a saline bag gravity drip at a rate of 4 µL/kg per 5 min. A cavitation emissions-based feedback controller was employed to modulate the acoustic power automatically according to prescribed target cavitation dose levels. BBB opening was measured by Gadolinium (Gd)-enhanced T1-weighted MR imaging, and the presence of potential micro-hemorrhages induced by the exposures was assessed via T2*-weighted MR imaging. A total of 12 treatment sessions were carried out across four patients, with target cavitation dose levels ranging from 0.20–0.40. BBB permeability in the targeted putamen was elevated successfully in all treatments, with a 14% ± 6% mean increase in Gd-enhanced T1-weighted MRI signal intensity relative to the untreated contralateral side. No indications of red blood cell extravasations were observed on MR imaging scans acquired one day following each treatment session. The cavitation emissions-based feedback controller was effective in modulating acoustic power levels to ensure BBB permeability enhancement while avoiding micro-hemorrhages, however, further technical advancements are warranted to improve its performance for use across a wide variety of brain diseases. Full article
(This article belongs to the Special Issue Ultrasonic Technologies in Imaging and Drug Delivery)
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18 pages, 4341 KiB  
Article
Large-Volume Focused-Ultrasound Mild Hyperthermia for Improving Blood-Brain Tumor Barrier Permeability Application
by Hsin Chan, Hsin-Yun Chang, Win-Li Lin and Gin-Shin Chen
Pharmaceutics 2022, 14(10), 2012; https://doi.org/10.3390/pharmaceutics14102012 - 22 Sep 2022
Cited by 1 | Viewed by 1503
Abstract
Mild hyperthermia can locally enhance permeability of the blood-tumor barrier in brain tumors, improving delivery of antitumor nanodrugs. However, a clinical transcranial focused ultrasound (FUS) system does not provide this modality yet. The study aimed at the development of the transcranial FUS technique [...] Read more.
Mild hyperthermia can locally enhance permeability of the blood-tumor barrier in brain tumors, improving delivery of antitumor nanodrugs. However, a clinical transcranial focused ultrasound (FUS) system does not provide this modality yet. The study aimed at the development of the transcranial FUS technique dedicated for large-volume mild hyperthermia in the brain. Acoustic pressure, multiple-foci, temperature and thermal dose induced by FUS were simulated in the brain through the skull. A 1-MHz, 114-element, spherical helmet transducer was fabricated to verify large-volume hyperthermia in the phantom. The simulated results showed that two foci were simultaneously formed at (2, 0, 0) and (−2, 0, 0) and at (0, 2, 0) and (0, −2, 0), using the phases of focusing pattern 1 and the phases of focusing pattern 2, respectively. Switching two focusing patterns at 5 Hz produced a hyperthermic zone with an ellipsoid of 7 mm × 6 mm × 11 mm in the brain and the temperature was 41–45 °C in the ellipsoid as the maximum intensity was 150 W/cm2 and sonication time was 3 min. The phased array driven by switching two mode phases generated a 41 °C-contour region of 10 ± 1 mm × 8 ± 2 mm × 13 ± 2 mm in the phantom after 3-min sonication. Therefore, we have demonstrated our developed FUS technique for large-volume mild hyperthermia. Full article
(This article belongs to the Special Issue Ultrasonic Technologies in Imaging and Drug Delivery)
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13 pages, 2919 KiB  
Article
Molecular Imaging of Steroid-Induced Osteonecrosis of the Femoral Head through iRGD-Targeted Microbubbles
by Ping Zhao, Shuai Zhao, Jiaqi Zhang, Manlin Lai, Litao Sun and Fei Yan
Pharmaceutics 2022, 14(9), 1898; https://doi.org/10.3390/pharmaceutics14091898 - 08 Sep 2022
Cited by 4 | Viewed by 1626
Abstract
Osteonecrosis of the femoral head (ONFH) is a disease that is commonly seen in the clinic, but its detection rate remains limited, especially at the early stage. We developed an ultrasound molecular imaging (UMI) approach for early diagnosis of ONFH by detecting the [...] Read more.
Osteonecrosis of the femoral head (ONFH) is a disease that is commonly seen in the clinic, but its detection rate remains limited, especially at the early stage. We developed an ultrasound molecular imaging (UMI) approach for early diagnosis of ONFH by detecting the expression of integrin αvβ3 during the pathological changes in steroid-induced osteonecrosis of the femoral head (SIONFH) in rat models. The integrin αvβ3-targeted PLGA or lipid microbubbles modified with iRGD peptides were fabricated and characterized. Their adhesion efficiency to mouse brain microvascular endothelial cells in vitro was examined, and the better LIPOiRGD was used for further in vivo molecular imaging of SIONFH rats at 1, 3 and 5 weeks; revealing significantly higher UMI signals could be observed in the 3-week and 5-week SIONFH rats but not in the 1-week SIONFH rats in comparison with the non-targeted microbubbles (32.75 ± 0.95 vs. 0.17 ± 0.09 for 5 weeks, p < 0.05; 5.60 ± 1.31 dB vs. 0.94 ± 0.81 dB for 3 weeks, p < 0.01; 1.13 ± 0.13 dB vs. 0.73 ± 0.31 dB for 1 week, p > 0.05). These results were consistent with magnetic resonance imaging data and confirmed by immunofluorescence staining experiments. In conclusion, our study provides an alternative UMI approach to the early evaluation of ONFH. Full article
(This article belongs to the Special Issue Ultrasonic Technologies in Imaging and Drug Delivery)
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16 pages, 8346 KiB  
Article
Holographic Acoustic Tweezers for 5-DoF Manipulation of Nanocarrier Clusters toward Targeted Drug Delivery
by Hiep Xuan Cao, Daewon Jung, Han-Sol Lee, Van Du Nguyen, Eunpyo Choi, Byungjeon Kang, Jong-Oh Park and Chang-Sei Kim
Pharmaceutics 2022, 14(7), 1490; https://doi.org/10.3390/pharmaceutics14071490 - 18 Jul 2022
Cited by 9 | Viewed by 2539
Abstract
Acoustic tweezers provide unique capabilities in medical applications, such as contactless manipulation of small objects (e.g., cells, compounds or living things), from nanometer-sized extracellular vesicles to centimeter-scale structures. Additionally, they are capable of being transmitted through the skin to trap and manipulate drug [...] Read more.
Acoustic tweezers provide unique capabilities in medical applications, such as contactless manipulation of small objects (e.g., cells, compounds or living things), from nanometer-sized extracellular vesicles to centimeter-scale structures. Additionally, they are capable of being transmitted through the skin to trap and manipulate drug carriers in various media. However, these capabilities are hindered by the limitation of controllable degrees of freedom (DoFs) or are limited maneuverability. In this study, we explore the potential application of acoustical tweezers by presenting a five-DoF contactless manipulation acoustic system (AcoMan). The system has 30 ultrasound transducers (UTs) with single-side arrangement that generates active traveling waves to control the position and orientation of a fully untethered nanocarrier clusters (NCs) in a spherical workspace in water capable of three DoFs translation and two DoFs rotation. In this method, we use a phase modulation algorithm to independently control the phase signal for 30 UTs and manipulate the NCs’ positions. Phase modulation and switching power supply for each UT are employed to rotate the NCs in the horizontal plane and control the amplitude of power supply to each UT to rotate the NCs in the vertical plane. The feasibility of the method is demonstrated by in vitro and ex vivo experiments using porcine ribs. A significant portion of this study could advance the therapeutic application such a system as targeted drug delivery. Full article
(This article belongs to the Special Issue Ultrasonic Technologies in Imaging and Drug Delivery)
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14 pages, 3506 KiB  
Article
Overcoming Hypoxia-Induced Drug Resistance via Promotion of Drug Uptake and Reoxygenation by Acousto–Mechanical Oxygen Delivery
by Yi-Ju Ho, Dinh Thi Thao and Chih-Kuang Yeh
Pharmaceutics 2022, 14(5), 902; https://doi.org/10.3390/pharmaceutics14050902 - 20 Apr 2022
Cited by 4 | Viewed by 1902
Abstract
Hypoxia-induced drug resistance (HDR) is a critical issue in cancer therapy. The presence of hypoxic tumor cells impedes drug uptake and reduces the cytotoxicity of chemotherapeutic drugs, leading to HDR and increasing the probability of tumor recurrence and metastasis. Microbubbles, which are used [...] Read more.
Hypoxia-induced drug resistance (HDR) is a critical issue in cancer therapy. The presence of hypoxic tumor cells impedes drug uptake and reduces the cytotoxicity of chemotherapeutic drugs, leading to HDR and increasing the probability of tumor recurrence and metastasis. Microbubbles, which are used as an ultrasound contrast agent and drug/gas carrier, can locally deliver drugs/gas and produce an acousto–mechanical effect to enhance cell permeability under ultrasound sonication. The present study applied oxygen-loaded microbubbles (OMBs) to evaluate the mechanisms of overcoming HDR via promotion of drug uptake and reoxygenation. A hypoxic mouse prostate tumor cell model was established by hypoxic incubation for 4 h. After OMB treatment, the permeability of HDR cells was enhanced by 23 ± 5% and doxorubicin uptake was increased by 11 ± 7%. The 61 ± 14% reoxygenation of HDR cells increased the cytotoxicity of doxorubicin from 18 ± 4% to 58 ± 6%. In combination treatment with OMB and doxorubicin, the relative contributions of uptake promotion and reoxygenation towards overcoming HDR were 11 ± 7% and 28 ± 10%, respectively. Our study demonstrated that reoxygenation of hypoxic conditions is a critical mechanism in the inhibition of HDR and enhancing the outcome of OMB treatment. Full article
(This article belongs to the Special Issue Ultrasonic Technologies in Imaging and Drug Delivery)
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14 pages, 3654 KiB  
Article
Imaging the Effects of Whole-Body Vibration on the Progression of Hepatic Steatosis by Quantitative Ultrasound Based on Backscatter Envelope Statistics
by Jui Fang, Ming-Wei Lai, Hao-Tsai Cheng, Anca Cristea, Zhuhuang Zhou and Po-Hsiang Tsui
Pharmaceutics 2022, 14(4), 741; https://doi.org/10.3390/pharmaceutics14040741 - 29 Mar 2022
Cited by 1 | Viewed by 1717
Abstract
Hepatic steatosis causes nonalcoholic fatty liver disease. Whole-body vibration (WBV) has been recommended to allow patients who have difficulty engaging in exercise to improve the grade of hepatic steatosis. This study proposed using ultrasound parametric imaging of the homodyned K (HK) distribution to [...] Read more.
Hepatic steatosis causes nonalcoholic fatty liver disease. Whole-body vibration (WBV) has been recommended to allow patients who have difficulty engaging in exercise to improve the grade of hepatic steatosis. This study proposed using ultrasound parametric imaging of the homodyned K (HK) distribution to evaluate the effectiveness of WBV treatments in alleviating hepatic steatosis. Sixty mice were assigned to control (n = 6), sedentary (n = 18), WBV (n = 18), and exercise (swimming) (n = 18) groups. Mice were fed a high-fat diet to induce hepatic steatosis and underwent the intervention for 4, 8, and 16 weeks. Ultrasound scanning was performed in vivo on each mouse after the interventions for ultrasound HK imaging using the parameter μ (the scatterer clustering parameter). Histopathological examinations and the intraperitoneal glucose tolerance test were carried out for comparisons with ultrasound findings. At the 16th week, WBV and exercise groups demonstrated lower body weights, glucose concentrations, histopathological scores (steatosis and steatohepatitis), and μ parameters than the control group (p < 0.05). The steatosis grade was significantly lower in the WBV group (mild) than in the exercise group (moderate) (p < 0.05), corresponding to a reduction in the μ parameter. A further analysis revealed that the correlation between the steatosis grade and the μ parameter was 0.84 (p < 0.05). From this animal study we conclude that WBV may be more effective than exercise in reducing the progression of hepatic steatosis, and ultrasound HK parametric imaging is an appropriate method for evaluating WBV’s effect on hepatic steatosis. Full article
(This article belongs to the Special Issue Ultrasonic Technologies in Imaging and Drug Delivery)
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14 pages, 3023 KiB  
Article
Focused Ultrasound-Induced Blood–Brain Barrier Opening Enhanced α-Synuclein Expression in Mice for Modeling Parkinson’s Disease
by Chung-Yin Lin, Ching-Yun Huang, Chiung-Mei Chen and Hao-Li Liu
Pharmaceutics 2022, 14(2), 444; https://doi.org/10.3390/pharmaceutics14020444 - 18 Feb 2022
Cited by 5 | Viewed by 2234
Abstract
Parkinson’s disease (PD) is characterized by α-synuclein (αSNCA) aggregation in dopaminergic neurons. Gradual accumulation of αSNCA aggregates in substantia nigra (SN) diminishes the normal functioning of soluble αSNCA, leading to a loss of dopamine (DA) neurons. In this study, we developed focused ultrasound-targeted [...] Read more.
Parkinson’s disease (PD) is characterized by α-synuclein (αSNCA) aggregation in dopaminergic neurons. Gradual accumulation of αSNCA aggregates in substantia nigra (SN) diminishes the normal functioning of soluble αSNCA, leading to a loss of dopamine (DA) neurons. In this study, we developed focused ultrasound-targeted microbubble destruction (UTMD)-mediated PD model that could generate the disease phenotype via αSNCA CNS gene delivery. The formation of neuronal aggregates was analyzed with immunostaining. To evaluate the DA cell loss, we used tyrosine hydroxylase immunostaining and HPLC analysis on DA and its two metabolites, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA). This loss of DA was associated with a dose-dependent impairment in motor function, as assessed by the rotarod motor assessment. We demonstrate that UTMD-induced SNCA expression initiates αSNCA aggregation and results in a 50% loss of DA in SN. UTMD-related dose-dependent neuronal loss was identified, and it correlates with the degree of impairment of motor function. In comparison to chemical neurotoxin 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated and conventional intracerebral (IC)-injected animal models of PD, the UTMD-mediated αSNCA-based mouse model offers the advantage of mimicking the rapid development of the PD phenotype. The PD models that we created using UTMD also prove valuable in assessing specific aspects of PD pathogenesis and can serve as a useful PD model for the development of new therapeutic strategies. Full article
(This article belongs to the Special Issue Ultrasonic Technologies in Imaging and Drug Delivery)
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