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Special Issue "Cavitation-Enhanced Drug Delivery and Immunotherapy"

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

Deadline for manuscript submissions: 10 June 2023 | Viewed by 10306

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Special Issue Editors

Dr. Brandon Helfield

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Guest Editor

1. Department of Physics, Concordia University, Montreal, QC, Canada
2. Department of Biology, Concordia University, Montreal, QC H3G 1M8, Canada
Interests: ultrasound; microbubbles; immunotherapy; sonoporation; cavitation; targeted drug delivery; acoustics; focused ultrasound; immunomodulation

Dr. Shashank Sirsi

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Guest Editor

Erik Jonsson School of Engineering and Computer Science, The University of Texas at Dallas, Richardson, TX 75080, USA
Interests: ultrasound; focused ultrasound; ultrasound contrast agents; drug delivery; sonoporation; sonopermeation

Dr. James Kwan

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Guest Editor

Department of Engineering Science, University of Oxford, Oxford OX1 3PJ, UK
Interests: stimuli-responsive microparticles and nanoparticles; ultrasound; cavitation; sonochemistry; physical acoustics

Dr. Michael Gray
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Guest Editor

Biomedical Ultrasonics, Biotherapies and Biopharmaceuticals Laboratory, University of Oxford, Oxford OX3 7DQ, UK
Interests: ultrasound-mediated drug delivery; cavitation monitoring techniques

Special Issue Information

Dear Colleagues,

We are pleased to invite you to contribute to this Special Issue intended to highlight new developments in Cavitation-Enhanced Drug Delivery and Immunotherapy. This rapidly evolving field has been buoyed in recent years by the development of methods harnessing the activity of ultrasound-stimulated bubbles known as cavitation. When properly controlled, cavitation can help overcome physical barriers to drug delivery whilst providing readily measurable information for timely quantitative feedback and treatment guidance. Microbubble-assisted therapies have demonstrated impressive advancements in clinical trials and pre-clinical areas, including applications in neurology, oncology, cardiology, and beyond.

This Special Issue will cover topics including the design of new cavitation nuclei constructs, cavitation-assisted immunotherapies and immunomodulation, targeted drug or gene delivery, and dual microbubble imaging and therapeutic approaches. In addition to manuscripts that investigate applications in drug delivery and immunotherapy, we also welcome numerical and/or experimental mechanistic studies, including but not limited to single-cell or single-bubble studies that glean insight into the biophysics of this technology.

This Special Issue is open to original research and review articles. We look forward to receiving your contributions.

Dr. Brandon Helfield
Dr. Shashank Sirsi
Dr. James Kwan
Dr. Michael Gray
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 2600 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
microbubbles
immunotherapy
sonoporation
cavitation
targeted drug delivery
acoustics
focused ultrasound
immunomodulation

Published Papers (10 papers)

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Research

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Open AccessArticle

Improved Therapeutic Delivery Targeting Clinically Relevant Orthotopic Human Pancreatic Tumors Engrafted in Immunocompromised Pigs Using Ultrasound-Induced Cavitation: A Pilot Study

Margaret A. Nagai-Singer

Hannah Ivester

McAlister Council-Troche

Michael Edwards

Sheryl Coutermarsh-Ott

and

Pharmaceutics 2023, 15(6), 1585; https://doi.org/10.3390/pharmaceutics15061585 - 24 May 2023

Viewed by 565

Abstract

Pancreatic tumors can be resistant to drug penetration due to high interstitial fluid pressure, dense stroma, and disarrayed vasculature. Ultrasound-induced cavitation is an emerging technology that may overcome many of these limitations. Low-intensity ultrasound, coupled with co-administered cavitation nuclei consisting of gas-stabilizing sub-micron scale SonoTran Particles, is effective at increasing therapeutic antibody delivery to xenograft flank tumors in mouse models. Here, we sought to evaluate the effectiveness of this approach in situ using a large animal model that mimics human pancreatic cancer patients. Immunocompromised pigs were surgically engrafted with human Panc-1 pancreatic ductal adenocarcinoma (PDAC) tumors in targeted regions of the pancreas. These tumors were found to recapitulate many features of human PDAC tumors. Animals were intravenously injected with the common cancer therapeutics Cetuximab, gemcitabine, and paclitaxel, followed by infusion with SonoTran Particles. Select tumors in each animal were targeted with focused ultrasound to induce cavitation. Cavitation increased the intra-tumor concentrations of Cetuximab, gemcitabine, and paclitaxel by 477%, 148%, and 193%, respectively, compared to tumors that were not targeted with ultrasound in the same animals. Together, these data show that ultrasound-mediated cavitation, when delivered in combination with gas-entrapping particles, improves therapeutic delivery in pancreatic tumors under clinically relevant conditions. Full article

(This article belongs to the Special Issue Cavitation-Enhanced Drug Delivery and Immunotherapy)

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Open AccessArticle

Cationic Microbubbles for Non-Selective Binding of Cavitation Nuclei to Bacterial Biofilms

and

Pharmaceutics 2023, 15(5), 1495; https://doi.org/10.3390/pharmaceutics15051495 - 13 May 2023

Viewed by 656

Abstract

The presence of multi-drug resistant biofilms in chronic, persistent infections is a major barrier to successful clinical outcomes of therapy. The production of an extracellular matrix is a characteristic of the biofilm phenotype, intrinsically linked to antimicrobial tolerance. The heterogeneity of the extracellular matrix makes it highly dynamic, with substantial differences in composition between biofilms, even in the same species. This variability poses a major challenge in targeting drug delivery systems to biofilms, as there are few elements both suitably conserved and widely expressed across multiple species. However, the presence of extracellular DNA within the extracellular matrix is ubiquitous across species, which alongside bacterial cell components, gives the biofilm its net negative charge. This research aims to develop a means of targeting biofilms to enhance drug delivery by developing a cationic gas-filled microbubble that non-selectively targets the negatively charged biofilm. Cationic and uncharged microbubbles loaded with different gases were formulated and tested to determine their stability, ability to bind to negatively charged artificial substrates, binding strength, and, subsequently, their ability to adhere to biofilms. It was shown that compared to their uncharged counterparts, cationic microbubbles facilitated a significant increase in the number of microbubbles that could both bind and sustain their interaction with biofilms. This work is the first to demonstrate the utility of charged microbubbles for the non-selective targeting of bacterial biofilms, which could be used to significantly enhance stimuli-mediated drug delivery to the bacterial biofilm. Full article

(This article belongs to the Special Issue Cavitation-Enhanced Drug Delivery and Immunotherapy)

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Open AccessArticle

Improved Tumor Control Following Radiosensitization with Ultrasound-Sensitive Oxygen Microbubbles and Tumor Mitochondrial Respiration Inhibitors in a Preclinical Model of Head and Neck Cancer

and

Pharmaceutics 2023, 15(4), 1302; https://doi.org/10.3390/pharmaceutics15041302 - 21 Apr 2023

Viewed by 609

Abstract

Tumor hypoxia (oxygen deficiency) is a major contributor to radiotherapy resistance. Ultrasound-sensitive microbubbles containing oxygen have been explored as a mechanism for overcoming tumor hypoxia locally prior to radiotherapy. Previously, our group demonstrated the ability to encapsulate and deliver a pharmacological inhibitor of tumor mitochondrial respiration (lonidamine (LND)), which resulted in ultrasound-sensitive microbubbles loaded with O₂ and LND providing prolonged oxygenation relative to oxygenated microbubbles alone. This follow-up study aimed to evaluate the therapeutic response to radiation following the administration of oxygen microbubbles combined with tumor mitochondrial respiration inhibitors in a head and neck squamous cell carcinoma (HNSCC) tumor model. The influences of different radiation dose rates and treatment combinations were also explored. The results demonstrated that the co-delivery of O₂ and LND successfully sensitized HNSCC tumors to radiation, and this was also enhanced with oral metformin, significantly slowing tumor growth relative to unsensitized controls (p < 0.01). Microbubble sensitization was also shown to improve overall animal survival. Importantly, effects were found to be radiation dose-rate-dependent, reflecting the transient nature of tumor oxygenation. Full article

(This article belongs to the Special Issue Cavitation-Enhanced Drug Delivery and Immunotherapy)

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Open AccessArticle

Low-Intensity Pulsed Ultrasound-Mediated Blood-Brain Barrier Opening Increases Anti-Programmed Death-Ligand 1 Delivery and Efficacy in Gl261 Mouse Model

Mohammed H. Ahmed

Isaias Hernández-Verdin

and

Pharmaceutics 2023, 15(2), 455; https://doi.org/10.3390/pharmaceutics15020455 - 30 Jan 2023

Viewed by 1404

Abstract

Therapeutic antibodies targeting immune checkpoints have shown limited efficacy in clinical trials in glioblastoma (GBM) patients. Ultrasound-mediated blood–brain barrier opening (UMBO) using low-intensity pulsed ultrasound improved drug delivery to the brain. We explored the safety and the efficacy of UMBO plus immune checkpoint inhibitors in preclinical models of GBM. A blood–brain barrier (BBB) opening was performed using a 1 MHz preclinical ultrasound system in combination with 10 µL/g microbubbles. Brain penetration of immune checkpoint inhibitors was determined, and immune cell populations were evaluated using flow cytometry. The impact of repeated treatments on survival was determined. In syngeneic GL261-bearing immunocompetent mice, we showed that UMBO safely and repeatedly opened the BBB. BBB opening was confirmed visually and microscopically using Evans blue dye and magnetic resonance imaging. UMBO plus anti-PDL-1 was associated with a significant improvement of overall survival compared to anti-PD-L1 alone. Using mass spectroscopy, we showed that the penetration of therapeutic antibodies can be increased when delivered intravenously compared to non-sonicated brains. Furthermore, we observed an enhancement of activated microglia percentage when combined with anti-PD-L1. Here, we report that the combination of UMBO and anti-PD-L1 dramatically increases GL261-bearing mice’s survival compared to their counterparts treated with anti-PD-L1 alone. Our study highlights the BBB as a limitation to overcome in order to increase the efficacy of anti-PD-L1 in GBM and supports clinical trials combining UMBO and in GBM patients. Full article

(This article belongs to the Special Issue Cavitation-Enhanced Drug Delivery and Immunotherapy)

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Open AccessArticle

Sonoporation of the Round Window Membrane on a Sheep Model: A Safety Study

and

Pharmaceutics 2023, 15(2), 442; https://doi.org/10.3390/pharmaceutics15020442 - 29 Jan 2023

Viewed by 839

Abstract

Sonoporation using microbubble-assisted ultrasound increases the permeability of a biological barrier to therapeutic molecules. Application of this method to the round window membrane could improve the delivery of therapeutics to the inner ear. The aim of this study was to assess the safety of sonoporation of the round window membrane in a sheep model. To achieve this objective, we assessed auditory function and cochlear heating, and analysed the metabolomics profiles of perilymph collected after sonoporation, comparing them with those of the control ear in the same animal. Six normal-hearing ewes were studied, with one sonoporation ear and one control ear for each. A mastoidectomy was performed on both ears. On the sonoporation side, Vevo MicroMarker^® microbubbles (MBs; VisualSonics—Fujifilm, Amsterdam, The Netherlands) at a concentration of 2 × 10⁸ MB/mL were locally injected into the middle ear and exposed to 1.1 MHz sinusoidal ultrasonic waves at 0.3 MPa negative peak pressure with 40% duty cycle and 100 μs interpulse period for 1 min; this was repeated three times with 1 min between applications. The sonoporation protocol did not induce any hearing impairment or toxic overheating compared with the control condition. The metabolomic analysis did not reveal any significant metabolic difference between perilymph samples from the sonoporation and control ears. The results suggest that sonoporation of the round window membrane does not cause damage to the inner ear in a sheep model. Full article

(This article belongs to the Special Issue Cavitation-Enhanced Drug Delivery and Immunotherapy)

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Open AccessArticle

Stable Cavitation-Mediated Delivery of miR-126 to Endothelial Cells

and

Pharmaceutics 2022, 14(12), 2656; https://doi.org/10.3390/pharmaceutics14122656 - 30 Nov 2022

Viewed by 781

Abstract

In endothelial cells, microRNA-126 (miR-126) promotes angiogenesis, and modulating the intracellular levels of this gene could suggest a method to treat cardiovascular diseases such as ischemia. Novel ultrasound-stimulated microbubbles offer a means to deliver therapeutic payloads to target cells and sites of disease. The purpose of this study was to investigate the feasibility of gene delivery by stimulating miR-126-decorated microbubbles using gentle acoustic conditions (stable cavitation). A cationic DSTAP microbubble was formulated and characterized to carry 6 µg of a miR-126 payload per 10⁹ microbubbles. Human umbilical vein endothelial cells (HUVECs) were treated at 20–40% duty cycle with miR-126-conjugated microbubbles in a custom ultrasound setup coupled with a passive cavitation detection system. Transfection efficiency was assessed by RT-qPCR, Western blotting, and endothelial tube formation assay, while HUVEC viability was monitored by MTT assay. With increasing duty cycle, the trend observed was an increase in intracellular miR-126 levels, up to a 2.3-fold increase, as well as a decrease in SPRED1 (by 33%) and PIK3R2 (by 46%) expression, two salient miR-126 targets. Under these ultrasound parameters, HUVECs maintained >95% viability after 96 h. The present work describes the delivery of a proangiogenic miR-126 using an ultrasound-responsive cationic microbubble with potential to stimulate therapeutic angiogenesis while minimizing endothelial damage. Full article

(This article belongs to the Special Issue Cavitation-Enhanced Drug Delivery and Immunotherapy)

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Open AccessArticle

Impact of Perfluoropentane Microdroplets Diameter and Concentration on Acoustic Droplet Vaporization Transition Efficiency and Oxygen Scavenging

and

Pharmaceutics 2022, 14(11), 2392; https://doi.org/10.3390/pharmaceutics14112392 - 05 Nov 2022

Viewed by 1094

Abstract

Acoustic droplet vaporization is the ultrasound-mediated phase change of liquid droplets into gas microbubbles. Following the phase change, oxygen diffuses from the surrounding fluid into the microbubble. An in vitro model was used to study the effects of droplet diameter, the presence of an ultrasound contrast agent, ultrasound duty cycle, and droplet concentration on the magnitude of oxygen scavenging in oxygenated deionized water. Perfluoropentane droplets were manufactured through a microfluidic approach at nominal diameters of 1, 3, 5, 7, 9, and 12 µm and studied at concentrations varying from 5.1 × 10⁻⁵ to 6.3 × 10⁻³ mL/mL. Droplets were exposed to an ultrasound transduced by an EkoSonic^TM catheter (2.35 MHz, 47 W, and duty cycles of 1.70%, 2.34%, or 3.79%). Oxygen scavenging and the total volume of perfluoropentane that phase-transitioned increased with droplet concentration. The ADV transition efficiency decreased with increasing droplet concentration. The increasing duty cycle resulted in statistically significant increases in oxygen scavenging for 1, 3, 5, and 7 µm droplets, although the increase was smaller than when the droplet diameter or concentration were increased. Under the ultrasound conditions tested, droplet diameter and concentration had the greatest impact on the amount of ADV and subsequent oxygen scavenging occurred, which should be considered when using ADV-mediated oxygen scavenging in therapeutic ultrasounds. Full article

(This article belongs to the Special Issue Cavitation-Enhanced Drug Delivery and Immunotherapy)

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Open AccessArticle

Cavitation Characterization of Size-Isolated Microbubbles in a Vessel Phantom Using Focused Ultrasound

Payton Martinez

Nick Bottenus

and

Mark Borden

Pharmaceutics 2022, 14(9), 1925; https://doi.org/10.3390/pharmaceutics14091925 - 12 Sep 2022

Cited by 6 | Viewed by 1514 | Correction

Abstract

Pharmaceutical delivery can be noninvasively targeted on-demand by microbubble (MB) assisted focused ultrasound (FUS). Passive cavitation detection (PCD) has become a useful method to obtain real-time feedback on MB activity due to a FUS pulse. Previous work has demonstrated the acoustic PCD response of MBs at a variety of acoustic parameters, but few have explored variations in microbubble parameters. The goal of this study was to determine the acoustic response of different MB size populations and concentrations. Four MB size distributions were prepared (2, 3, 5 µm diameter and polydisperse) and pulled through a 2% agar wall-less vessel phantom. FUS was applied by a 1.515 MHz geometrically focused transducer for 1 ms pulses at 1 Hz PRF and seven distinct mechanical indices (MI) ranging from 0.01 to 1.0 (0.0123 to 1.23 MPa PNP). We found that the onset of harmonic (HCD) and broadband cavitation dose (BCD) depends on the mechanical index, MB size and MB concentration. When matched for MI, the HCD and BCD rise, plateau, and decline as microbubble concentration is increased. Importantly, when microbubble size and concentration are combined into gas volume fraction, all four microbubble size distributions align to similar onset and peak; these results may help guide the planning and control of MB + FUS therapeutic procedures. Full article

(This article belongs to the Special Issue Cavitation-Enhanced Drug Delivery and Immunotherapy)

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Review

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Open AccessReview

Targeted Microbubbles for Drug, Gene, and Cell Delivery in Therapy and Immunotherapy

J. Angel Navarro-Becerra

and

Mark A. Borden

Pharmaceutics 2023, 15(6), 1625; https://doi.org/10.3390/pharmaceutics15061625 - 30 May 2023

Viewed by 272

Abstract

Microbubbles are 1–10 μm diameter gas-filled acoustically-active particles, typically stabilized by a phospholipid monolayer shell. Microbubbles can be engineered through bioconjugation of a ligand, drug and/or cell. Since their inception a few decades ago, several targeted microbubble (tMB) formulations have been developed as ultrasound imaging probes and ultrasound-responsive carriers to promote the local delivery and uptake of a wide variety of drugs, genes, and cells in different therapeutic applications. The aim of this review is to summarize the state-of-the-art of current tMB formulations and their ultrasound-targeted delivery applications. We provide an overview of different carriers used to increase drug loading capacity and different targeting strategies that can be used to enhance local delivery, potentiate therapeutic efficacy, and minimize side effects. Additionally, future directions are proposed to improve the tMB performance in diagnostic and therapeutic applications. Full article

(This article belongs to the Special Issue Cavitation-Enhanced Drug Delivery and Immunotherapy)

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Open AccessReview

Microbubble–Nanoparticle Complexes for Ultrasound-Enhanced Cargo Delivery

Rachel Chapla

Katherine T. Huynh

and

Carolyn E. Schutt

Pharmaceutics 2022, 14(11), 2396; https://doi.org/10.3390/pharmaceutics14112396 - 07 Nov 2022

Cited by 1 | Viewed by 1761

Abstract

Targeted delivery of therapeutics to specific tissues is critically important for reducing systemic toxicity and optimizing therapeutic efficacy, especially in the case of cytotoxic drugs. Many strategies currently exist for targeting systemically administered drugs, and ultrasound-controlled targeting is a rapidly advancing strategy for externally-stimulated drug delivery. In this non-invasive method, ultrasound waves penetrate through tissue and stimulate gas-filled microbubbles, resulting in bubble rupture and biophysical effects that power delivery of attached cargo to surrounding cells. Drug delivery capabilities from ultrasound-sensitive microbubbles are greatly expanded when nanocarrier particles are attached to the bubble surface, and cargo loading is determined by the physicochemical properties of the nanoparticles. This review serves to highlight and discuss current microbubble–nanoparticle complex component materials and designs for ultrasound-mediated drug delivery. Nanocarriers that have been complexed with microbubbles for drug delivery include lipid-based, polymeric, lipid–polymer hybrid, protein, and inorganic nanoparticles. Several schemes exist for linking nanoparticles to microbubbles for efficient nanoparticle delivery, including biotin–avidin bridging, electrostatic bonding, and covalent linkages. When compared to unstimulated delivery, ultrasound-mediated cargo delivery enables enhanced cell uptake and accumulation of cargo in target organs and can result in improved therapeutic outcomes. These ultrasound-responsive delivery complexes can also be designed to facilitate other methods of targeting, including bioactive targeting ligands and responsivity to light or magnetic fields, and multi-level targeting can enhance therapeutic efficacy. Microbubble–nanoparticle complexes present a versatile platform for controlled drug delivery via ultrasound, allowing for enhanced tissue penetration and minimally invasive therapy. Future perspectives for application of this platform are also discussed in this review. Full article

(This article belongs to the Special Issue Cavitation-Enhanced Drug Delivery and Immunotherapy)

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