Recent Advances in the Use of Ultrasound to Enhance Drug Delivery and Efficacy for the Treatment of Cancer

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

Deadline for manuscript submissions: 30 November 2024 | Viewed by 5183

Special Issue Editors


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Guest Editor
Department of Physics, Division of Radiotherapy and Imaging, The Institute of Cancer Research, Sutton, London SM2 5NG, UK
Interests: therapy ultrasound; thermal ablation; cavitation; ultrasound bio-effects; cancer research; vascular occlusion
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Guest Editor
Department of Physics, Division of Radiotherapy and Imaging, The Institute of Cancer Research, Sutton, London SM2 5NG, UK
Interests: HIFU; histotripsy; therapy ultrasound; cancer treatment; ablation; biological effects; immunology
Department of Physics, Division of Radiotherapy and Imaging, The Institute of Cancer Research, Sutton, London SM2 5NG, UK
Interests: therapy ultrasound; cancer; ablation; histotripsy; drug delivery; heating cavitation; vascular occlusion

Special Issue Information

Dear Colleagues,

Therapeutic ultrasound is under investigation for the treatment of more than 150 indications, including tumors in prostate, breast, liver, pancreas, kidney, and other soft tissues. Significant research activity is being devoted to investigating ultrasound as a means of enhancing delivery and efficacy of drugs, biotherapeutics, and genetic material in these tumors. Sonication of tissues can induce local heating, or mechanical effects, resulting in the activation of drug delivery systems and the enhancement of drug concentration in the target tissue. It can also be used as an adjuvant to enhance the efficacy of chemotherapy, radiotherapy, and immunotherapy. There is growing interest in the use of low-intensity ultrasound in combination with microbubbles to open the blood–brain barrier and disrupt the tumor microenvironment, improving access to the interstitium of malignant lesions. This Special Issue aims to highlight and capture contemporary progress and the current landscape of preclinical and clinical applications of ultrasonic therapeutic agents and related drugs in the treatment of cancer. We are pleased to invite you to submit articles on all aspects of “The Use of Ultrasound to Enhance Drug Delivery and Efficacy in the Treatment of Cancer”.

In this Special Issue, original research articles and reviews are welcome. Research areas may include (but are not limited to) the following: ultrasound-based drug delivery; applications of ultrasound in cancer therapy and imaging; sonodynamic therapy; blood–brain barrier opening.

Prof. Dr. Gail Ter Haar
Dr. Petros Mouratidis
Dr. Ian Rivens
Guest Editors

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Keywords

  • therapy ultrasound
  • HIFU
  • drug delivery
  • sonodynamic therapy
  • cancer treatment
  • histotripsy
  • hyperthermia
  • thermal ablation
  • cavitation
  • blood–brain barrier

Published Papers (3 papers)

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Research

14 pages, 3161 KiB  
Article
Effect of Phase-Change Nanodroplets and Ultrasound on Blood–Brain Barrier Permeability In Vitro
by Stavros Vlatakis, Weiqi Zhang, Sarah Thomas, Paul Cressey, Alexandru Corneliu Moldovan, Hilde Metzger, Paul Prentice, Sandy Cochran and Maya Thanou
Pharmaceutics 2024, 16(1), 51; https://doi.org/10.3390/pharmaceutics16010051 - 28 Dec 2023
Viewed by 1282
Abstract
Phase-change nanodroplets (PCND;NDs) are emulsions with a perfluorocarbon (PFC) core that undergo acoustic vaporisation as a response to ultrasound (US). Nanodroplets change to microbubbles and cavitate while under the effect of US. This cavitation can apply forces on cell connections in biological barrier [...] Read more.
Phase-change nanodroplets (PCND;NDs) are emulsions with a perfluorocarbon (PFC) core that undergo acoustic vaporisation as a response to ultrasound (US). Nanodroplets change to microbubbles and cavitate while under the effect of US. This cavitation can apply forces on cell connections in biological barrier membranes, such as the blood–brain barrier (BBB), and trigger a transient and reversible increased permeability to molecules and matter. This study aims to present the preparation of lipid-based NDs and investigate their effects on the brain endothelial cell barrier in vitro. The NDs were prepared using the thin-film hydration method, followed by the PFC addition. They were characterised for size, cavitation (using a high-speed camera), and PFC encapsulation (using FTIR). The bEnd.3 (mouse brain endothelial) cells were seeded onto transwell inserts. Fluorescein with NDs and/or microbubbles were applied on the bEND3 cells and the effect of US on fluorescein permeability was measured. The Live/Dead assay was used to assess the BBB integrity after the treatments. Size and PFC content analysis indicated that the NDs were stable while stored. High-speed camera imaging confirmed that the NDs cavitate after US exposure of 0.12 MPa. The BBB cell model experiments revealed a 4-fold increase in cell membrane permeation after the combined application of US and NDs. The Live/Dead assay results indicated damage to the BBB membrane integrity, but this damage was less when compared to the one caused by microbubbles. This in vitro study shows that nanodroplets have the potential to cause BBB opening in a similar manner to microbubbles. Both cavitation agents caused damage on the endothelial cells. It appears that NDs cause less cell damage compared to microbubbles. Full article
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16 pages, 2421 KiB  
Article
Radioenhancement with the Combination of Docetaxel and Ultrasound Microbubbles: In Vivo Prostate Cancer
by Firas Almasri, Emmanuel H. Sakarya and Raffi Karshafian
Pharmaceutics 2023, 15(5), 1468; https://doi.org/10.3390/pharmaceutics15051468 - 11 May 2023
Viewed by 1430
Abstract
Using an in vitro prostate cancer model, we previously demonstrated the significant enhancement of radiotherapy (XRT) with the combined treatment of docetaxel (Taxotere; TXT) and ultrasound-microbubbles (USMB). Here, we extend these findings to an in vivo cancer model. Severe combined immune-deficient male mice [...] Read more.
Using an in vitro prostate cancer model, we previously demonstrated the significant enhancement of radiotherapy (XRT) with the combined treatment of docetaxel (Taxotere; TXT) and ultrasound-microbubbles (USMB). Here, we extend these findings to an in vivo cancer model. Severe combined immune-deficient male mice were xenografted with the PC-3 prostate cancer cell line in the hind leg and treated with USMB, TXT, radiotherapy (XRT), and their combinations. The tumors were imaged with ultrasound pre-treatment and 24 h post-treatment, following which they were extracted for the histological analysis of the tumor-cell death (DN; H&E) and apoptosis (DA; TUNEL). The tumors’ growths were assessed for up to ~6 weeks and analysed using the exponential Malthusian tumor-growth model. The tumors’ doubling time (VT) was characterized as growth (positive) or shrinkage (negative). The cellular death and apoptosis increased ~5-fold with the TXT + USMB + XRT (Dn = 83% and Da = 71%) compared to the XRT alone (Dn = 16% and Da = 14%), and by ~2–3-fold with the TXT + XRT (Dn = 50% and Da = 38%) and USMB + XRT (Dn = 45% and Da = 27%) compared to the XRT. The USMB enhanced the cellular bioeffects of the TXT by ~2–5-fold with the TXT + USMB (Dn = 42% and Da = 50%), compared with the TXT alone (Dn = 19% and Da = 9%). The USMB alone caused cell death (Dn = 17% and Da = 10%) compared to the untreated control (Dn = 0.4% and Da = 0%). The histological cellular bioeffects were correlated with the changes in the ultrasound RF mid-band-fit data, which were associated with the cellular morphology. The linear regression analysis displayed a positive linear correlation between the mid-band fit and the overall cell death (R2 = 0.9164), as well as a positive linear correlation between the mid-band fit and the apoptosis (R2 = 0.8530). These results demonstrate a correlation between the histological and spectral measurements of the tissue microstructure and that cellular morphological changes can be detected by ultrasound scattering analysis. In addition, the tumor volumes from the triple-combination treatment were significantly smaller than those from the control, XRT, USMB + XRT, and TXT + XRT, from day 2 onward. The TXT + USMB + XRT-treated tumors shrank from day 2 and at each subsequent time-point measured (VT ~−6 days). The growth of the XRT-treated tumors was inhibited during the first 16 days, following which the tumors grew (VT ~9 days). The TXT + XRT and USMB + XRT groups displayed an initial decrease in tumor size (day 1–14; TXT + XRT VT ~−12 days; USMB + XRT VT ~−33 days), followed by a growth phase (day 15–37; TXT + XRT VT ~11 days; USMB + XRT VT ~22 days). The triple-combination therapy induced tumor shrinkage to a greater extent than any of the other treatments. This study demonstrates the in vivo radioenhancement potential of chemotherapy combined with therapeutic ultrasound-microbubble treatment in inducing cell death and apoptosis, as well as long-term tumor shrinkage. Full article
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16 pages, 2723 KiB  
Article
Ultrasound and Microbubbles Mediated Bleomycin Delivery in Feline Oral Squamous Cell Carcinoma—An In Vivo Veterinary Study
by Josanne S. de Maar, Maurice M. J. M. Zandvliet, Stefanie Veraa, Mauricio Tobón Restrepo, Chrit T. W. Moonen and Roel Deckers
Pharmaceutics 2023, 15(4), 1166; https://doi.org/10.3390/pharmaceutics15041166 - 6 Apr 2023
Cited by 1 | Viewed by 1918
Abstract
To investigate the feasibility and tolerability of ultrasound and microbubbles (USMB)-enhanced chemotherapy delivery for head and neck cancer, we performed a veterinary trial in feline companion animals with oral squamous cell carcinomas. Six cats were treated with a combination of bleomycin and USMB [...] Read more.
To investigate the feasibility and tolerability of ultrasound and microbubbles (USMB)-enhanced chemotherapy delivery for head and neck cancer, we performed a veterinary trial in feline companion animals with oral squamous cell carcinomas. Six cats were treated with a combination of bleomycin and USMB therapy three times, using the Pulse Wave Doppler mode on a clinical ultrasound system and EMA/FDA approved microbubbles. They were evaluated for adverse events, quality of life, tumour response and survival. Furthermore, tumour perfusion was monitored before and after USMB therapy using contrast-enhanced ultrasound (CEUS). USMB treatments were feasible and well tolerated. Among 5 cats treated with optimized US settings, 3 had stable disease at first, but showed disease progression 5 or 11 weeks after first treatment. One cat had progressive disease one week after the first treatment session, maintaining a stable disease thereafter. Eventually, all cats except one showed progressive disease, but each survived longer than the median overall survival time of 44 days reported in literature. CEUS performed immediately before and after USMB therapy suggested an increase in tumour perfusion based on an increase in median area under the curve (AUC) in 6 out of 12 evaluated treatment sessions. In this small hypothesis-generating study, USMB plus chemotherapy was feasible and well-tolerated in a feline companion animal model and showed potential for enhancing tumour perfusion in order to increase drug delivery. This could be a forward step toward clinical translation of USMB therapy to human patients with a clinical need for locally enhanced treatment. Full article
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