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14 pages, 7417 KiB

Open AccessArticle

Remote Loading: The Missing Piece for Achieving High Drug Payload and Rapid Release in Polymeric Microbubbles

by Ghazal Rastegar, Mohammad Musa Salman and Shashank R. Sirsi

Pharmaceutics 2023, 15(11), 2550; https://doi.org/10.3390/pharmaceutics15112550 - 28 Oct 2023

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The use of drug-loaded microbubbles for targeted drug delivery, particularly in cancer treatment, has been extensively studied in recent years. However, the loading capacity of microbubbles has been limited due to their surface area. Typically, drug molecules are loaded on or within the [...] Read more.

The use of drug-loaded microbubbles for targeted drug delivery, particularly in cancer treatment, has been extensively studied in recent years. However, the loading capacity of microbubbles has been limited due to their surface area. Typically, drug molecules are loaded on or within the shell, or drug-loaded nanoparticles are coated on the surfaces of microbubbles. To address this significant limitation, we have introduced a novel approach. For the first time, we employed a transmembrane ammonium sulfate and pH gradient to load doxorubicin in a crystallized form in the core of polymeric microcapsules. Subsequently, we created remotely loaded microbubbles (RLMBs) through the sublimation of the liquid core of the microcapsules. Remotely loaded microcapsules exhibited an 18-fold increase in drug payload compared with physically loaded microcapsules. Furthermore, we investigated the drug release of RLMBs when exposed to an ultrasound field. After 120 s, an impressive 82.4 ± 5.5% of the loaded doxorubicin was released, demonstrating the remarkable capability of remotely loaded microbubbles for on-demand drug release. This study is the first to report such microbubbles that enable rapid drug release from the core. This innovative technique holds great promise in enhancing drug loading capacity and advancing targeted drug delivery. Full article

(This article belongs to the Special Issue Ultrasound-Mediated Drug Delivery)

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14 pages, 2292 KiB

Open AccessArticle

Development of a Gene and Nucleic Acid Delivery System for Skeletal Muscle Administration via Limb Perfusion Using Nanobubbles and Ultrasound

by Shohko Sekine, Sayaka Mayama, Nobuaki Nishijima, Takuo Kojima, Yoko Endo-Takahashi, Yuko Ishii, Hitomi Shiono, Saki Akiyama, Akane Sakurai, Sanae Sashida, Nobuhito Hamano, Rui Tada, Ryo Suzuki, Kazuo Maruyama and Yoichi Negishi

Pharmaceutics 2023, 15(6), 1665; https://doi.org/10.3390/pharmaceutics15061665 - 06 Jun 2023

Viewed by 1607

Abstract

Strategies for gene and nucleic acid delivery to skeletal muscles have been extensively explored to treat Duchenne muscular dystrophy (DMD) and other neuromuscular diseases. Of these, effective intravascular delivery of naked plasmid DNA (pDNA) and nucleic acids into muscles is an attractive approach, [...] Read more.

Strategies for gene and nucleic acid delivery to skeletal muscles have been extensively explored to treat Duchenne muscular dystrophy (DMD) and other neuromuscular diseases. Of these, effective intravascular delivery of naked plasmid DNA (pDNA) and nucleic acids into muscles is an attractive approach, given the high capillary density in close contact with myofibers. We developed lipid-based nanobubbles (NBs) using polyethylene-glycol-modified liposomes and an echo-contrast gas and found that these NBs could improve tissue permeability by ultrasound (US)-induced cavitation. Herein, we delivered naked pDNA or antisense phosphorodiamidate morpholino oligomers (PMOs) into the regional hindlimb muscle via limb perfusion using NBs and US exposure. pDNA encoding the luciferase gene was injected with NBs via limb perfusion into normal mice with application of US. High luciferase activity was achieved in a wide area of the limb muscle. DMD model mice were administered PMOs, designed to skip the mutated exon 23 of the dystrophin gene, with NBs via intravenous limb perfusion, followed by US exposure. The number of dystrophin-positive fibers increased in the muscles of mdx mice. Combining NBs and US exposure, which can be widely delivered to the hind limb muscles via the limb vein, could be an effective therapeutic approach for DMD and other neuromuscular disorders. Full article

(This article belongs to the Special Issue Ultrasound-Mediated Drug Delivery)

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22 pages, 5545 KiB

Open AccessArticle

The Assessment of Calcium and Bleomycin Cytotoxic Efficiency in Relation to Cavitation Dosimetry

by Martynas Maciulevičius, Renaldas Raišutis, Baltramiejus Jakštys, Linas Svilainis, Andrius Chaziachmetovas and Saulius Šatkauskas

Pharmaceutics 2023, 15(5), 1463; https://doi.org/10.3390/pharmaceutics15051463 - 11 May 2023

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Abstract

Microbubble (MB)- and ultrasound (US)-facilitated intracellular Ca²⁺ delivery, known as sonoporation (SP), is a promising anticancer treatment modality, since it allows a spatio-temporally controllable and side-effect-free alternative to conventional chemotherapy. The current study provides extensive evidence that a 5 mM concentration of [...] Read more.

Microbubble (MB)- and ultrasound (US)-facilitated intracellular Ca²⁺ delivery, known as sonoporation (SP), is a promising anticancer treatment modality, since it allows a spatio-temporally controllable and side-effect-free alternative to conventional chemotherapy. The current study provides extensive evidence that a 5 mM concentration of Ca²⁺ in combination with US alone or US and Sonovue MBs can be an alternative to the conventional 20 nM concentration of the anticancer drug bleomycin (BLM). Ca²⁺ application together with SP induces a similar level of death in Chinese hamster ovary cells to the combination of BLM and SP but does not cause systemic toxicity, as is inherent to conventional anticancer drugs. In addition, Ca²⁺ delivery via SP alters three vital characteristics essential for viable cells: membrane permeability, metabolic activity and proliferation ability. Most importantly, Ca²⁺ delivery via SP elicits sudden cell death—occurring within 15 min—which remains similar during 24–72 h and 6 d periods. The extensive study of US waves side-scattered by MBs led to the quantification of the cavitation dose (CD) separately for subharmonics, ultraharmonics, harmonics and broadband noise (up to 4 MHz). The CD was suitable for the prognostication of the cytotoxic efficiency of both anticancer agents, Ca²⁺ and BLM, as was indicated by an overall high (R² ≥ 0.8) correlation (22 pairs in total). These extensive analytical data imply that a broad range of frequencies are applicable for the feedback-loop control of the process of US-mediated Ca²⁺ or BLM delivery, successively leading to the eventual standardization of the protocols for the sonotransfer of anticancer agents as well as the establishment of a universal cavitation dosimetry model. Full article

(This article belongs to the Special Issue Ultrasound-Mediated Drug Delivery)

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14 pages, 4648 KiB

Open AccessArticle

Microbubble-Assisted Ultrasound for Drug Delivery to the Retina in an Ex Vivo Eye Model

by Charis Rousou, Nicky van Kronenburg, Andreas F. P. Sonnen, Marijke van Dijk, Chrit Moonen, Gert Storm, Enrico Mastrobattista and Roel Deckers

Pharmaceutics 2023, 15(4), 1220; https://doi.org/10.3390/pharmaceutics15041220 - 11 Apr 2023

Cited by 3 | Viewed by 1906

Abstract

Drug delivery to the retina is one of the major challenges in ophthalmology due to the biological barriers that protect it from harmful substances in the body. Despite the advancement in ocular therapeutics, there are many unmet needs for the treatment of retinal [...] Read more.

Drug delivery to the retina is one of the major challenges in ophthalmology due to the biological barriers that protect it from harmful substances in the body. Despite the advancement in ocular therapeutics, there are many unmet needs for the treatment of retinal diseases. Ultrasound combined with microbubbles (USMB) was proposed as a minimally invasive method for improving delivery of drugs in the retina from the blood circulation. This study aimed to investigate the applicability of USMB for the delivery of model drugs (molecular weight varying from 600 Da to 20 kDa) in the retina of ex vivo porcine eyes. A clinical ultrasound system, in combination with microbubbles approved for clinical ultrasound imaging, was used for the treatment. Intracellular accumulation of model drugs was observed in the cells lining blood vessels in the retina and choroid of eyes treated with USMB but not in eyes that received ultrasound only. Specifically, 25.6 ± 2.9% of cells had intracellular uptake at mechanical index (MI) 0.2 and 34.5 ± 6.0% at MI 0.4. Histological examination of retinal and choroid tissues revealed that at these USMB conditions, no irreversible alterations were induced at the USMB conditions used. These results indicate that USMB can be used as a minimally invasive targeted means to induce intracellular accumulation of drugs for the treatment of retinal diseases. Full article

(This article belongs to the Special Issue Ultrasound-Mediated Drug Delivery)

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10 pages, 5282 KiB

Open AccessArticle

Evading Doxorubicin-Induced Systemic Immunosuppression Using Ultrasound-Responsive Liposomes Combined with Focused Ultrasound

by Jeongjin Lee, Wooram Um, Hyungwon Moon, Hyeyeon Joo, Yeari Song, Minsung Park, Been Yoon, Hyun-Ryoung Kim and Jae Hyung Park

Pharmaceutics 2022, 14(12), 2603; https://doi.org/10.3390/pharmaceutics14122603 - 25 Nov 2022

Cited by 2 | Viewed by 1660

Abstract

Doxorubicin (DOX) is a representative anticancer drug with a unique ability to induce immunogenic cell death of cancer cells. However, undesired toxicity on immune cells has remained a significant challenge, hindering the usage of DOX in cancer immunotherapy. Here, we report a combined [...] Read more.

Doxorubicin (DOX) is a representative anticancer drug with a unique ability to induce immunogenic cell death of cancer cells. However, undesired toxicity on immune cells has remained a significant challenge, hindering the usage of DOX in cancer immunotherapy. Here, we report a combined therapy to avoid the off-target toxicity of DOX by adapting ultrasound-responsive liposomal doxorubicin and focused ultrasound exposure. Histological analysis demonstrated that the combined therapy induced less hemosiderosis of splenocytes and improved tumor infiltration of cytotoxic T lymphocytes. Additionally, in vivo therapeutic evaluation results indicate that the combined therapy achieved higher efficacy when combined with PD-1 immune-checkpoint blockade therapy by improving immunogenicity. Full article

(This article belongs to the Special Issue Ultrasound-Mediated Drug Delivery)

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16 pages, 3747 KiB

Open AccessArticle

Acoustically Driven Cell-Based Microrobots for Targeted Tumor Therapy

by Hiep Xuan Cao, Van Du Nguyen, Daewon Jung, Eunpyo Choi, Chang-Sei Kim, Jong-Oh Park and Byungjeon Kang

Pharmaceutics 2022, 14(10), 2143; https://doi.org/10.3390/pharmaceutics14102143 - 09 Oct 2022

Cited by 9 | Viewed by 1926

Abstract

Targeted drug delivery using microrobots manipulated by an external actuator has significant potential to be a practical approach for wireless delivery of therapeutic agents to the targeted tumor. This work aimed to develop a novel acoustic manipulation system and macrophage-based microrobots (Macbots) for [...] Read more.

Targeted drug delivery using microrobots manipulated by an external actuator has significant potential to be a practical approach for wireless delivery of therapeutic agents to the targeted tumor. This work aimed to develop a novel acoustic manipulation system and macrophage-based microrobots (Macbots) for a study in targeted tumor therapy. The Macbots containing superparamagnetic iron oxide nanoparticles (SPIONs) can serve as drug carriers. Under an acoustic field, a microrobot cluster of the Macbots is manipulated by following a predefined trajectory and can reach the target with a different contact angle. As a fundamental validation, we investigated an in vitro experiment for targeted tumor therapy. The microrobot cluster could be manipulated to any point in the 4 × 4 × 4 mm region of interest with a position error of less than 300 μm. Furthermore, the microrobot could rotate in the O-XY plane with an angle step of 45 degrees without limitation of total angle. Finally, we verified that the Macbots could penetrate a 3D tumor spheroid that mimics an in vivo solid tumor. The outcome of this study suggests that the Macbots manipulated by acoustic actuators have potential applications for targeted tumor therapy. Full article

(This article belongs to the Special Issue Ultrasound-Mediated Drug Delivery)

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12 pages, 2019 KiB

Open AccessArticle

High Incidence of Intracerebral Hemorrhaging Associated with the Application of Low-Intensity Focused Ultrasound Following Acute Cerebrovascular Injury by Intracortical Injection

by Evgenii Kim, Jared Van Reet, Hyun-Chul Kim, Kavin Kowsari and Seung-Schik Yoo

Pharmaceutics 2022, 14(10), 2120; https://doi.org/10.3390/pharmaceutics14102120 - 06 Oct 2022

Cited by 3 | Viewed by 1646

Abstract

Low-intensity transcranial focused ultrasound (FUS) has gained momentum as a non-/minimally-invasive modality that facilitates the delivery of various pharmaceutical agents to the brain. With the additional ability to modulate regional brain tissue excitability, FUS is anticipated to confer potential neurotherapeutic applications whereby a [...] Read more.

Low-intensity transcranial focused ultrasound (FUS) has gained momentum as a non-/minimally-invasive modality that facilitates the delivery of various pharmaceutical agents to the brain. With the additional ability to modulate regional brain tissue excitability, FUS is anticipated to confer potential neurotherapeutic applications whereby a deeper insight of its safety is warranted. We investigated the effects of FUS applied to the rat brain (Sprague-Dawley) shortly after an intracortical injection of fluorescent interstitial solutes, a widely used convection-enhanced delivery technique that directly (i.e., bypassing the blood–brain-barrier (BBB)) introduces drugs or interstitial tracers to the brain parenchyma. Texas Red ovalbumin (OA) and fluorescein isothiocyanate-dextran (FITC-d) were used as the interstitial tracers. Rats that did not receive sonication showed an expected interstitial distribution of OA and FITC-d around the injection site, with a wider volume distribution of OA (21.8 ± 4.0 µL) compared to that of FITC-d (7.8 ± 2.7 µL). Remarkably, nearly half of the rats exposed to the FUS developed intracerebral hemorrhaging (ICH), with a significantly higher volume of bleeding compared to a minor red blood cell extravasation from the animals that were not exposed to sonication. This finding suggests that the local cerebrovascular injury inflicted by the micro-injection was further exacerbated by the application of sonication, particularly during the acute stage of injury. Smaller tracer volume distributions and weaker fluorescent intensities, compared to the unsonicated animals, were observed for the sonicated rats that did not manifest hemorrhaging, which may indicate an enhanced degree of clearance of the injected tracers. Our results call for careful safety precautions when ultrasound sonication is desired among groups under elevated risks associated with a weakened or damaged vascular integrity. Full article

(This article belongs to the Special Issue Ultrasound-Mediated Drug Delivery)

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Review

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39 pages, 2718 KiB

Open AccessReview

Tumor Spheroids as Model to Design Acoustically Mediated Drug Therapies: A Review

by Marie Roy, Corentin Alix, Ayache Bouakaz, Sophie Serrière and Jean-Michel Escoffre

Pharmaceutics 2023, 15(3), 806; https://doi.org/10.3390/pharmaceutics15030806 - 01 Mar 2023

Cited by 4 | Viewed by 2945

Abstract

Tumor spheroids as well as multicellular tumor spheroids (MCTSs) are promising 3D in vitro tumor models for drug screening, drug design, drug targeting, drug toxicity, and validation of drug delivery methods. These models partly reflect the tridimensional architecture of tumors, their heterogeneity and [...] Read more.

Tumor spheroids as well as multicellular tumor spheroids (MCTSs) are promising 3D in vitro tumor models for drug screening, drug design, drug targeting, drug toxicity, and validation of drug delivery methods. These models partly reflect the tridimensional architecture of tumors, their heterogeneity and their microenvironment, which can alter the intratumoral biodistribution, pharmacokinetics, and pharmacodynamics of drugs. The present review first focuses on current spheroid formation methods and then on in vitro investigations exploiting spheroids and MCTS for designing and validating acoustically mediated drug therapies. We discuss the limitations of the current studies and future perspectives. Various spheroid formation methods enable the easy and reproducible generation of spheroids and MCTSs. The development and assessment of acoustically mediated drug therapies have been mainly demonstrated in spheroids made up of tumor cells only. Despite the promising results obtained with these spheroids, the successful evaluation of these therapies will need to be addressed in more relevant 3D vascular MCTS models using MCTS-on-chip platforms. These MTCSs will be generated from patient-derived cancer cells and nontumor cells, such as fibroblasts, adipocytes, and immune cells. Full article

(This article belongs to the Special Issue Ultrasound-Mediated Drug Delivery)

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