Polymeric micelles are demonstrating high potential as nanomedicines capable of controlling the distribution and function of loaded bioactive agents in the body, effectively overcoming biological barriers, and various formulations are engaged in intensive preclinical and clinical testing. This Review focuses on polymeric micelles assembled through multimolecular interactions between block copolymers and the loaded drugs, proteins, or nucleic acids as translationable nanomedicines. The aspects involved in the design of successful micellar carriers are described in detail on the basis of the type of polymer/payload interaction, as well as the interplay of micelles with the biological interface, emphasizing on the chemistry and engineering of the block copolymers. By shaping these features, polymeric micelles have been propitious for delivering a wide range of therapeutics through effective sensing of targets in the body and adjustment of their properties in response to particular stimuli, modulating the act...

Block Copolymer Micelles in Nanomedicine Applications.

Bubbles in liquids, soft and squeezy objects made of gas and vapour, yet so strong as to destroy any material and so mysterious as at times turning into tiny light bulbs, are the topic of the present report. Bubbles respond to pressure forces and reveal their full potential when periodically driven by sound waves. The basic equations for nonlinear bubble oscillation in sound fields are given, together with a survey of typical solutions. A bubble in a liquid can be considered as a representative example from nonlinear dynamical systems theory with its resonances, multiple attractors with their basins, bifurcations to chaos and not yet fully describable behaviour due to infinite complexity. Three stability conditions are treated for stable trapping of bubbles in standing sound fields: positional, spherical and diffusional stability. Chemical reactions may become important in that respect, when reacting gases fill the bubble, but the chemistry of bubbles is just touched upon and is beyond the scope of the present report. Bubble collapse, the runaway shrinking of a bubble, is presented in its current state of knowledge. Pressures and temperatures that are reached at this occasion are discussed, as well as the light emission in the form of short flashes. Aspherical bubble collapse, as for instance enforced by boundaries nearby, mitigates most of the phenomena encountered in spherical collapse, but introduces a new effect: jet formation, the self-piercing of a bubble with a high velocity liquid jet. Examples of this phenomenon are given from light induced bubbles. Two oscillating bubbles attract or repel each other, depending on their oscillations and their distance. Upon approaching, attraction may change to repulsion and vice versa. When being close, they also shoot self-piercing jets at each other. Systems of bubbles are treated as they appear after shock wave passage through a liquid and with their branched filaments that they attain in standing sound fields. The N-bubble problem is formulated in the spirit of the n-body problem of astrophysics, but with more complicated interaction forces. Simulations are compared with three-dimensional bubble dynamics obtained by stereoscopic high speed digital videography.

Physics of bubble oscillations

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Two Dimensional Phase Unwrapping Theory Algorithms And Software

The fast development of photoactivation for cancer treatment provides an efficient photo-therapeutic strategy for cancer treatment, but traditional photodynamic or photothermal therapy suffers from the critical issue of low in vivo penetration depth of tissues. As a non-invasive therapeutic modality, sonodynamic therapy (SDT) can break the depth barrier of photoactivation because ultrasound has an intrinsically high tissue-penetration performance. Micro/nanoparticles can efficiently augment the SDT efficiency based on nanobiotechnology. The state-of-art of the representative achievements on micro/nanoparticle-enhanced SDT is summarized, and specific functions of micro/nanoparticles for SDT are discussed, from the different viewpoints of ultrasound medicine, material science and nanobiotechnology. Emphasis is put on the relationship of structure/composition-SDT performance of micro/nanoparticle-based sonosensitizers. Three types of micro/nanoparticle-augmented SDT are discussed, including organic and inorganic sonosensitizers and micro/nanoparticle-based but sonosensitizer-free strategies to enhance the SDT outcome. SDT-based synergistic cancer therapy augmented by micro/nanoparticles and their biosafety are also included. Some urgent critical issues and potential developments of micro/nanoparticle-augmented SDT for efficient cancer treatment are addressed. It is highly expected that micro/nanoparticle-augmented SDT will be quickly developed as a new and efficient therapeutic modality which will find practical applications in cancer treatment. At the same time, fundamental disciplines regarding materials science, chemistry, medicine and nanotechnology will be advanced.

Micro/Nanoparticle-Augmented Sonodynamic Therapy (SDT): Breaking the Depth Shallow of Photoactivation.

Acoustic cavitation has been shown to play a key role in a wide array of novel therapeutic ultrasound applications. This paper presents a brief discussion of the physics of thermally relevant acoustic cavitation in the context of high-intensity focussed ultrasound (HIFU). Models for how different types of cavitation activity can serve to accelerate tissue heating are presented, and results suggest that the bulk of the enhanced heating effect can be attributed to the absorption of broadband acoustic emissions generated by inertial cavitation. Such emissions can be readily monitored using a passive cavitation detection (PCD) scheme and could provide a means for real-time treatment monitoring. It is also shown that the appearance of hyperechoic regions (or bright-ups) on B-mode ultrasound images constitutes neither a necessary nor a sufficient condition for inertial cavitation activity to have occurred during HIFU exposure. Once instigated at relatively large HIFU excitation amplitudes, bubble activity tends to grow unstable and to migrate toward the source transducer, causing potentially undesirable pre-focal damage. Potential means of controlling inertial cavitation activity using pulsed excitation so as to confine it to the focal region are presented, with the intention of harnessing cavitation-enhanced heating for optimal HIFU treatment delivery. The role of temperature elevation in mitigating bubble-enhanced heating effects is also discussed, along with other bubble-field effects such as multiple scattering and shielding.

/pdf/role-of-acoustic-cavitation-in-the-delivery-and-monitoring-yl5f0v0dlm.pdf

Role of acoustic cavitation in the delivery and monitoring of cancer treatment by high-intensity focused ultrasound (HIFU)

Cloud cavitation is potentially the most destructive form of cavitation. When the cloud cavitation is acoustically forced into a collapse, it has the potential to concentrate a very high pressure, more than 100 times the acoustic pressure, at its center. We experimentally investigate a method to control the collapse of high intensity focused ultrasound (HIFU)-induced cloud cavitation to fragment kidney stones. Our study examines a novel two-frequency wave designed to control the cloud cavitation (cavitation control [C-C] waveform); a high-frequency ultrasound pulse (1 to 4 MHz) to create the cloud cavitation and a low-frequency trailing pulse (545 kHz) following the high-frequency pulse to force the cloud into collapse. High-speed photography has revealed that a localized distribution of the cloud cavitation can be produced within 1 mm on the solid surface by the high-frequency pulse. The low-frequency ultrasound was irradiated to the high-frequency-induced cloud cavitation. A subsequent shock wave emitted from the cloud cavitation was observed both in the shadowgraph photography and the remote hydrophone measurement. Furthermore, in vitro erosion tests of model and natural stones were conducted. In the case of model stones, the erosion rate of the C-C waveform showed a distinct advantage with the combined high- and low-frequency waves over either wave alone. Natural stones were eroded and most of the resulting fragments were less than 1 mm in diameter. The results show that the control of the cloud cavitation has untapped potential for the lithotripsy applications upon further optimization of the ultrasound parameters and complementary in vivo studies.

Cloud cavitation control for lithotripsy using high intensity focused ultrasound.

In the medical ultrasound field, microbubbles have recently been the subject of much interest. Controlling actively the effect of the microbubbles, a novel therapeutic method has been investigated. In this paper, our works on high intensity focused ultrasound (HIFU) lithotripsy with cavitating microbubbles are reviewed and the cavitation detection method to optimize the HIFU intensity is investigated. In the HIFU lithotripsy, collapse of the cloud cavitation is used to fragment kidney stones. Cloud cavitation is potentially the most destructive form of cavitation. When the cloud cavitation is acoustically forced into a collapse, it has the potential to concentrate a very high pressure. For the control of the cloud cavitation collapse, a novel two-frequency wave (cavitation control [C-C] waveform) is designed; a high-frequency ultrasound pulse (1-4 MHz) to create the cloud cavitation and a low-frequency trailing pulse (500 kHz) following the high-frequency pulse to force the cloud into collapse. High-speed photography showed the cavitation collapse on the stone and the shock-wave emission from the cloud. In vitro erosion tests of model and natural stones were also conducted. In the case of model stones, the erosion rate of the C-C waveform showed a distinct advantage with the combined high- and low-frequency waves over either wave alone. For the optimization of the high-frequency ultrasound intensity, the subharmonic acoustic pressure was examined. The results showed relationship between the subharmonic pressure from cavitating bubbles induced by the high-frequency ultrasound and eroded volume of the model stones. Natural stones were eroded and most of the resulting fragments were less than 1 mm in diameter. The method has the potential to provide a novel lithotripsy system with small fragments and localized cavitating bubbles on a stone.

High intensity focused ultrasound lithotripsy with cavitating microbubbles.

Sonodynamic therapy (SDT) consists of the synergetic interaction between ultrasound and a chemical agent. In SDT, the cytotoxicity is triggered by ultrasonic stimuli, notably through cavitation. The unique features of SDT are relevant in the clinical context more than ever: the need for efficacy, accuracy, and safety while being noninvasive and preserving the patient's quality of life. However, despite the promising results of this technique, only a few clinical reports describe the use of SDT. The objective of this article is to provide an extensive overview of the clinical and preclinical research conducted in vivo on SDT, to identify the limitations, and to detail the developed strategies to overcome them.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/jum.14733

Sonodynamic Therapy: Advances and Challenges in Clinical Translation.

Medical ultrasound with microbubbles

Background: 5-Aminolevulinic acid (5-ALA) has already been applied clinically as a photosensitizer. In this study, sonodynamically induced selective antitumour effect of 5-ALA for deep-seated lesions was evaluated. Materials and Methods: First, normal rat brains were sonicated via a transducer placed on the dural surface to confirm safe acoustic conditions for normal rat brains. One week after inoculation of brains with C6 rat glioma cells, brains with/without administration of 5-ALA (100 mg/kg body weight) were sonicated. Results: Sonodynamic therapy (SDT) with 5-ALA and focused ultrasound (10 W/cm 2 , 1.04 MHz, 5 min) achieved selective antitumour effect against deep-seated experimental glioma. Mean tumour sizes in the largest coronal section in sham-operated rats and rats receiving ultrasound with/without 5-ALA were 29.94±10.39, 18.32±5.69 and 30.81±9.65 mm 2 , respectively. Tumour size was significantly smaller in the SDT group than in other groups (p<0.05). Conclusion: This experimental rat model showed that SDT appears to be useful in the treatment of deep-seated malignant glioma. Human malignant glial tumours, particularly glioblastomas, strongly invade neighbouring tissue and cannot be completely resected surgically, even with up-to-date technologies, such as the neuronavigator or photodynamic diagnosis (PDD). Fewer than half of such patients survive more than 1 year, and 5-year survival is only 5 to 8%, even when all treatment modalities, including radio-chemo-immunotherapy are applied (1). More aggressive therapy is required to eradicate unresectable nests of tumour cells invading adjacent normal brain tissue. 5-Aminolevulinic acid (5-ALA) is a natural porphyrin precursor that has already been used in PDD and photodynamic therapy (PDT) for human glioma. Therefore, it is easy to apply to the treatment of human brain tumours, unlike other materials. PDT has been extensively investigated as a treatment for various brain tumours and has been applied in clinical trials (2). The selective antitumour effect of PDT is based on selective uptake of a photosensitizer by neoplastic tissue (3-5). However, it is quite difficult to focus PDT on deep-seated tumours and selectively kill the tumour cells without placing indwelling optical fibers directly into tumours (6). In contrast, the energy of focused ultrasound can be delivered into deep- seated lesions and can be focused into a small volume (7-9). Furthermore, Fry et al. reported that they were able to create focused ultrasound-induced lesions in brains of craniectomized cat through a formaldehyde-fixed human skull (10). Hynynen et al. also created focal lesions in rabbit brains through a piece of human skull (11). By adjusting the acoustic intensity of the ultrasound, hazardous effects to surrounding tissues can be minimized (12). In addition, the photosensiting haematoporphyrin derivative and antitumour drugs (13, 14) have been found to localise selectively in some tumour cells and to be activated by ultrasound, resulting in a significant antitumour effect. Sonodynamic therapy (SDT) has the potential to be very a useful and noninvasive treatment in the future if it can destroy deep-seated brain tumour by sonication through the human skull while avoiding destruction of surrounding normal brain tissue. We investigated the antitumour effect of SDT in experimental rat glioma by using focused ultrasound in combination with 5-ALA.

Shin Yoshizawa

Papers

Cloud cavitation control for lithotripsy using high intensity focused ultrasound.

High intensity focused ultrasound lithotripsy with cavitating microbubbles.

Sonodynamic Therapy: Advances and Challenges in Clinical Translation.

Medical ultrasound with microbubbles

Sonodynamic therapy with 5-aminolevulinic acid and focused ultrasound for deep-seated intracranial glioma in rat.