Research progress of ultrasound-responsive drug release and drug activation strategies in cancer therapy

The controllable drug release or drug activation strategy can effectively avoid the toxic and side effects caused by traditional chemotherapeutic drugs
.

In recent years, ultrasound (US) has attracted much attention in the research of drug delivery systems due to its advantages of high tissue penetration and clinical safety
.

At the same time, the rapid development of mechanochemistry also provides new possibilities for the regulation of drug activity by ultrasound at the molecular level
.

Based on the new concept of ultrasonic mechanical force activation of drugs proposed by the previous research team (Nature Chemistry 2021, 13, 131, ACS Macro Letters, 2022, 11, 15), the use of ultrasonic mechanical force to regulate protein structure and properties (Angewandte Chemie, 2021, 60 , 1493, Angewandte Chemie, 2021, 60, 14707) and the regulation of DNA structural transition (Chemical Communications, 2021, 57, 7438) and other research results
.

Recently, the team of Prof.
Huo Shuaidong from Xiamen University and Prof.
Andreas Herrmann from the Leibniz Institute for Materials Research in Germany published a review titled "Ultrasound-controlled drug release and drug activation for cancer therapy" on Exploration, and was selected as Inside Front Cover
.

Starting from the US-responsive drug release and drug activation mechanism, this paper summarizes the main factors affecting the US response law of drug carriers, explains the relevant examples of US-responsive drug release and drug activation, and makes a comprehensive review and in-depth study of this research field.
Discussion and fresh outlook
.

Introduction Tumor is a major disease that endangers human health
.

At present, chemotherapy is still the most important means of clinical treatment of tumors.
However, serious toxic and side effects have been restricting the further application of chemotherapy drugs
.

In recent years, the development of nanotechnology has provided new possibilities for the realization of tumor-targeted therapy
.

Among them, as a trigger that can generate periodic mechanical waves, ultrasonic instruments are widely used in the controllable release and selective activation of drugs
.

With the help of mechanical and thermal effects induced by ultrasound, the stability of the drug carrier structure can be destabilized and the drug released
.

At the same time, ultrasonic mechanical force can selectively manipulate the breaking or rearrangement of chemical bonds, providing a new method for the regulation of the activity of drug molecules
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In addition, ultrasound can penetrate the skin and most tumor tissues, facilitating the uptake of drugs by tumor cells
.

Therefore, ultrasound is expected to help people minimize the toxic and side effects of drugs and achieve more precise and controllable cancer treatment
.

Fig.
1 Schematic illustration of ultrasound-responsive drug release and drug activation strategies
.

The inner ring is a schematic diagram of the ultrasonic-induced thermal and mechanical effects used to control drug release and drug activation, and the outer ring is a variety of factors that affect the ultrasonic response behavior of the carrier material
.

1 Ultrasound-responsive drug release and drug activation mechanisms Generally, ultrasound mainly affects the physical, chemical or thermal stability of drug delivery systems through its mechanical and thermal effects, thereby releasing or activating drug units for controllable treatment of diseases
.

1.
1 Mechanical effects Ultrasound-induced mechanical effects are mainly in two ways: one is stable cavitation caused by continuous oscillation of microbubbles; the other is inertial cavitation caused by rapid growth and rupture of microbubbles
.

The fluid shear force caused by the continuous oscillation of the stable cavitation microbubbles can destroy the carrier to release the drug.
At the same time, a certain shear force will also form temporary pores on the cell membrane, increase the membrane permeability, and thus enhance the cell's ability to respond to the drug.
ingestion
.

When the ultrasound reaches a certain intensity, inertial cavitation occurs
.

In short, the collapse of cavitating microbubbles will instantly generate shock waves much higher than atmospheric pressure, which in turn affects the structural stability of the drug carrier to release the drug
.

More importantly, the extensional flow force generated by this cavitation effect can also lead to the breaking of chemical bonds with lower bond energy, such as disulfide bonds (SS), hydrogen peroxide bonds (OO), and various coordination bonds.
, resulting in the transformation of the chemical structure of drug molecules, which can be used to modulate the activity of drug molecules
.

1.
2 Thermal effect The thermal effect is due to the fact that part of the sound energy is absorbed by the medium and converted into heat energy when the ultrasonic wave propagates in the medium.
There are usually two ways: one is the continuous thermal effect generated by the continuous oscillation of the cavitation microbubbles; the other is the instantaneous thermal effect of the cavitation microbubbles.
Transient thermal effects due to collapse
.

The generation of ultrasonic thermal effect is beneficial to control thermally sensitive or poorly thermally stable carriers for drug release, such as thermosensitive liposomes, polymer micelles,
etc.

2 Factors Affecting the Ultrasonic Response of the Carrier ①Strong chemical bond (Fig.
2A)
.

In general, the lower the bond energy of a chemical bond, the stronger its ultrasonic mechanical response
.

Non-covalent bonds are more responsive to ultrasound than covalent bonds
.

② Molecular weight and degree of polymerization (Fig.
2B)
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For homopolymers, the mechanical force generated by the ultrasonic effect is usually transferred through the polymer chain to force-responsive groups (force-sensitive groups)
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Since the chain length depends on the molecular weight and degree of polymerization of the polymer, the higher the molecular weight and degree of polymerization of the polymer, the stronger its ultrasonic response
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③ Molecular weight distribution (Fig.
2C)
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For non-homopolymers, due to the asymmetric distribution of molecular weight, the ultrasonic mechanical force tends to deviate during transmission, and tends to induce random fragmentation of polymer chains at non-specific sites
.

④ Polymer structure (Fig.
2D & 2E)
.

Changes in the polymer structure can lead to changes in its molecular weight distribution, which can affect the mechanical response behavior of polymer molecules
.

⑤ Supramolecular assembly (Fig.
2F)
.

Compared with the polymer chains in the free state, the polymer assembly has a larger cross-section in the entangled or expanded state, which increases the action area of ​​mechanical force, so the supramolecularly assembled carrier has higher mechanical force-responsive activity
.

⑥ Heterogeneous interface (Fig.
2G)
.

Heterogeneous interface refers to a heterogeneous system formed between nanoparticles and polymers
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The mechanical force response behavior of heterointerfaces generally decreases with increasing polymer grafting density on the nanoparticle surface, since increasing the polymer grafting density on the nanoparticle surface weakens the force distribution in individual polymer chains
.

Figure 2 Several main factors affecting the ultrasonic response of carrier materials 3.
Drug release strategies of ultrasonic response With the continuous understanding of the ultrasonic response laws of different carrier materials, a variety of ultrasonic-responsive drug delivery systems have been successfully constructed
.

In short, the general strategy is to encapsulate chemotherapeutic drugs in these carriers, temporarily shielding the drug's activity, and when the drug-carrying system reaches a specific site and applies ultrasound, the drug will be released to exert its effect
.

Such drug delivery systems mainly include microvesicles, liposomes, silicon-based nanoparticles, and polymer nanoparticles (Fig.
3)
.

Fig.
3 Research example of controlled drug release by ultrasonic response 4 Ultrasound-controlled drug activation strategy Up to now, ultrasonic-responsive drug release systems have made many progress, but such systems still face problems such as poor carrier stability, early drug leakage, Low controllability and other issues
.

To make up for these deficiencies, ultrasound-controlled drug activation strategies have begun to attract researchers' attention
.

Since ultrasound can affect the effects of covalent bonds (Fig.
4) and non-covalent bonds (Fig.
5), this strategy can achieve precise control of the structure of drug molecules or proteins by ultrasonic mechanical force at the molecular level.
Offers new ideas
.

Fig.
4 Research example of ultrasound-controlled covalent bond cleavage for drug activationFig.
5 Ultrasound-controlled non-covalent bond cleavage for drug activation and biomacromolecular structure change Basic research and application progress of drug activation strategies for cancer treatment
.

Although ultrasound has unique advantages and application prospects in drug controlled release and drug activation, some challenges still need to be overcome at this stage
.

First, in order to ensure biological safety, clinical ultrasound equipment should be used as much as possible in basic research in the laboratory, and efforts should be made to improve the mechanical response efficiency of carrier materials to high-frequency ultrasound; second, most of the current research focuses on conceptual innovation, and there is still a long way to go before the clinical application of ultrasonic regulation of drug activity; in addition, many studies have proved that nanostructures have high ultrasonic response efficiency, how to combine them with traditional polymer systems to construct a process Simple, mechanosensitive new drug delivery systems will also be the focus of the next research direction
.

Acknowledgments The School of Pharmacy of Xiamen University and the Key Laboratory of New Drug Target Research of Fujian Province are the first publishing units of this article.
Tu Li, a doctoral student and Liao Zhihuan, a master student of the School of Pharmacy, Xiamen University, are the co-first authors of this article.
Professor Huo Shuaidong and Andreas Prof.
Herrmann is the co-corresponding author
.

This work has been supported by the National Natural Science Foundation of China, the Fundamental Research Fund for Central Universities, and the Nanqiang Young Talents Project of Xiamen University
.

About the corresponding author Dr.
Shuaidong Huo, professor, doctoral supervisor Distinguished professor of “Minjiang Scholar” in Fujian Province, “Nanqiang Young Top-notch Talent A” of Xiamen University, School of Pharmacy, Xiamen University, research group of drug activity regulation, team leader’s personal experience 2006.
09 -2010.
07, Donghua University of Science and Technology, major in materials science and engineering, bachelor's degree 2010.
09-2013.
07, joint training between National Nanoscience Center and Tianjin University of Technology, master's degree 2013.
09-2016.
07, National Nanoscience Center, Ph.
D.
2014.
09-2015.
09, American Hemp Department of Chemistry, Provincial University Amherst, joint training doctoral student 2016.
10-2017.
09, Zernike Institute for Advanced Materials, University of Groningen, Netherlands, postdoctoral fellow 2017.
10-2019.
12, Leibniz Institute for Interactive Materials/RWTH Aachen University, postdoctoral fellow 2020.
01 -Up to now, the professor's research direction of the School of Pharmacy, Xiamen University has mainly focused on "overcoming biological barriers and achieving efficient delivery" and "regulating drug activity and reducing toxic and side effects", and has achieved a series of original results
.

Dr.
Andreas Herrmann, Professor, Doctoral Supervisor Deputy Director of Leibniz Institute for Interactive Materials, Germany, Director of Chemistry Department, RWTH Aachen University, Germany Personal experience 1997-2000, Max-Planck-Institute for Polymer Research, Germany, Ph.
D.
2000-2001 , Roland Berger Management Consultants, Germany, consultant 2002-2003, Swiss Federal Institute of Technology, Switzerland, postdoctoral fellow 2004-2007, Max-Planck-Institute for Polymer Research, Germany, research group leader 2007-2016, Zernike Advanced Materials Research, University of Groningen, Netherlands Institute, Professor 2017-present, Leibniz Institute for Interactive Materials / RWTH Aachen University, Professor's research direction is mainly dedicated to the development of new biomolecular structures or new technologies through chemical and biological processes, in nucleic acid and protein molecular engineering research A series of research results have been achieved in nano-biomedical applications
.

 Scan the QR code on the left to read the original text The content of this article is based on "Ultrasound-controlled drug release and drugactivation for cancer therapy" published in Review Article, Volume 1, Issue 3 of the Wiley Publishing Group's cooperative journal Exploration, DOI: 10.
1002/EXP.
20210023 Citation format: L.
Tu, Z.
Liao, Z.
Luo, Y.
-L.
Wu, A.
Herrmann, S.
Huo, Exploration 2021, 1, 20210023.
https://doi.
org/10.
1002/EXP.
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