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      Construction of a Tumor-Targeting Nanobubble with Multiple Scattering Interfaces and its Enhancement of Ultrasound Imaging

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          Abstract

          Introduction

          Recently, nanobubbles (NBs) have gained significant traction in the field of tumor diagnosis and treatment owing to their distinctive advantages. However, the application of NBs is limited due to their restricted size and singular reflection section, resulting in low ultrasonic reflection.

          Methods

          We synthesized a nano-scale ultrasound contrast agent (IR783-SiO 2NPs@NB) by encapsulating SiO 2 nanoparticles in an IR783-labeled lipid shell using an improved film hydration method. We characterized its physicochemical properties, examined its microscopic morphology, evaluated its stability and cytotoxicity, and assessed its contrast-enhanced ultrasound imaging capability both in vitro and in vivo.

          Results

          The results show that IR783-SiO 2NPs@NB had a “donut-type” composite microstructure, exhibited uniform particle size distribution (637.2 ± 86.4 nm), demonstrated excellent stability (30 min), high biocompatibility, remarkable tumor specific binding efficiency (99.78%), and an exceptional contrast-enhanced ultrasound imaging capability.

          Conclusion

          Our newly developed multiple scattering NBs with tumor targeting capacity have excellent contrast-enhanced imaging capability, and they show relatively long contrast enhancement duration in solid tumors, thus providing a new approach to the structural design of NBs.

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          Most cited references36

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          Orchestrating immune responses: How size, shape and rigidity affect the immunogenicity of particulate vaccines.

          Particulate carrier systems are promising drug delivery vehicles for subunit vaccination as they can enhance and direct the type of T cell response. In order to develop vaccines with optimal immunogenicity, a thorough understanding of parameters that could affect the strength and quality of immune responses is required. Pathogens have different dimensions and stimulate the immune system in a specific way. It is therefore not surprising that physicochemical characteristics of particulate vaccines, such as particle size, shape, and rigidity, affect multiple processes that impact their immunogenicity. Among these processes are the uptake of the particles from the site of administration, passage through lymphoid tissue and the uptake, antigen processing and activation of antigen-presenting cells. Herein, we systematically review the role of the size, shape and rigidity of particulate vaccines in enhancing and skewing T cell response and attempted to provide a "roadmap" for rational vaccine design.
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            Micro/nano-bubble-assisted ultrasound to enhance the EPR effect and potential theranostic applications

            Drug delivery for tumor theranostics involves the extensive use of the enhanced permeability and retention (EPR) effect. Previously, various types of nanomedicines have been demonstrated to accumulate in solid tumors via the EPR effect. However, EPR is a highly variable phenomenon because of tumor heterogeneity, resulting in low drug delivery efficacy in clinical trials. Because ultrasonication using micro/nanobubbles as contrast agents can disrupt blood vessels and enhance the specific delivery of drugs, it is an effective approach to improve the EPR effect for the passive targeting of tumors. In this review, the basic thermal effect, acoustic streaming, and cavitation mechanisms of ultrasound, which are characteristics that can be utilized to enhance the EPR effect, are briefly introduced. Second, micro/nanobubble-enhanced ultrasound imaging is discussed to understand the validity and variability of the EPR effect. Third, because the tumor microenvironment is complicated owing to elevated interstitial fluid pressure and the deregulated extracellular matrix components, which may be unfavorable for the EPR effect, few new trends in smart bubble drug delivery systems, which may improve the accuracy of EPR-mediated passive drug targeting, are summarized. Finally, the challenging and major concerns that should be considered in the next generation of micro/nanobubble-contrast-enhanced ultrasound theranostics for EPR-mediated passive drug targeting are also discussed.
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              Nanobubble-Affibody: Novel ultrasound contrast agents for targeted molecular ultrasound imaging of tumor.

              Nanobubbles (NBs), as novel ultrasound contrast agents (UCAs), have attracted increasing attention in the field of molecular ultrasound imaging for tumors. However, the preparation of uniform-sized NBs is considered to be controversial, and poor tumor selectivity in in vivo imaging has been reported. In this study, we fabricated uniform nano-sized NBs (478.2 ± 29.7 nm with polydispersity index of 0.164 ± 0.044, n = 3) using a thin-film hydration method by controlling the thickness of phospholipid films; we then conjugated the NBs with Affibody molecules to produce nano-sized UCAs referred to as NB-Affibody with specific affinity to human epidermal growth factor receptor type 2 (HER2)-overexpressing tumors. NB-Affibody presented good ultrasound enhancement, demonstrating a peak intensity of 104.5 ± 2.1 dB under ultrasound contrast scanning. Ex vivo experiments further confirmed that the NB-Affibody conjugates were capable of targeting HER2-expressing tumor cells in vivo with high affinity. The newly prepared nano-sized NB-Affibody conjugates were observed to be novel targeted UCAs for efficient and safe specific molecular imaging and may have potential applications in early cancer quantitative diagnosis and targeted therapy in the future.
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                Author and article information

                Journal
                Int J Nanomedicine
                Int J Nanomedicine
                ijn
                International Journal of Nanomedicine
                Dove
                1176-9114
                1178-2013
                22 May 2024
                2024
                : 19
                : 4651-4665
                Affiliations
                [1 ]Department of Ultrasound Medicine, Tangdu Hospital, Air Force Medical University , Xi’an, People’s Republic of China
                [2 ]Department of Pharmaceutical Chemistry and Analysis, School of Pharmacy, Air Force Medical University , Xi’an, People’s Republic of China
                Author notes
                Correspondence: Li Fan; Li Zhang, Email xxfanny@fmmu.edu.cn; lilyzhang319_20@hotmail.com
                Author information
                http://orcid.org/0009-0002-5099-5934
                http://orcid.org/0000-0003-0769-8328
                http://orcid.org/0000-0001-8719-4407
                Article
                462917
                10.2147/IJN.S462917
                11128256
                38799698
                75867e05-edf5-4161-9c7f-166b1e9a388f
                © 2024 Ma et al.

                This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms ( https://www.dovepress.com/terms.php).

                History
                : 04 February 2024
                : 13 May 2024
                Page count
                Figures: 7, Tables: 2, References: 36, Pages: 15
                Funding
                Funded by: research was funded by the National Natural Science Foundation of China;
                Funded by: National Natural Science Foundation of China, open-funder-registry 10.13039/501100001809;
                Funded by: Key Research and Development Program of Science and Technology Department of Shaanxi Province;
                Funded by: Key Research and Development Program of Science and Technology Department of Shaanxi Province;
                The research was funded by the National Natural Science Foundation of China (Funder: Li, Fan) (No. 82171962), the National Natural Science Foundation of China (Funder: Li, Zhang) (No. 81571730), the Key Research and Development Program of Science and Technology Department of Shaanxi Province (Funder: Li, Fan) (No. 2022ZDLSF01-03), and the Key Research and Development Program of Science and Technology Department of Shaanxi Province (Funder: Li, Zhang) (No. 2023YBSF-497).
                Categories
                Original Research

                Molecular medicine
                ultrasound contrast agents,nanobubbles,ceus,scattering cross-section,sio2 nps
                Molecular medicine
                ultrasound contrast agents, nanobubbles, ceus, scattering cross-section, sio2 nps

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