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Microbubbles (MB) are used as ultrasound (US) contrast agents in clinical settings because of their ability to oscillate upon exposure to acoustic pulses and generate nonlinear responses with a stable cavitation profile. Polymeric MB have recently attracted increasing attention as molecular imaging probes and drug delivery agents based on their tailorable acoustic responses, high drug loading capacity, and surface functionalization capabilities. While many of these applications require MB to be functionalized with biological ligands, the impact of bioconjugation on polymeric MB cavitation and acoustic properties remains poorly understood. Hence, we here evaluated the effects of MB shell hydrolysis and subsequent streptavidin conjugation on the acoustic behavior of poly(butyl cyanoacrylate) (PBCA) MB. We show that upon biofunctionalization, MB display higher acoustic stability, stronger stable cavitation, and enhanced second harmonic generation. Furthermore, functionalized MB preserve the binding capabilities of streptavidin conjugated on their surface. These findings provide insights into the effects of bioconjugation chemistry on polymeric MB acoustic properties, and they contribute to improving the performance of polymer-based US imaging and theranostic agents.

Gas-filled microbubbles (MB) are routinely used in the clinic as ultrasound contrast agents. MB are also increasingly explored as drug delivery vehicles based on their ultrasound stimuli-responsiveness and well-established shell functionalization routes. Broadening the range of MB properties can enhance their performance in both imaging and drug delivery applications. This can be promoted by systematically varying the reagents used in the synthesis of MB, which in the case of polymeric MB include surfactants. We therefore set out to study the effect of key surfactant characteristics, such as the chemical structure, molecular weight, and hydrophilic-lipophilic balance on the formation of poly(butyl cyanoacrylate) (PBCA) MB, as well as on their properties, including shell thickness, drug loading capacity, ultrasound contrast, and acoustic stability. Two different surfactant families ( i.e. , Triton X and Tween) were employed, which show opposite molecular weight vs hydrophilic-lipophilic balance trends. For both surfactant types, we found that the shell thickness of PBCA MB increased with higher-molecular-weight surfactants and that the resulting MB with thicker shells showed higher drug loading capacities and acoustic stability. Furthermore, the higher proportion of smaller polymer chains of the Triton X-based MB (as compared to those of the Tween-based ones) resulted in lower polymer entanglement, improving drug loading capacity and ultrasound contrast response. These findings open up new avenues to fine-tune the shell properties of polymer-based MB for enhanced ultrasound imaging and drug delivery applications.

Liquid/surfactant/gas interfaces are promising objects for nanoengineered multimodal contrasts, which can be used for biomedical imaging in preclinical and clinical applications. Microbubbles with the gaseous core and shell made of lipids/proteins have already acted as ultrasound (US) contrast agents for angiography. In the present work, microbubbles with a shell composed of Span 60 and Tween 80 surfactants functionalized with fluorescein isothiocyanate and gold nanorods to achieve a multimodal combination of US, fluorescence, and optoacoustic imaging are described. Optimal conditions for microbubble generation by studying the surface tension of the initial solutions and analyzing the size, stability, and charge of the resulting bubbles were found. By controlling and modifying bubbles' surface properties, an increase in stability and storage time can be achieved. The functionalization of bubbles with gold nanoparticles and a dye by using an optimally selected sonication protocol was performed. The biomedical application's potential in imaging modalities of functionalized microbubbles using a medical US device with a frequency of 50 MHz, fluorescence tomography, and raster-scanning optoacoustic mesoscopy measurements was evaluated. The obtained results are important for optimum stabilization and functionalization of gas/liquid interfaces and the following applications in the multimodal biomedical imaging., Competing Interests: The authors declare no competing financial interest., (© 2021 The Authors. Published by American Chemical Society.)