In vivo biological fate of poly(vinylalcohol) microbubbles in mice

Abstract

Microbubbles (MBs) are used in clinical practice as vascular ultrasound contrast agents, and are gaining popularity as a platform supporting multimodal imaging and targeted therapy, facilitating drug delivery under ultrasound exposure. Here, we report on the in vivo biological impact of newly discovered MBs with promising features as a multimodal theranostic device. The shell of the air-filled MBs is made of the poly(vinyl alcohol) (PVA), a well-established, FDA-approved polymer. Nevertheless, as size, shape and dispersity can significantly impact the biological response of particulate systems, studying their fate after administration is crucial. The safety and the biodistribution of PVA MBs were analysed in vivo and ex vivo by coupling a near infrared (NIR) fluorophore on their shell: MBs accumulated mainly in liver and spleen at 24 hours post-injection with their clearance from the spleen 7 days post-dosing. A possible way of elimination was identified in macrophages ability to engulf MBs both in vitro and in vivo. One month post-dosing, transmission electron microscopy (TEM) highlighted the lack of relevant defects and the elimination of PVA MBs by Kupffer cells. This study is the first successful attempt to fill the lack of knowledge necessary to bring PVA MBs one step closer to their possible clinical use.

Long-term physical evolution of an elastomeric ultrasound contrast microbubble

“…Focusing on air-filled elastomeric PVA-shelled MBs, we demonstrated here that such agents when dispersed in water medium are found to become strongly stable over time in terms of morphology and structure, as compared to lipid-shelled MBs (months vs. hours). The system showed a good echogenicity in a range of frequencies centred at around 10 MHz, complementary to that of MBs with a lipid shell and useful to minimise the biological risks related to high-resolution imaging [11,20,57,58]. This should facilitate their use as UCAs as well as in derivatisation protocols for drug delivery and theranostics [1,7,18].…”

“…The ageing of polymer MBs mainly involves some changes in the polymer network which surrounds and sustains the MB during storing time and cavitation. Undoubtedly, the understanding of ageing is pivotal for the optimisation of the acoustic properties, injectability, and biodistribution of UCAs [2,10,11]. To this end, valuable methodologies such as confocal [12] and near-field microscopies [13][14][15], together with acoustic spectroscopy [16,17], can be used and combined to detect morphological, structural, and, thus, functional fine alterations on the MB's wall at the liquid interface.…”

Modulating ultrasound contrast generation from injectable nanodroplets for proton range verification by varying the degree of superheat

“…Besides, online ultrasound imaging (either active or passive, relying on the detection of individual acoustic signals emitted during phase change 69 ) enables realtime feedback over the course of the irradiation, and could greatly improve the microbubble localization accuracy through super-resolution ultrasound imaging. 70 While targeted microbubbles could potentially be imaged offline a few minutes post-irradiation (expecting their in vivo lifetime to be sufficient 71 ), online high frame rate imaging would allow to perform range verification both for targeted or nonfunctionalized, freely flowing contrast agents, by means of differential imaging and microbubble tracking. 70 Similarly to PET and prompt gamma imaging, at 37°C, the radiation-induced nanodroplet response is expected to rely solely on nuclear reaction products, only indirectly visualizing the proton irradiation.…”

Micro‐Bio‐Chemo‐Mechanical‐Systems: Micromotors, Microfluidics, and Nanozymes for Biomedical Applications

“…The biological fate of PVA microbubbles in CD1 mice was assessed by coupling a NIR fluorophore on the shell. [ 353 ] Thus, microbubbles accumulated mainly in the liver and spleen at 24 h after IV injection. Also, limited ultrastructural alterations were monitored in the kidneys, lungs, and liver 10 min post‐injection, but after one month, they were fully recovered.…”