The advent of therapeutic ultrasound (US) has extended the application of microbubbles from US imaging contrast agents to drug delivery vehicles able to breach intact vasculature, including the blood-brain barrier. These micron-sized agents are composed of a gaseous core, typically perfluorocarbon gas, encapsulated by a lipid, polymeric or protein shell. Despite their broad clinical and preclinical applications, characterization of microbubble shell fate both in the presence and absence of therapeutic US is limited. This is particularly pertinent for lipid microbubbles (the most widely used shell variant), which undergo an in-situ conversion in the presence of therapeutic US, generating nanoparticles that may no longer be confined to the intravascular space for clearance. Thus, given the increasing exploration of drug-loaded microbubbles, there is a need for chemical labeling strategies that enable quantitative and qualitative evaluation of microbubble and daughter nanobubble shell fate.<br/> <br/>Here, we present a one-pot Cu-chelation strategy that generates multimodal porphyrin-lipid microbubbles (PMBs) amenable to fluorescence, positron emission tomography and US imaging of lipid microbubble shell fate. This rapid (30 min) metal chelation maintains PMB structure, size, stability and pharmacokinetic profile. It can be applied with high efficiency across microbubbles with varying lipid acyl chain lengths (C16 through C20) and porphyrin-lipid compositions. Furthermore, this chelation remains stable following sonication and conversion of the PMBs into nanoparticles, allowing for the first time, multimodal, longitudinal, and quantifiable imaging of both microbubble and daughter nanoparticle shell fate. Ultimately, the versatility and stability of our labeling strategy allows our results to apply to a diverse arsenal of lipid microbubbles, thereby broadly informing further development and application of microbubbles as theranostic drug delivery vehicles.

<sup>64</sup>Cu chelation-enabled multimodal imaging of porphyrin-lipid micro and nanobubble shell fate: Applications in therapeutic ultrasound

256th National Meeting (2018)

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.

64Cu chelation-enabled multimodal imaging of porphyrin-lipid micro and nanobubble shell fate: Applications in therapeutic ultrasound

⁶⁴Cu chelation-enabled multimodal imaging of porphyrin-lipid micro and nanobubble shell fate: Applications in therapeutic ultrasound