Organic block copolymer micelle nanoparticles (NPs) have shown tremendous potential for active drug delivery in vivo. The synthesis of micelle NPs is typically controlled via methods involving cosolvent mixtures, with the assumption that the structures produced are stable following transfer to aqueous solution. Recent studies suggest that ongoing dynamic interactions occur in amphiphilic micelle NPs in solution, including fusion/fission events and unimer exchange, resulting in unexpected particle size/shape evolution. However, these dynamic nanoscale processes have never been directly observed and are not well understood. NP size and dispersity are critical parameters in dictating in vivo functional properties. Understanding the fundamental mechanisms and kinetics involved in micelle NP formation and size evolution is essential in order to effectively design next-generation polymer NP systems with controlled functionality. In this work, we use in situ liquid cell transmission electron microscopy (LCTEM) to directly observe the dynamic evolution of organic zwitterionic polymer micelle NPs in aqueous solution. The results from this study represent the first real-time imaging characterization of organic micelle NP dynamics, and provide unprecedented insight into the fundamental mechanisms and kinetics involved in micelle assembly and growth. We observe the formation of larger (~150 nm diameter) spherical NPs, by a combination of fusion events between NPs and unimer attachment from solution. Using multiparticle tracking algorithms and modeling, we are able to quantify the kinetics of individual particles, such as fusion relaxation rates, unimer attachment growth rates and the rate and directionality of motion for a range of particle sizes, and begin to understand the energetics involved in fusion and other particle interactions. We find that only a fraction of particle interactions or collisions result in fusion events, though the range of particle sizes involved in fusion is larger than expected, from the small NPs (&lt;40 nm) up to the largest sized NPs (&gt;100 nm). We correlate the in situ LCTEM results with cryo-TEM imaging of the system as-synthesized and after several bulk solution treatments that are known to increase system kinetics and trigger size evolution to demonstrate that the growth processes observed by LCTEM are not beam induced artifacts, and represent the natural rearrangement of the kinetically trapped system to more stable structures.

In situ liquid cell TEM observations of the size evolution pathways of amphiphilic polymer micelle nanoparticles

251st National Meeting (2016)

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