High viscosity is a major challenge with protein therapeutics at extremely high concentrations. To overcome this obstacle, it is essential to understand the relationship between the concentration of a protein solution and its viscosity as a function of shear rate and temperature. Here, lysozyme is a model charged globular protein having both short-ranged attraction (SA) and long-ranged repulsion (LR) that promote the formation of dynamic clusters at high concentrations. We report viscosity measurements from a micro-capillary rheometer (using only several microliters of solution) over a wide range of lysozyme solution concentrations, shear rates, and temperatures. Solution structural relaxation dynamics are also probed by dynamic light scattering (DLS). As a result of lysozyme's SALR interactions, the viscosity increased dramatically across all shear rates with increasing concentration and decreasing temperature. While most of the solutions exhibited Newtonian behavior, shear thinning was exhibited at the highest concentration (480 g/l) and lowest temperatures at shear rates above approximately 10(4 )s(-1). The onset shear rate for thinning and a structural relaxation rate estimated from a slow-mode measured by DLS are compared. These measurements provide insights into the properties of protein solutions and their microscopic structural origins.

Understanding the complex interplay of factors affecting nanoparticle accumulation in solid tumors is a challenge that must be surmounted to develop effective cancer nanomedicine. Among other unique microenvironment properties, tumor vascular permeability is an important feature of leaky tumor vessels which enables nanoparticles to extravasate. However, permeability has thus far been measured by intravital microscopy on optical window tumors, which has many limitations of its own. Additionally, mathematical models of particle tumor transport are often too complicated to be accessible to most researchers. Here, we present a more simplified and accessible mathematical model based on diffusive flux, which uses particle tumor accumulation and plasma pharmacokinetics to yield effective permeability, P eff. This model, called diffusive flux modeling (DFM), allows effects from multiple parameters to be decoupled and is also the first demonstration, to the best our knowledge, of extracting P eff values from bulk biodistribution results (e.g., routine positron emission tomography studies). The DFM equation was used to explain in vivo results of sub-20 nm nanocarriers called three-helix-micelles (3HM), particularly 3HM’s selective accumulation in different tumor models. When DFM was applied to multiple published biodistribution data, a semiquantitative comparison of various tumor models, particle size, and active targeting strategies could be made. The analysis clearly pointed out the importance of balancing multiple characteristics of nanoparticles to ensure successful treatment outcome and highlights the usefulness of this simple model for initial particle design, selection, and subsequent optimization.

The viscosity of a shear-banding wormlike micelle solution at high shear rates is investigated using capillary rheology and particle streak velocimetry. Measurements of the flow profile and pressure gradient show an extended entrance region, which exceeds a length to diameter ratio of 100, to reach a fully developed flow. We characterized this entrance region for capillaries with different cross-sections and use the results to select a downstream portion of the capillary where viscosity measurements can be made on fully developed flow. Measurements from this portion of the channel show a shear-thinning power-law behavior for all channel geometries from shear rates of 1000 s −1 to 120000 s −1 . Varying the surfactant concentration shows two distinct power-law behaviors that depend on both shear rate and concentration and are an indication of change in micelle length.

Understanding the complex interplay of factors affecting nanoparticle accumulation in solid tumors is a challenge that must be surmounted to develop effective cancer nanomedicine. The tumor microenvironment is unique in comparison to healthy tissue, possessing elevated interstitial pressure that limits convective transport, hence leaving diffusive processes to predominate especially in the tumor necrotic core. Certain tumor types such as glioblastoma multiforme and pancreatic tumor are known to be poorly permeable, making them less accessible for nanoparticle drug delivery. Evidence indicates that small and long-circulating nanoparticles are ideal for taking advantage of the enhanced permeability and retention effect, even in such intractable tumor models. Three-helix-micelle (3HM) self-assembled nanoparticles possess these characteristics, and previous studies have shown that 3HM can achieve more favorable tumor accumulation and penetration than liposomes in several tumor models. The reason for its superior performance had yet to be determined, and thus we sought to examine its passive transport into tumors. In this paper we present a simple mathematical model based on diffusive flux to describe particle accumulation in tumors with respect to particle plasma pharmacokinetics. Fitting the diffusive flux equation to in vivo particle tumor concentration yields the particle effective permeability value, which for 3HM is 2.31 ± 0.18 x 10-8 cm/s in U87MG glioblastoma and 4.25 ± 0.91 x 10-8 cm/s in HT29 colon cancer murine models. Applying this diffusive flux model to other nanoparticles reported in literature enables the effect of plasma half-life to be decoupled from particle permeability in influencing tumor accumulation, reinforced trends reported in the field regarding the impact of particle size, and provided a semi-quantitative means of comparing various tumor models. This work is also the first demonstration, to the best our knowledge, of extracting particle permeability values from bulk biodistribution data obtained via positron emission tomography, as opposed to laborious tumor optical window intravital microscopy experiments. As such the analysis provided here presents a simple and accessible tool to further enhance nanomedicine development.