Nanosuspension delivery of paclitaxel to xenograft mice can alter drug disposition and anti-tumor activity.

Paclitaxel is a common chemotherapeutic agent that is effective against various cancers. The poor aqueous solubility of paclitaxel necessitates a large percentage of Cremophor EL:ethanol (USP) in its commercial formulation which leads to hypersensitivity reactions in patients. We evaluate the use of a crystalline nanosuspension versus the USP formulation to deliver paclitaxel to tumor-bearing xenograft mice. Anti-tumor efficacy was assessed following intravenous administration of three 20 mg/kg doses of paclitaxel. Paclitaxel pharmacokinetics and tissue distribution were evaluated, and differences were observed between the two formulations. Plasma clearance and tissue to plasma ratio of mice that were dosed with the nanosuspension are approximately 33- and 11-fold higher compared to those of mice that were given the USP formulation. Despite a higher tumor to plasma ratio for the nanosuspension treatment group, absolute paclitaxel tumor exposure was higher for the USP group. Accordingly, a higher anti-tumor effect was observed in the xenograft mice that were dosed with the USP formulation (90% versus 42% tumor growth inhibition). This reduction in activity of nanoparticle formulation appeared to result from a slower than anticipated dissolution in vivo. This study illustrates a need for careful consideration of both dose and systemic solubility prior utilizing nanosuspension as a mode of intravenous delivery.

The effect of nanotopography on modulating protein adsorption and the fibrotic response.

Understanding and modulating the cellular response to implanted biomaterials is crucial for the field of tissue engineering and regenerative medicine. Since cells typically reside in an extracellular matrix containing nanoscale architecture, identifying synthetic nanostructures that induce desirable cellular behaviors could greatly impact the field. Using nanoimprint lithography, nanostructured patterns were generated on thin film polymeric materials. The ability of these surfaces to influence protein adsorption, fibroblast proliferation and morphology, and fibrotic markers was investigated. Nanostructured features with aspect ratios greater than five allowed for less protein adsorption, resulting in decreased fibroblast proliferation and rounded cellular morphology. These nanofeatures also induced significantly lower gene expression of collagen 1α2, collagen 3α1, and growth factors such as connective tissue growth factor, integrin linked kinase, transforming growth factor ß1 (TGF-ß1), and epidermal growth factor, key factors associated with a fibrotic response. The results demonstrate that select nanostructured surfaces could be used to modulate the fibrotic behavior in cells and have the potential to be used as antifibrotic architecture for medical implants or tissue engineering scaffolds.

Nano- and microfabrication for overcoming drug delivery challenges.

This highlight article describes current nano- and microfabrication techniques for creating drug delivery devices. We first review the main physiological barriers to delivering therapeutic agents. Then, we describe how novel fabrication methods can be utilized to combine many features into a single physiologically relevant device to overcome drug delivery challenges.

Nanostructure-mediated transport of biologics across epithelial tissue: enhancing permeability via nanotopography.

Herein, we demonstrate that nanotopographical cues can be utilized to enable biologics >66 kDa to be transported across epithelial monolayers. When placed in contact with epithelial monolayers, nanostructured thin films loosen the epithelial barrier and allow for significantly increased transport of FITC-albumin, FITC-IgG, and a model therapeutic, etanercept. Our work highlights the potential to use drug delivery systems which incorporate nanotopography to increase the transport of biologics across epithelial tissue.

Multivalency of Sonic hedgehog conjugated to linear polymer chains modulates protein potency.

A potently active multivalent form of the protein Sonic hedgehog (Shh) was produced by bioconjugation of a modified recombinant form of Shh to the linear polymers poly(acrylic acid) (pAAc) and hyaluronic acid (HyA) via a two-step reaction exploiting carboimiide and maleimide chemistry. Efficiency of the conjugation was approximately 75% even at stoichiometric ratios of 30 Shh molecules per linear HyA chain (i.e., 30:1 Shh/HyA). Bioactivity of the conjugates was tested via a cellular assay across a range of stoichiometric ratios of Shh molecules to HyA linear chains, which was varied from 0.6:1 Shh/HyA to 22:1 Shh/HyA. Results indicate that low conjugation ratios decrease Shh bioactivity and high ratios increase this activity beyond the potency of monomeric Shh, with approximately equal activity between monomeric soluble Shh and conjugated Shh at 7:1 Shh/HyA. In addition, high-ratio constructs increased angiogenesis determined by the in vivo chick chorioallantoic membrane (CAM) assay. These results are captured by a kinetic model of multiple interactions between the Shh/HyA conjugates and cell surface receptors resulting in higher cell signaling at lower bulk Shh concentrations.