Enhanced relative biological effectiveness of proton radiotherapy in tumor cells with internalized gold nanoparticles.

The development and use of sensitizing agents to improve the effectiveness of radiotherapy have long been sought to improve our ability to treat cancer. In this letter, we have studied the relative biological effectiveness of proton beam radiotherapy on prostate tumor cells with and without internalized gold nanoparticles. The effectiveness of proton radiotherapy for the killing of prostate tumor cells was increased by approximately 15%-20% for those cells containing internalized gold nanoparticles.

On the synergistic effects of ligand-mediated and phage-intrinsic properties during in vivo selection.

Phage display has been used as a powerful tool in the discovery and characterization of ligand-receptor complexes that can be utilized for therapeutic applications as well as to elucidate disease mechanisms. While the basic properties of phage itself have been well described, the behavior of phage in an in vivo setting is not as well understood due to the complexity of the system. Here, we take a dual approach in describing the biophysical mechanisms and properties that contribute to the efficacy of in vivo phage targeting. We begin by considering the interaction between phage and target by applying a kinetic model of ligand-receptor complexation and internalization. The multivalent display of peptides on the pIII capsid of phage is also discussed as an augmenting factor in the binding affinity of phage-displayed peptides to cellular targets accessible in a microenvironment of interest. Lastly, we examine the physical properties of the total phage particle that facilitate improved delivery and targeting in vivo compared to free peptides.

Three-dimensional tissue culture based on magnetic cell levitation.

Cell culture is an essential tool in drug discovery, tissue engineering and stem cell research. Conventional tissue culture produces two-dimensional cell growth with gene expression, signalling and morphology that can be different from those found in vivo, and this compromises its clinical relevance. Here, we report a three-dimensional tissue culture based on magnetic levitation of cells in the presence of a hydrogel consisting of gold, magnetic iron oxide nanoparticles and filamentous bacteriophage. By spatially controlling the magnetic field, the geometry of the cell mass can be manipulated, and multicellular clustering of different cell types in co-culture can be achieved. Magnetically levitated human glioblastoma cells showed similar protein expression profiles to those observed in human tumour xenografts. Taken together, these results indicate that levitated three-dimensional culture with magnetized phage-based hydrogels more closely recapitulates in vivo protein expression and may be more feasible for long-term multicellular studies.

From combinatorial peptide selection to drug prototype (II): targeting the epidermal growth factor receptor pathway.

The epidermal growth factor receptor (EGFR), a tyrosine kinase, is central to human tumorigenesis. Typically, three classes of drugs inhibit tyrosine kinase pathways: blocking antibodies, small kinase inhibitors, and soluble ligand receptor traps/decoys. Only the first two types of EGFR-binding inhibitory drugs are clinically available; notably, no EGFR decoy has yet been developed. Here we identify small molecules mimicking EGFR and that functionally behave as soluble decoys for EGF and TGFalpha, ligands that would otherwise activate downstream signaling. After combinatorial library selection on EGFR ligands, a panel of binding peptides was narrowed by structure-function analysis. The most active motif was CVRAC (EGFR 283-287), which is necessary and sufficient for specific EGFR ligand binding. Finally, a synthetic retro-inverted derivative, (D)(CARVC), became our preclinical prototype of choice. This study reveals an EGFR-decoy drug candidate with translational potential.