In Vivo Biodistribution of Dendrimers and Dendrimer Nanocomposites — Implications for Cancer Imaging and Therapy

Our results indicate that the surface chemistry, composition, and 3-D structure of nanoparticles are critical in determining their in vivo biodistribution, and therefore the efficacy of nanodevice imaging and therapies. We demonstrate that gold/dendrimer nanocomposites in vivo, present biodistribution characteristics different from PAMAM dendrimers in a B16 mouse tumor model system. We review important chemical and biologic uses of these nanodevices and discuss the potential of nanocomposite devices to greatly improve cancer imaging and therapy, in particular radiation therapy. We also discuss major issues confronting the use of nanoparticles in the near future, with consideration of toxicity analysis and whether biodegradable devices are needed or even desirable.

Role of Epidermal Growth Factor Receptor Signaling in RAS-Driven Melanoma

ABSTRACT The identification of essential genetic elements in pathways governing the maintenance of fully established tumors is critical to the development of effective antioncologic agents. Previous studies revealed an essential role for H-RASV12G in melanoma maintenance in an inducible transgenic model. Here, we sought to define the molecular basis for RAS-dependent tumor maintenance through determination of the H-RASV12G-directed transcriptional program and subsequent functional validation of potential signaling surrogates. The extinction of H-RASV12G expression in established tumors was associated with alterations in the expression of proliferative, antiapoptotic, and angiogenic genes, a profile consistent with the observed phenotype of tumor cell proliferative arrest and death and endothelial cell apoptosis during tumor regression. In particular, these melanomas displayed a prominent RAS-dependent regulation of the epidermal growth factor (EGF) family, leading to establishment of an EGF receptor signaling loop. Genetic complementation and interference studies demonstrated that this signaling loop is essential to H-RASV12G-directed tumorigenesis. Thus, this inducible tumor model system permits the identification and validation of alternative points of therapeutic intervention without neutralization of the primary genetic lesion.