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Nanoparticles have garnered widespread interest for both the imaging and treatment of cancer due to their unique and tunable pharmacokinetics and their ability to carry a high payload of diverse compounds. However, despite these favorable attributes, the extent of tumor accumulation can be severely restricted due to the dense stroma surrounding the often-permeable blood vessel wall and high intratumoral pressure. In this study, we investigated whether modifying the surface of pegylated gold nanoparticles (AuNPs) with collagenase could improve the accumulation of nanoparticles within a murine tumor xenograft. It was determined that collagenase remains active after surface conjugation and the presence of collagenase has no measureable effect on cell proliferation in vitro. Following intravenous injection, the largest fractions of collagenase-labeled AuNPs were found in the liver and spleen. Histological analysis revealed no signs of toxicity in either of these organs. Blood chemistry revealed normal levels of liver enzymes, but a slightly elevated level of total bilirubin. Within the tumor, AuNPs labeled with collagenase exhibited a 35% increase in accumulation compared with unlabeled AuNPs. Therefore, these studies provide preliminary evidence that the functionalization of nanoparticles with collagenase represent an effective and safe approach to improve tumor accumulation.

CD44, a receptor for the extracellular matrix glycosaminoglycan hyaluronan, has been implicated in many adhesion-dependent cellular processes including tumor growth and metastasis. Soluble CD44 has been identified in the serum of normal individuals. Furthermore, tumor progression is often associated with marked increases in plasma levels of soluble CD44. Release of soluble CD44 by proteolytic cleavage (shedding) of membrane-anchored CD44 is likely to alter cellular responses to the environment due to modification of the cell surface and the potential for soluble CD44 to influence CD44-mediated hyaluronan binding to cell surfaces. Cellular activation is typically required to induce hyaluronan binding to cell surface CD44 but the affinity of endogenous soluble CD44 for hyaluronan remains unknown. In this study, we demonstrate that oncostatin M and transforming growth factor beta1 (TGF-beta1) which stimulate hyaluronan binding to HTB58 lung epithelial-derived tumor cells, also induce the release of soluble CD44. Interestingly, soluble CD44 released by oncostatin M-treated cells retained the ligand-binding properties of the membrane-anchored receptor. In contrast, soluble CD44 released from TGF-beta1-treated HTB58 cells differed in its hyaluronan-binding capacity from cell surface CD44 expressed on TGF-beta1-stimulated cells. These data indicate that the mechanisms that regulate the generation of soluble CD44 may also govern the binding of the released receptor to hyaluronan and therefore determine the impact on CD44-dependent physiologic and pathologic processes.

CD44 is a transmembrane glycoprotein known to be involved in endothelial cell recognition, lymphocyte trafficking, and regulation of cytokine gene expression in inflammatory diseases. In the present study, we demonstrated that the expression of CD44 mRNA was induced in a mouse model of cerebral ischemia. A potential role of CD44 in ischemic brain injury was investigated using CD44-deficient (CD44-/-) mice. Over 50% (p < 0.05, n = 14) and 78% (p < 0.05, n = 10) reduction in ischemic infarct was observed in CD44-/- mice compared with that of wild-type mice following transient (30 min ischemia) and permanent (24 h) occlusion of the middle cerebral artery (MCAO), respectively. Similarly, significant improvement was observed in neurological function in CD44-/- mice as evidenced by spontaneous and forced motor task scores. The marked protection from ischemic brain injury in CD44-/- mice was associated with normal physiological parameters, cytokine gene expression, astrocyte and microglia activation as compared with wild-type mice. However, in CD44-/- mice, significantly lower expression of soluble interleukin-1beta protein was noted after brain ischemia. Our data provide new evidence on the potential role of CD44 in brain tissue in response to ischemia and may suggest that this effect might be associated with selective reduction in inflammatory cytokines such as interleukin-1beta.

Oncostatin M (OSM) is a potent modulator of human lung-derived epithelial cell function. This cytokine binds two distinct receptor complexes: type I OSM receptor which is also a functional receptor for leukemia inhibitory factor (LIF), and type II OSM-specific receptor. The role of these two distinct receptors in mediating the response of individual cell types to OSM has not been delineated. In contrast to LIF, OSM induces synthesis of α1-antichymotrypsin and α1-antiproteinase inhibitor in lung-derived epithelial cells. The differential responsiveness to LIF and OSM suggested that the response of lung epithelial cells to OSM may be mediated by the OSM-specific receptor. Therefore, we characterized lung-derived epithelial cells for the expression of type II OSM receptor mRNAs, and the regulation of the mRNAs encoding the components of the OSM-specific receptor by cytokines and dexamethasone.