Molecular heterogeneity of the vascular endothelium revealed by in vivo phage display.

Abstract

Vascular beds are known to differ in structure and metabolic function, but less is known about their molecular diversity. We have studied organ-specific molecular differences of the endothelium in various tissues by using in vivo screening of peptide libraries expressed on the surface of a bacteriophage. We report here that targeting of a large number of tissues with this method yielded, in each case, phage that homed selectively to the targeted organ. Different peptide motifs were recovered from each of these tissues. The enrichment in homing to the target organs relative to an unselected phage was 3-35-fold. Peptide sequences that conferred selective phage homing to the vasculature of lung, skin, and pancreas were characterized in detail. Immunohistochemistry showed that the phage localized in the blood vessels of their target organ. When tested, the phage homing was blocked in the presence of the cognate peptide. By targeting several tissues and by showing that specific homing could be achieved in each case, we provide evidence that organ-and tissue-specific molecular heterogeneity of the vasculature is a general, perhaps even universal, phenomenon. Our results also show that these molecular differences can serve as molecular addresses. ( J. Clin. Invest.

Targeting adenovirus

“…Multiple peptide ligands have been identified which home to particular organs such as the lung, brain, skin, intestines and pancreas, as well as peptides which home to tumors. 16 However, it remains to be seen whether such peptides are functional in directing adenovirus to these targets.…”

Modeling metastasis in the mouse

“…Some evidence suggests the existence of an address system whereby tumor cells preferentially recognize and adhere to organ-speci®c vasculature or stroma. This idea is supported by studies that have identi®ed the existence of organ-speci®c vascular cell-surface markers (Pasqualini and Ruoslahti, 1996;Rajotte et al, 1998). In fact, the redirection of tumor cell metastasis to the bone has been achieved in vivo in mice through the forced expression of a4b1 integrin on the surface of tumor cells (Matsuura et al, 1996).…”

Targeting the inflamed synovium: The quest for specificity

“…This technique has been successfully used to demonstrate substantial molecular heterogeneity between tissues. After injection of a peptide phage library into mice, unique binding sequences were identified for every tissue examined (55), and similarly encouraging results were found when a library was screened in a human subject (56). Because of the ethical and technical considerations of using this technology in humans and the fact that endothelial cells have a tendency to dedifferentiate under culture conditions (57), xenograft models have been used, in which human tissues are transplanted into immunodeficient animals prior to intravenous injection of a phage library.…”