Selection of recombinant phages binding to pathological endothelial and tumor cells of rat glioblastoma by in-vivo display

Abstract

Pathological endothelial cells are attractive targets to selectively abrogate tumor growth. However, only a few cell surface molecules to address the endothelium of pathological blood vessels are known, but it could be anticipated that many more molecular addresses associated with abnormal endothelial function and proliferation could serve as potential candidates for development of drug delivery agents. To obtain a library of peptides mediating binding of recombinant M13 phages to endothelium of experimental rat brain tumors, in-vivo display of a combinatorial heptapeptide and a splenocyte M13 library was used. Phage clones were selected that bind to rat brain tumor endothelium in-vivo and phage proteins detected in tissues by immunohistochemistry. Some of the recombinant phages diffused or were transported far into the surrounding tumor tissue, where they persisted for several days. Sequence analysis of insertion peptides revealed surprising similarities to angiogenic and anti-angiogenic factors or matrix and guidance molecules that appear to be involved in glioblastoma pathology. In-vivo phage display of recombinant M13 phages is a tool to select peptides targeting pathological endothelium. Insertion peptides, their corresponding cellular proteins and ligands might have a variety of applications in providing molecular tools for targeting tumor vascular beds with diagnostic probes and therapeutic substances and might open new opportunities for treating frequently fatal glial tumors.