Search

Patterns of luminal vascular protein expression vary according to tissue of origin, and these so-called vascular zip codes play an important role in the maintenance of normal physiological processes in multiorgan species. These zip codes are also often modified in response to pathology and play a critical role in the response to and recovery from disease. These differentially expressed proteins offer opportunities for organ- and disease-specific ligand-targeted molecular delivery, offering clear pharmacologic advantages to traditional systemic drug delivery. However, this approach depends on the availability of frequently elusive targets. Combinatorial screening is a valuable tool for identifying optimal ligands for targeted delivery to the vasculature, especially when adapted for in vivo selection. Here we discuss molecular heterogeneity of the vascular endothelium and the use of phage display as a combinatorial screening method to exploit this heterogeneity for tissue or disease-specific vascular targeting. We also highlight applications of this approach for both drug delivery and molecular imaging. [ABSTRACT FROM AUTHOR]

Abstract  In cancer therapy and imaging, the systemic passive delivery of particulate systems has relied on the enhanced permeability and retention (EPR) effect: sufficiently small particles can cross the endothelial fenestrations and accumulate in the tumor parenchyma. The vast majority of man-made particulates exhibit a spherical shape as a result of surface energy minimization during their synthesis. The advent of phage display libraries, which are revealing the extraordinary molecular diversity of endothelial cells, and the development of processes for fabricating particles with shapes other than spherical are opening the path to new design solutions for systemically administered targeted particulates. In this paper, the role of particle geometry (i.e., size and shape) is discussed at the tissue and cellular scales. Emphasis is placed on how the synergistic effect of particle geometry and molecular targeting can enhance the specificity of delivery. The intravascular delivery process has been broken into three events: margination, firm adhesion and control of internalization. Predictions from mathematical models and observations from in-vitro experiments were used to show the relevance of particle geometry in systemic delivery. Rational design of particulate systems should consider, beside the physico-chemical properties of the surface coatings, geometrical features as size and shape. The integration of mathematical modeling with in-vitro and in-vivo testing provides the tools for establishing a rational design of nanoparticles. [ABSTRACT FROM AUTHOR]