期刊名称:Proceedings of the National Academy of Sciences
印刷版ISSN:0027-8424
电子版ISSN:1091-6490
出版年度:2015
卷号:112
期号:18
页码:5579-5584
DOI:10.1073/pnas.1500622112
语种:English
出版社:The National Academy of Sciences of the United States of America
摘要:SignificanceA basic requirement in biomedical research is the ability to specifically target cells and tissues. Targeting typically relies on the specific binding of a "ligand" on a tailor-made probe to a "receptor" on the desired cell/tissue. Conventional probes efficiently distinguish a biological entity displaying the receptor from others that do not, but exhibit limited selectivity when the entities to be distinguished display a given receptor at different densities. Multivalent probes that bind several receptors simultaneously potentially can sharply discriminate between different receptor densities. We demonstrate how such "superselective" binding can be tuned through probe design to target a desired receptor density, and thus lay the foundation for the rational design of a new generation of analytical, diagnostic, and therapeutic probes. Specific targeting is common in biology and is a key challenge in nanomedicine. It was recently demonstrated that multivalent probes can selectively target surfaces with a defined density of surface binding sites. Here we show, using a combination of experiments and simulations on multivalent polymers, that such "superselective" binding can be tuned through the design of the multivalent probe, to target a desired density of binding sites. We develop an analytical model that provides simple yet quantitative predictions to tune the polymer's superselective binding properties by its molecular characteristics such as size, valency, and affinity. This work opens up a route toward the rational design of multivalent probes with defined superselective targeting properties for practical applications, and provides mechanistic insight into the regulation of multivalent interactions in biology. To illustrate this, we show how the superselective targeting of the extracellular matrix polysaccharide hyaluronan to its main cell surface receptor CD44 is controlled by the affinity of individual CD44-hyaluronan interactions.