Hypoxia-Activated\nPEGylated Conditional Aptamer/Antibody\nfor Cancer Imaging with Improved Specificity

Abstract

Aptamers\nand antibodies, as molecular recognition probes, play\ncritical roles in cancer diagnosis and therapy. However, their recognition\nability is based on target overexpression in disease cells, not target\nexclusivity, which can cause on-target off-tumor effects. To address\nthe limitation, we herein report a novel strategy to develop a conditional\naptamer conjugate which recognizes its cell surface target, but only\nafter selective activation, as determined by characteristics of the\ndisease microenvironment, which, in our model, involve tumor hypoxia.\nThis conditional aptamer is the result of conjugating the aptamer\nwith PEG₅₀₀₀-azobenzene-NHS, which is responsive to hypoxia,\nhere acting as a caging moiety of conditional recognition. More specifically,\nthe caging moiety is unresponsive in the intact conjugate and prevents\ntarget recognition. However, in the presence of sodium dithionite\nor hypoxia (<0.1% O₂) or in the tumor microenvironment,\nthe caging moiety responds by allowing conditional recognition of\nthe cell-surface target, thereby reducing the chance of on-target\noff-tumor effects. It is also confirmed that the strategy can be used\nfor developing a conditional antibody. Therefore, this study demonstrates\nan efficient strategy by which to develop aptamer/antibody-based diagnostic\nprobes and therapeutic drugs for cancers with a unique hypoxic microenvironment.