Click Therapy: Novel Concept in Pretargeting Drug Delivery

Abstract

Click therapy is a pretargeted therapeutic strategy that utilizes bioorthogonal click chemistry for treating cancers that overexpress cell surface receptors. In this strategy, pretargeting component and the drug delivery component undergo click reaction on the cell surface. Click chemistry is a concept of rapid and selective reactions between two functional groups under mild, convenient and reliable conditions1). This synthetic approach is now widely used in the drug development because of high yielding, wide in scope and producing only byproducts that can be removed without chromatography. Click reactions which can be performed in biological systems without interfering regular biochemical and physiological in the living systems are called bioorthogonal click chemistry. Examples of bioorthogonal click chemistry reactions and their reaction rates are shown in the Fig. 1 2). However, only few click reactions can be used as bioorthogonal click reactions in living systems, since they should be biocompatible, fast and feasible in physiological conditions. In click therapy, target-specific mAbs are delivered first to pretarget the cancer cells and are followed by the functionalized drug-carrier nanoplatform (Fig. 2). Two components react chemoselectively on the target cell surface via azide (Az) and dibenzylcyclooctyne (DBCO) (Click-1) or trans-cyclooctene (TCO) and tetrazine (Tt) (Click-2) bioorthogonal click reactions3,4). Due to the close proximity, multiple click reactions between two components are possible on cells with high receptor density on the cell surface. These reactions result in the formation of nanoclusters, which generate tension in the cell membrane and lead to rapid internalization via receptor-mediated endocytosis5).