Hypoxia-responsive supramolecular systems based on macrocycles and self-assembly structures

Hypoxia is closely associated with tumor progression, metastasis, therapeutic resistance, and diagnostic challenges. The timely detection of hypoxia in live cancer cells is critical for early cancer diagnosis and for monitoring the effectiveness of anticancer therapies. Recently, there has been growing interest in non-covalent supramolecular design strategies for the development of hypoxia-sensitive sensors and prodrugs. Unlike the widely employed covalent approach, supramolecular chemistry eliminates the need for complex and time-consuming synthetic processes. Instead, the individual components of the sensor autonomously self-assemble into the desired structure. This review provides an overview of hypoxia-targeted and hypoxia-activated supramolecular probes, along with their mechanisms of action in tumor diagnosis and therapy. The supramolecular systems considered are classified according to the use of certain classes of macrocycles. The role of macrocyclic derivatives in the various proposed approaches and the response patterns of hypoxic targets will also be analyzed. Various representatives of the macrocyclic platforms, namely cyclodextrins, cucurbiturils, pillararenes, (thia)calixarenes, due to their properties such as molecular recognition, are used as molecular containers-carriers for pharmaceuticals and bio-organic fluorescent dyes. As a result of complex formation, the photostability and the signal-to-noise ratio of dyes increase. In addition, the solubility of hydrophobic guests in water improves, cytotoxicity is reduced, and targeted delivery promotes the accumulation of drugs/dyes in tumor cells.