Water-soluble pillar[5]arenes: synthetic strategies, host–guest chemistry, and emerging supramolecular platforms for anticancer drug delivery

Abstract

Cavity-bearing macrocycles play a pivotal role in supramolecular chemistry, particularly in the construction of host–guest systems for biomedical applications. Although classical macrocycles such as cyclodextrins, cucurbiturils, crown ethers, and calixarenes exhibit useful molecular recognition properties, their biomedical applications are often limited by poor aqueous solubility and limited structural tunability. Pillar[n]arenes (P[n]As), a relatively recent class of rigid and highly symmetrical macrocycles, have emerged as promising alternatives for drug delivery applications. In particular, pillar[5]arene (P[5]A) offers versatile platforms for chemical functionalization at both rims, enabling the development of water-soluble derivatives (WP5As) with tunable physicochemical properties and strong host–guest binding affinities driven by multiple noncovalent interactions. Recent studies have demonstrated that WP5As can efficiently encapsulate a wide range of therapeutic agents, enhance drug solubility, and enable controlled and stimuli-responsive release. This review summarizes recent advances in the synthesis and functional modification of P[5]A derivatives and highlights their growing potential as smart supramolecular nanocarriers for cancer therapy and other biomedical applications.