Curcumin (Cur) is a naturally occurring anticancer drug isolated from the Curcuma longa plant. It is known to exhibit anticancer properties via inhibiting the STAT3 phosphorylation process. However, its poor water solubility and low bioavailability impede its clinical application. Herein, we used organoplatinum(II) ← pyridyl coordination-driven self-assembly and a cucurbit[8]uril (CB[8])-mediated heteroternary host–guest complex formation in concert to produce an effective delivery system that transports Cur into the cancer cells. Specifically, a hexagon 1, containing hydrophilic methyl viologen (MV) units and 3,4,5-Tris[2-[2-(2-methoxyethoxy)ethoxy]ethoxy]benzoyl groups alternatively at the vertices, has been synthesized and characterized by several spectroscopic techniques. The MV units of 1 underwent noncovalent complexation with CB[8] to yield a host–guest complex 4. Cur can be encapsulated in 4, via a 1:1:1 heteroternary complex formation, resulting in a water-soluble host–guest complex 5. The host–guest complex 5 exhibited ca. 100-fold improved IC₅₀ values relative to free Cur against human melanoma (C32), melanoma of rodents (B16F10), and hormone-responsive (MCF-7) and triple-negative (MDA-MB231) breast cancer cells. Moreover, strong synergisms of Cur with 1 and 4 with combinatorial indexes of <1 across all of the cell lines were observed. An induced apoptosis with fragmented DNA pattern and inhibited expression of phosphor-STAT3 supported the improved therapeutic potential of Cur in heteroternary complex 5. Significance Despite decades of research, the development of efficient strategies that can effectively deliver poorly water-soluble anticancer drugs remains a challenge. Hierarchical self-assembly strategy allows combining multiple therapeutic agents to produce a synergistic effect, thus enhancing the therapeutic efficacy. Herein we describe a hierarchical approach to solubilize a hydrophobic anticancer drug, curcumin in water via a combination of coordination-driven self-assembly and host–guest interactions. The water-soluble orthogonal self-assembly constructed by a hexagonal Pt(II) metallacycle, cucurbit[8]uril, and curcumin exhibited enhanced anticancer activity against melanoma and breast cancer cells compared with the corresponding precursors. This paper provides a platform for efficient delivery of hydrophobic anticancer drugs to cancer cells by the judicious implementation of multiple orthogonal interactions in a single process.

Contact lens as controllable route for ocular drug delivery.