Supramolecular co-encapsulation of a photosensitizer and chemotherapeutic drug in cucurbit[8]uril for potential chemophototherapy

Abstract

Supramolecular strategies as well as combinatorial approaches have been proposed to improve cancer therapeutics. In this work, we investigated the encapsulation of the photosensitizer acridine orange (AO) and the chemotherapeutic drug oxaliplatin (OxPt) in cucurbit[8]uril (CB[8]), and tested their effect both separate and combined on tumoral cells cultivated in vitro. Binding constants and enthalpies of reaction for the AO@CB[8], (AO) 2 @CB[8] and OxPt@CB[8] complexes were determined by isothermal titration calorimetry. In the case of AO, a negative cooperativity for the binding of the second AO molecule was found, in agreement with previous fluorescence titration data. We show herein that the AO@CB[8] complex was effectively incorporated within the cells and showed important phototoxicity, while the OxPt@CB[8] complex was cytotoxic only at long incubation times (24 h). Pre-treatment of the cells with the OxPt@CB[8] complex for 24 h inhibited any photodynamic action by the later treatment with the AO@CB[8] complex. However, when both complexes were co-incubated for 90 min, the combined cytotoxicity/phototoxicity was superior to any of the treatments individually. A cooperative effect was identified that added up to an extra 30% cytotoxicity/phototoxicity. The results point to an interesting system where a photosensitizer and chemotherapeutic drug are co-encapsulated in a macrocycle to develop chemophototherapy applications.

Stimuli-Responsive Cucurbit[n]uril-Based Supramolecular Nanocarriers for Delivery of Chemotherapeutics

“…In this regard, 5 μM OxPt or 0.3 μM AO was mixed with 10 μM CB [8]. 4 With respect to AO and CB [8] complexation, both 1:1 and 2:1 complexes were formed ((AO) 2 +CB [8] and AO+CB [8]). However, a 1:1 complex was reported to be favored at high concentrations of CB [8].…”

“…On the other hand, HeLa cells were treated with AO+CB [8] and irradiated with 520 nm LED for 15 min showed a 40% decrease in viability. 4 Moreover, the treatment of HeLa cells with AO+OxPt+CB [8] for 90 min only and then irradiated using 520 nm LED killed 70% of the cells. On the other hand, treatment with OxPt+CB [8] for 90 min showed minimal cytotoxicity.…”

“…thus controlling the release of their loaded guest molecules . In this regard, several studies developed stimuli-responsive supramolecular-based drug delivery nanosystems, exploiting the reversible and dynamic characteristics of the noncovalent interactions that govern the supramolecular complexes. ,− Supramolecular nanosystems can form either host–guest complexes or self-assembled nanovesicles to entrap high concentrations of hydrophilic and hydrophobic guest molecules via noncovalent interactions, such as ion-dipole interactions, π– π- stacking interactions, hydrogen bonding, etc . ,, …”

“…In addition, the surface of supramolecular nanosystems can be functionalized with various stimuli-responsive moieties enabling the release of their cargos upon exposure to external stimuli (pH, temperature, enzyme, light, and redox reactions). , Therefore, supramolecular nanosystems would reduce the off-target adverse effects of chemotherapeutics and improve their selective targeting, biological distribution, stability, solubility, and ultimately therapeutic efficiency. ,− Thus, such macrocyclic nanovesicular delivery systems hold great potential for cancer treatment and tumor targeting. This review presents state-of-the-art approaches for designing single or multiple stimuli-responsive CB-based nanovesicles for efficient cancer therapy.…”

“…Recent advances in nanotechnology allowed the development of numerous nanocarriers that have been effectively utilized for the targeted delivery of various medications. , Supramolecular systems, in particular, have been used as intelligent vehicles which can accommodate various chemotherapeutic agents and overcome their drawbacks. Furthermore, drug delivery nanosystems based on supramolecular systems can be designed to target tumors and exert sustainable release of chemotherapeutics. , …”