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.
The
formation of inclusion complexes between drugs and macrocycles
has proven to be an effective strategy to increase solubilization
and stabilization of the drug, while in several cases improving their
biological activity. In this context, we explored the formation of
an inclusion complex between chemotherapeutic drug Melphalan (Mel)
and cucurbit[7]uril (CB[7]), and studied its effect on Mel alkylating
activity, hydrolysis, and cytotoxicity. The formation of the inclusion
complex (Mel@CB[7]) was proven by absorption and fluorescence spectroscopy,
NMR, docking studies, and molecular dynamics simulations. The binding
constant for Mel and CB[7] was fairly high at pH 1 ((1.7 ± 0.7)
× 106 M–1), whereas no binding was
observed at neutral pH. The Mel@CB[7] complex showed a slightly decreased
alkylating activity, whereas the cytotoxicity on the HL-60 cell line
was maintained. The formation of the complex did not protect Mel from
hydrolysis, and this result is discussed based on the simulated structure
for the complex.
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