Encapsulation of Chemotherapeutic Drug Melphalan in Cucurbit[7]uril: Effects on Its Alkylating Activity, Hydrolysis, and Cytotoxicity

Abstract

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.

pH-Mediated Single Molecule Conductance of Cucurbit[7]uril

“…Slightly decrease for the absorption spectra of Mel was observed at pH 4 with the increasing of CB[7] ( Figure 3C ). Interestingly, this change was not observed at pH 7 ( Figure 3D ) because of the weak host-guest interaction of the complex at this pH, which is also consistent with the simulation of Mel@CB[7] complex in the docking study (Villarroel-Lecourt et al, 2018 ). Considering the rapid hydrolysis of Mel as well as the lack of obvious binding between Mel and CB[7] under alkaline conditions, subsequent conductance measurements focused on pH values at 1, 4, and 7.…”

“…The chemical structure of CB[7] and Mel are shown in Figure 3A . Mel has been reported to form 1:1 host-guest complex with CB[7], with the equilibrium binding affinity log K = 6 at pH 1 (Villarroel-Lecourt et al, 2018 ). The protonation of Mel is essential for binding to the macrocycle due to the cation-dipole interactions.…”

“…While the usability of Mel is limited to its poor water solubility at neutral pH as well as rapid hydrolysis in physiological conditions. However, the solubility and stability of Mel can be efficiently improved upon introducing CB molecule, which promotes further application for therapy (Zhang and Isaacs, 2014 ; Villarroel-Lecourt et al, 2018 ). Notably, the binding affinity between Mel and CB[7] differs as the pH changes (Villarroel-Lecourt et al, 2018 ).…”

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

“…After the incubation period, the media were removed and replaced with fresh DMEM. The cells were allowed to develop for another 24 h and the viability was measured using the MTT assay [40]. Statistical significance was assayed using the GraphPad 9 software with the one-way ANOVA test (p < 0.01).…”

A cucurbit[7]uril-based supramolecular fluorescent probe for the detection of metronidazole with high sensitivity and strong anti-interference capacity

“…[17][18][19][20][21][22][23] Among different CB[n]s, CB [7] (Figure 1) is the most widely used host molecule due to its good water solubility and its ability to the formation of the stable inclusion complexes. [24][25][26] Recently, CB [7]-based host-guest complexes have been utilized as optical sensors in drug detection. [27][28][29][30][31] Nevertheless, there are a few reports on the selective detection of drugs based on CB [7] host-guest complexes in the presence of other antibiotics.…”