Light and pH responsive catanionic vesicles based on a chalcone/flavylium photoswitch for smart drug delivery: From molecular design to the controlled release of doxorubicin

Abstract

Spatially and temporally localized delivery is a promising strategy to circumvent adverse effects of traditional drug therapy such as drug toxicity and prolonged treatments. Stimuli-responsive colloidal nanocarriers can be crucial to attain such goals. Here, we develop a delivery system based on dual light and pH responsive vesicles having a cationic bis-quat gemini surfactant, 12-2-12, and a negatively charged amphiphilic chalcone, C₄SCh. The premise is to exploit the chalcone/flavylium interconversion to elicit a morphological change of the vesicles leading to the controlled release of an encapsulated drug. First, the phase behavior of the catanionic system is studied and the desirable composition yielding stable unilamellar vesicles identified and selected for further studies. The solutions containing vesicles (D_h ≈ 200 nm, ζ-potential ≈ 80 mV) are in-depth characterized by light microscopy, cryo-transmission electron microscopy (cryo-TEM), dynamic light scattering (DLS) and surface tension measurements. Upon subjecting the vesicles to UV irradiation (λ = 365 nm) at near neutral pH (≈ 6.0), no morphological effects are observed, yet when irradiation is coupled with pH = 3.0, the majority of the vesicles are disrupted into bilayer fragments. The anticancer drug doxorubicin (DOX) is successfully entrapped in the non-irradiated vesicles, yielding an encapsulation efficiency of ≈ 25% and a loading capacity of ≈ 3%. The release profile of the drug-loaded vesicles is then studied in vitro in four conditions: i) no stimuli (pH = 6.0); ii) irradiation, pH = 6.0; iii) no irradiation and adjusted pH = 3.0; iv) irradiation and adjusted pH = 3.0 Crucially, irradiation at pH = 3.0 leads to a sustained release of DOX to ca. 80% (within 4 h), whereas cases i) and ii) lead to only ≈ 25 % release and case iii) to 50% release but precipitation of the vesicles. Thus, our initial hypothesis is confirmed: we present a proof of concept delivery system where light and pH act as inputs of an AND logic gate mechanism for the controlled release of a relevant biomedical drug (output). This may prove useful if the irradiated nanocarriers meet acidified physiological environments such as tumors sites, endosomes or lysosomes.

Keywords: Anticancer drug; Catanionic vesicles; Liposomal delivery; Photoresponsive surfactant; Smart drug delivery; Stimuli-responsive nanocarriers; Sustained release.