Metal Ion (Fe2+ and Co2+) Induced Morphological Transformation of Self-Aggregates of Cholesterol-Tethered Bipyridine Amphiphiles: Selective Cancer Cell Killing by Pro-Drug Activation

Abstract

Design and development of diverse supramolecular self-assemblies from a single amphiphilic molecule has always been challenging, and it can have prospects in different task-specific applications. The present study reports the formation of different morphologies of self-aggregates by the inclusion of transition metals that are biologically more relevant due to their participation in biochemical reactions. A cholesterol-tethered bipyridine-appended amphiphile (CBB) has been synthesized that spontaneously formed vesicles in a 2:1 DMSO–water (v/v) solvent mixture. This vesicle undergoes metal-ion-induced transition from the vesicle to associated vesicles or sheets. The formation of the associated vesicular structure was observed in the presence of a transition metal ion, Fe2+, while morphological transformation from the vesicle to sheet took place in the presence of Co2+. Different spectroscopic and microscopic investigations showed that both the morphological transformations took place via the alteration of the molecular-level aggregation pattern from H-type (for vesicle formed by only CBB) to J-type (for the associated vesicle or sheet formed by metal ion included CBB). Moreover, the Fe2+-containing self-aggregate successfully produced reactive oxygen species (ROS, i.e., hydroxyl/superoxide radicals) from H2O2 through Fenton reactions. This unique characteristic of Fe2+ including a self-aggregate was utilized for oxidative DNA damage in the presence of H2O2. Consequently, this Fe(II)–CBB complex self-aggregate was exploited in selective and efficient killing of cancer cells owing to its high H2O2 content. Thus, Fe(II)-included self-assembly (associated vesicular aggregate) of CBB becomes the unique pro-drug activator which can selectively destroy the cancer cells through Fenton reaction even in the absence of any anticancer drug.