A CO2-Responsive Imidazole-Functionalized Fluorescent Material Mediates Cancer Chemotherapy

Abstract

We present a breakthrough in the synthesis and development of functional gas-responsive materials as highly potent anticancer agents suitable for applications in cancer treatment. Herein, we successfully synthesised a stimuli-responsive multifunctional material (I-R6G) consisting of a carbon dioxide (CO2)-sensitive imidazole moiety and spirolactam-containing conjugated rhodamine 6G (R6G) molecule. The resulting I-R6G is highly hydrophobic and non- or weakly fluorescent. Simple CO2 bubbling treatment induces hydrophobic I-R6G to completely dissolve in water and subsequently form self-assembled nanoparticles, which exhibit unique optical absorption and fluorescence behaviours in water and extremely low haemolytic ability against sheep red blood cells. Reversibility testing indicated that I-R6G undergoes reversible CO2/nitrogen (N2)-dependent stimulation in water, as its structural and physical properties can be reversibly and stably switched by alternating cycles of CO2 and N2 bubbling. Importantly, in vitro cellular assays clearly demonstrated that the CO2-protonated imidazole moiety promotes rapid internalisation of CO2-treated I-R6G into cancer cells, which subsequently induces massive levels of necrotic cell death. In contrast, CO2-treated I-R6G was not internalised and did not affect the viability of normal cells. Therefore, this newly created system may provide an innovative and efficient route to remarkably improve the selectivity, safety and efficacy of cancer treatment.

CO2-Responsive Water-Soluble Conjugated Polymers as a Multifunctional Fluorescent Probe for Bioimaging Applications

“…40−43 Thus, it is reasonable to hypothesize that bubbling CO 2 into an aqueous solution of I-PT might facilitate a rapid reaction between the imidazole side groups of I-PT with CO 2 to form imidazolium salts with a bicarbonate ion, and thereby affect the surface charge and selfassembly properties of I-PT and possibly enhance its fluorescence performance in an aqueous environment. 32,44 As expected, after bubbling CO 2 into 0.1 mg/mL I-PT aqueous solution at 25 °C for 0−600 s, the maximum fluorescence band of I-PT gradually red-shifted from 552 to 563 nm, while the fluorescence intensity also gradually increased from 2800 to 6500 (Figure 2a). This remarkable red shift and greatly enhanced fluorescence intensity may be due to the introduction of a large amount of imidazolium salt into the self-assembled spherical I-PT nanoparticles on CO 2 bubbling, thereby promoting salt-induced phase separation within the nanoparticles, eventually leading to the formation of aggregates that greatly enhance the fluorescence properties of I-PT.…”

“…Recent research reported that imidazole and imidazole-derivative materials exhibit specific selectivity and excellent adsorption/desorption characteristics for CO 2 in water or solid-state environments. − Thus, it is reasonable to hypothesize that bubbling CO 2 into an aqueous solution of I-PT might facilitate a rapid reaction between the imidazole side groups of I-PT with CO 2 to form imidazolium salts with a bicarbonate ion, and thereby affect the surface charge and self-assembly properties of I-PT and possibly enhance its fluorescence performance in an aqueous environment. , Therefore, the effects of CO 2 bubbling on the fluorescence properties and self-assembly behavior of I-PT in aqueous solution at 25 °C were subsequently explored by PL and DLS. As expected, after bubbling CO 2 into 0.1 mg/mL I-PT aqueous solution at 25 °C for 0–600 s, the maximum fluorescence band of I-PT gradually red-shifted from 552 to 563 nm, while the fluorescence intensity also gradually increased from 2800 to 6500 (Figure a).…”

“…I-R6G exhibits reversible, stable, and controllable physical properties in aqueous environments upon CO 2 and nitrogen (N 2 ) bubbling and could thus significantly improve the selectivity, efficacy, and safety of chemotherapy drugs in cancer cells. 32 In addition, a drug carrier system composed of I-R6G and multiple hydrogen-bonded supramolecular nanocarriers not only accelerated selective internalization into cancer cells in a CO 2 -rich microenvironment but also induced massive apoptotic cell death at a minimum effective dose, thus resulting in safer, more effective cancer treatment. 33,34 The findings described above demonstrate that CO 2 can efficiently improve the amphiphilic properties and self-assembly behavior of CO 2 -responsive materials to extend their applications to various fields.…”

Thermoreversible Gels Based on Chitosan Copolymers as “Intelligent” Drug Delivery System with Prolonged Action for Intramuscular Injection

“…R6G was chosen as a model dye, which radically changes its fluorescence during the transition from an aqueous medium to a hydrophobic one, both the intensity of fluorescence emission and the λ max [ 37 , 38 ]. Therefore, we study the thermograms of gels and monitor the phase transition via the fluorescence of rhodamine 6G, the fluorescence intensity of which increases when interacting with the Chit5-PEG5 polymer at 25–35 °C, and then, with further heating, the fluorescence intensity drops sharply due to the formation of a gel from disordered polymer chains around fluorophore molecules ( Figure 4 ).…”

Specific FRET Probes Sensitive to Chitosan-Based Polymeric Micelles Formation, Drug-Loading, and Fine Structural Features

“…The choice of fluorophores for FRET probes is also justified by their potential as potential medicines: Rhodamine 6G and its derivatives [ 11 , 12 ], as well as Coumarin and derivatives, are model cytostatics proposed for use as medicines [ 13 ] and as model fluorophores for studying the loading degree.…”