Development of CO2-responsive supramolecular drug carrier system for potential application in anticancer treatment

Abstract

A strategy to construct carbon dioxide (CO2)-responsive supramolecular drug delivery systems for effective cancer treatment was successfully confirmed using self-assembled supramolecular nanoparticles containing water-soluble terminal uracil-functionalized poly(ethylene glycol) (U-PEG) as a functional carrier and CO2-sensitive imidazole-functionalized rhodamine 6 G (I-R6G) as a potent anticancer agent. Owing to the high-affinity interactions between I-R6G and U-PEG, U-PEG can effectively encapsulate I-R6G and spontaneously co-assembles into spherical nanoparticles in water, which possess tunable drug loading contents and particle sizes, unique intense fluorescence features, and good structural stability and anti-hemolytic capacity in aqueous biological environments, as well as rapid, selective CO2-responsiveness and well-controlled CO2-responsive drug release. Cytotoxicity evaluations revealed I-R6G-loaded U-PEG nanoparticles exhibited highly selective cytotoxic activity towards cancer cells, without affecting normal cells. In addition, in CO2-rich media, I-R6G-loaded nanoparticles led to higher cytotoxicity at lower doses than I-R6G-loaded nanoparticles in pristine media or pristine I-R6G in CO2-rich media. Crucially, cellular assays confirmed the presence of CO2 in the culture media substantially increased selective cell internalization of the I-R6G-loaded nanoparticles by cancer cells, and subsequently promoted intracellular release of I-R6G from the disassembled nanoparticles and subsequent reaction of I-R6G with CO2, which ultimately resulted in more rapid induction of apoptotic cancer cell death than I-R6G-loaded nanoparticles in pristine media. Therefore, the introduction of the CO2-sensitive agent I-R6G within this self-assembled nanocarrier system is an essential factor that may provide a potential way to enhance efficacy and reduce the side effects of chemotherapy.