Potential of a CO2-Responsive supramolecular drug-carrier system as a safer and more effective treatment for cancer
Enyew Alemayehu Bayle, Fasih Bintang Ilhami, Jem-Kun Chen, Chih‐Chia Cheng
Abstract
We combined carbon dioxide (CO 2 )-responsive cytosine-containing rhodamine 6G (Cy-R6G) as a hydrophobic anticancer agent with hydrogen-bonded cytosine-functionalized polyethylene glycol (Cy-PEG) as a hydrophilic supramolecular carrier to construct a CO 2 -responsive drug delivery system, with the aim of enhancing the responsiveness of the system to the tumor microenvironment and thus the overall effectiveness of anticancer therapy. Due to self-complementary hydrogen bonding interactions between cytosine units, Cy-R6G and Cy-PEG co-assemble in water to form spherical-like nanogels, with Cy-R6G effectively encapsulated within the nanogels. The nanogels exhibit several distinctive physical features, such as widely tunable nanogel size and drug loading capacity for Cy-R6G, intriguing fluorescence properties, high co-assembled structural stability in normal aqueous environments, enhanced anti-hemolytic characteristics, sensitive dual CO 2 /pH-responsive behavior, and precise and easily controllable CO 2 -induced release of Cy-R6G. Cytotoxicity assays clearly indicated that, due to the presence of cytosine receptors on the surface of cancer cells, Cy-R6G-loaded nanogels exert selective cytotoxicity against cancer cells in pristine culture medium, but do not affect the viability of normal cells. Surprisingly, in CO 2 -rich culture medium, Cy-R6G-loaded nanogels exhibit a further significant enhancement in cytotoxicity against cancer cells, and remain non-cytotoxic to normal cells. More importantly, a series of in vitro experiments demonstrated that compared to pristine culture medium, CO 2 -rich culture medium promotes more rapid selective internalization of Cy-R6G-loaded nanogels into cancer cells through cytosine-mediated macropinocytosis and thus accelerates the induction of apoptosis. Therefore, this newly developed system provides novel avenues for the development of highly effective CO 2 -responsive drug delivery systems with potent anticancer capabilities. A new drug delivery system composed of a cytosine-functionalized CO 2 -responsive anticancer agent and polymer nanocarrier not only undergoes accelerated selective internalization into cancer cells in hypercapnic-like tumor microenvironments, but also confers significantly enhanced cytotoxicity and induces massive levels of apoptosis, and could therefore achieve safer, more effective anticancer chemotherapy. • CO 2 -responsive supramolecular Cy-R6G/Cy-PEG system was successfully established. • Cy-R6G and Cy-PEG effectively co-assemble into spherical-like nanogels in water. • A CO 2 -rich microenvironment significantly accelerates selective uptake of nanogels by cancer cells. • Cy-R6G-loaded Cy-PEG nanogels induce massive apoptosis in cancer cells. • This system holds potential to make cancer treatment safer and more effective.