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

doi:10.1016/j.mtbio.2024.101319

Potential of a CO₂-Responsive supramolecular drug-carrier system as a safer and more effective treatment for cancer

Mater Today Bio. 2024 Oct 29:29:101319. doi: 10.1016/j.mtbio.2024.101319. eCollection 2024 Dec.

Authors

Enyew Alemayehu Bayle¹, Fasih Bintang Ilhami^{1

2}, Jem-Kun Chen³, Chih-Chia Cheng^{1

4}

Affiliations

¹ Graduate Institute of Applied Science and Technology, National Taiwan University of Science and Technology, Taipei, 10607, Taiwan.
² Department of Natural Science, Faculty of Mathematics and Natural Science, Universitas Negeri Surabaya, Surabaya, 60231, Indonesia.
³ Department of Materials Science and Engineering, National Taiwan University of Science and Technology, Taipei, 10607, Taiwan.
⁴ Advanced Membrane Materials Research Center, National Taiwan University of Science and Technology, Taipei, 10607, Taiwan.

Abstract

We combined carbon dioxide (CO₂)-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 CO₂-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 CO₂/pH-responsive behavior, and precise and easily controllable CO₂-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 CO₂-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, CO₂-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 CO₂-responsive drug delivery systems with potent anticancer capabilities.

Keywords: CO2 responsiveness; Cytosine; Hypercapnic tumor microenvironment; Selective cellular uptake and cytotoxicity; Supramolecular drug-carrier system.