CO2-Responsive drug delivery system created by supramolecular design and assembly for safer, more effective cancer therapy

We developed a carbon dioxide (CO2)-responsive supramolecular drug carrier system through a combination of hydrophobic CO2-sensitive imidazole-containing rhodamine 6G (I-R6G) as an efficient anticancer agent and hydrophilic ureido-cytosine (UrCy) end-capped polyethylene glycol (UrCy-PEG) as a self-assembled nanocarrier that could potentially enhance the safety and efficiency of cancer treatment. Owing to the self-complementary quadruple hydrogen bonding interactions between the UrCy moieties at the polymer chain ends, UrCy-PEG can spontaneously self-assemble into spherical-like nanoobjects in water that can effectively encapsulate hydrophobic I-R6G and form co-assembled nanoparticles with tunable sizes (depending on the I-R6G loading content). These nanoparticles display several notable physical features, including high structural stability in normal physiological aqueous media or red blood cell-containing media, unique CO2-responsiveness, and controlled CO2-sensitive I-R6G release. In vitro cytotoxicity assays clearly indicated I-R6G-loaded nanoparticles exerted selective cytotoxicity towards cancer cells, but had no adverse effects on normal cells. I-R6G-loaded nanoparticles exerted significantly higher levels of cytotoxicity at lower doses in CO2-treated cell culture media compared to I-R6G-loaded nanoparticles in pristine media. More importantly, cellular assays demonstrated that-in comparison to I -R6G-loaded nanoparticles in pristine media-CO2-treated culture media accelerated macropinocytic internalization of I-R6G-loaded nanoparticles into cancer cells, and subsequently led to more rapid induction of apoptosis in cancer cells and massive programmed cell death. Thus, this newly created system may act as a potential route to manipulate the drug delivery and release performance of selfassembled nanobjects for efficient cancer therapy. & COPY; 2023 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Automated summary

We developed a CO2-responsive supramolecular drug carrier system using hydrophobic CO2-sensitive imidazole-containing rhodamine 6G (I-R6G) as an anticancer agent and hydrophilic ureido-cytosine (UrCy) end-capped polyethylene glycol (UrCy-PEG) as a self-assembled nanocarrier. The system showed high stability, CO2 responsiveness, and controlled release of I-R6G. In vitro cytotoxicity assays demonstrated selective cytotoxicity towards cancer cells, higher levels of cytotoxicity in CO2-treated media, and accelerated internalization and apoptosis induction in cancer cells. This system has potential for efficient cancer therapy.