Bayle Enyew Alemayehu, Ilhami Fasih Bintang, Chen Jem-Kun, Cheng Chih-Chia
Graduate Institute of Applied Science and Technology, National Taiwan University of Science and Technology, Taipei, 10607, Taiwan.
Department of Natural Science, Faculty of Mathematics and Natural Science, Universitas Negeri Surabaya, Surabaya, 60231, Indonesia.
Mater Today Bio. 2024 Oct 29;29:101319. doi: 10.1016/j.mtbio.2024.101319. eCollection 2024 Dec.
We combined carbon dioxide (CO)-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-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/pH-responsive behavior, and precise and easily controllable CO-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-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 experiments demonstrated that compared to pristine culture medium, CO-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-responsive drug delivery systems with potent anticancer capabilities.
我们将二氧化碳（CO）响应性含胞嘧啶的罗丹明6G（Cy-R6G）作为一种疏水性抗癌剂，与氢键连接的胞嘧啶功能化聚乙二醇（Cy-PEG）作为亲水性超分子载体相结合，构建了一种CO响应性药物递送系统，旨在增强该系统对肿瘤微环境的响应性，从而提高抗癌治疗的整体效果。由于胞嘧啶单元之间的自互补氢键相互作用，Cy-R6G和Cy-PEG在水中共同组装形成球形纳米凝胶，Cy-R6G有效地包裹在纳米凝胶内。这些纳米凝胶具有几个独特的物理特性，如纳米凝胶尺寸和Cy-R6G的载药量可广泛调节、有趣的荧光特性、在正常水环境中具有较高的共组装结构稳定性、增强的抗溶血特性、敏感的双CO/pH响应行为以及精确且易于控制的CO诱导的Cy-R6G释放。细胞毒性试验清楚地表明，由于癌细胞表面存在胞嘧啶受体，负载Cy-R6G的纳米凝胶在原始培养基中对癌细胞具有选择性细胞毒性，但不影响正常细胞的活力。令人惊讶的是，在富含CO的培养基中，负载Cy-R6G的纳米凝胶对癌细胞的细胞毒性进一步显著增强，并且对正常细胞仍无细胞毒性。更重要的是，一系列实验表明，与原始培养基相比，富含CO的培养基通过胞嘧啶介导的巨胞饮作用促进负载Cy-R6G的纳米凝胶更快地选择性内化到癌细胞中，从而加速细胞凋亡的诱导。因此，这种新开发的系统为开发具有强大抗癌能力的高效CO响应性药物递送系统提供了新途径。
