A new concept in cooperative adenine–uracil (A–U) hydrogen bonding interactions between anticancer drugs and nanocarrier complexes was successfully demonstrated by invoking the co-assembly of water soluble, uracil end-capped polyethylene glycol polymer (BU-PEG) upon association with the hydrophobic drug adenine-modified rhodamine (A-R6G). This concept holds promise as a smart and versatile drug delivery system for the achievement of targeted, more efficient cancer chemotherapy. Due to A–U base pairing between BU-PEG and A-R6G, BU-PEG has high tendency to interact with A-R6G, which leads to the formation of self-assembled A-R6G/BU-PEG nanogels in aqueous solution. The resulting nanogels exhibit a number of unique physical properties, including extremely high A-R6G-loading capacity, well-controlled, pH-triggered A-R6G release behavior, and excellent structural stability in biological media. Importantly, a series of in vitro cellular experiments clearly demonstrated that A-R6G/BU-PEG nanogels improved the selective uptake of A-R6G by cancer cells via endocytosis and promoted the intracellular release of A-R6G to subsequently induce apoptotic cell death, while control rhodamine/BU-PEG nanogels did not exert selective toxicity in cancer or normal cell lines. Overall, these results indicate that cooperative A–U base pairing within nanogels is a critical factor that improves selective drug uptake and effectively promotes apoptotic programmed cell death in cancer cells.
We present a breakthrough in the synthesis and development of functional gas-responsive materials as highly potent anticancer agents suitable for applications in cancer treatment. Herein, we successfully synthesised a stimuli-responsive multifunctional material (I-R6G) consisting of a carbon dioxide (CO2)-sensitive imidazole moiety and spirolactam-containing conjugated rhodamine 6G (R6G) molecule. The resulting I-R6G is highly hydrophobic and non- or weakly fluorescent. Simple CO2 bubbling treatment induces hydrophobic I-R6G to completely dissolve in water and subsequently form self-assembled nanoparticles, which exhibit unique optical absorption and fluorescence behaviours in water and extremely low haemolytic ability against sheep red blood cells. Reversibility testing indicated that I-R6G undergoes reversible CO2/nitrogen (N2)-dependent stimulation in water, as its structural and physical properties can be reversibly and stably switched by alternating cycles of CO2 and N2 bubbling. Importantly, in vitro cellular assays clearly demonstrated that the CO2-protonated imidazole moiety promotes rapid internalisation of CO2-treated I-R6G into cancer cells, which subsequently induces massive levels of necrotic cell death. In contrast, CO2-treated I-R6G was not internalised and did not affect the viability of normal cells. Therefore, this newly created system may provide an innovative and efficient route to remarkably improve the selectivity, safety and efficacy of cancer treatment.
3 (2) have been synthesized and characterized by ultraviolet−visible (UV−vis) spectroscopy, Fourier transform infrared (FTIR) spectroscopy, mass spectrometry, thermogravimetric analysis/differential thermal analysis (TGA/ DTA), X-ray diffraction (XRD), scanning electron microscopy− energy-dispersive X-ray spectroscopy (SEM-EDX), and molar conductance, and supported by density functional theory (DFT) and time-dependent DFT (TD-DFT) calculations. Square pyramidal and tetrahedral geometries are proposed for Cu(II) and Zn(II) complexes, respectively, and the XRD patterns showed the polycrystalline nature of the complexes. Furthermore, in vitro cytotoxic activity of the complexes was evaluated against the human breast cancer cell line (MCF-7). A Cu(II) centered complex with an IC 50 value of 4.09 μM was more effective than the Zn(II) centered complex and positive control, cisplatin, which displayed IC 50 values of 75.78 and 18.62 μM, respectively. In addition, the newly synthesized complexes experienced the innate antioxidant nature of the metal centers for scavenging the DPPH free radical (up to 81% at 400 ppm). The biological significance of the metal complexes was inferred from the highest occupied molecular orbital−lowest unoccupied molecular orbital (HOMO−LUMO) energy band gap, which was found to be 2.784 and 3.333 eV, respectively for 1 and 2, compared to the ligands, 1,10-phenathroline (4.755 eV) and chrysin (4.403 eV). Moreover, the molecular docking simulations against estrogen receptor alpha (ERα; PDB: 5GS4) were strongly associated with the in vitro biological activity results (E B and K i are −8.35 kcal/mol and 0.76 μM for 1, −7.52 kcal/mol and 3.07 μM for 2, and −6.32 kcal/mol and 23.42 μM for cisplatin). However, more research on in vivo cytotoxicity is suggested to confirm the promising cytotoxicity results.
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