RESUMEN
The epidermal growth factor receptor (EGFR) is a tyrosine kinase receptor that plays a crucial role in cell differentiation and tumor progression, and its overexpression is closely associated with the development and metastasis of multiple cancers. The development of a fluorescent probe capable of targeting EGFR while simultaneously integrating diagnostic and therapeutic functions could have a profound impact on the treatment of related cancers. In this study, we developed a series of EGFR-targeting probes that consisted of an environment-sensitive 1,8-naphthalimide fluorophore, a linker unit and a targeting unit (gefitinib), using a coupling strategy. The synthesized probes were first evaluated for their spectroscopic properties and cytotoxicities against different cell lines, which were selected based on their intrinsic EGFR expression levels. Remarkably, among the probes tested, GP1 showed outstanding environmental sensitivity and exhibited a specific response to tumor cells that overexpress EGFR. Furthermore, the representative probe GP1 was evaluated for its EGFR-specific targeting ability in live-cell fluorescence imaging and in vivo xenograft imaging, as well as its in vivo anti-tumor activity. The results showed that the probe GP1 had excellent EGFR-specific targeting ability, exhibited competitive replacement behavior towards the EGFR inhibitor gefitinib, and demonstrated potent anti-tumor effects in a CT-26 tumor-bearing mouse model. Overall, as a turn-on EGFR targeting fluorescent ligand, GP1 holds immense promise as a valuable tool for tumor detection and treatment.
Asunto(s)
Antineoplásicos , Neoplasias Pulmonares , Neoplasias , Humanos , Ratones , Animales , Gefitinib/farmacología , Gefitinib/uso terapéutico , Colorantes Fluorescentes , Quinazolinas/farmacología , Receptores ErbB , Neoplasias/tratamiento farmacológico , Línea Celular Tumoral , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Neoplasias Pulmonares/patologíaRESUMEN
A novel 2-phenylquinoline-polyamine conjugate (QPC) was synthesized and characterized, its interaction with bovine serum albumin (BSA) was evaluated using UV-Vis, fluorescence and circular dichroism (CD) spectroscopy. The results showed that QPC caused a whole train of spectral variation, including enhancement of UV-vis absorption and reduction of fluorescence (FL), indicating QPC-BSA complex formed. FL results showed that the type of FL quenching waslarge static quenching, which was also accompanied with a process of dynamic quenching. Binding constants, thermodynamic parameters and docking results showed that the interaction between QPC and BSA was basically a Van der Waals, hydrogen bond and hydrophobic interaction. Synchronous and 3D-FL analysis revealed that QPC resulted in unapparent conformational alteration of BSA. The docking study suggested QPC was situated at the binding sites II of BSA, and 2-phenylquinoline moiety contributed to the hydrophobic interaction. The results of molecular dynamics revealed QPC altered the conformation of BSA, which showed that the inconsistency between experimental data and theoretical calculation results may be due to the instability of the compound.