Lanthanide MOF-based luminescent sensor arrays for the detection of castration-resistant prostate cancer curing drugs and biomarkers

Abstract

In recent years, castration-resistant prostate cancer (CRPC) has profoundly impacted the lives of many men, and early diagnosis of medication and illness is crucial. Therefore, a highly efficient detection method for CRPC biomarkers and curing drugs is required. However, the complex and diverse structures of CRPC drugs pose significant challenges for their detection and differentiation. Lanthanide metal-organic frameworks (Ln-MOFs) show great potential for sensing applications due to their intense and characteristic luminescence. In this work, a series of new bimetallic Ln-MOFs (Eu_xTb_1-x-MOF) based luminescent sensor arrays have been developed to identify CRPC drugs, including in mixtures, via principal component analysis (PCA) and hierarchical cluster analysis (HCA) methods. These Ln-MOFs are built with a highly conjugated H₂L linker (H₂L = 5-(4-(triazole-1-yl)phenyl)isophthalic acid) and exhibit robust strong luminescence emissions (mainly located at 543 and 614 nm) and high energy transfer efficiencies. More specifically, Eu_0.096Tb_0.904-MOF (MOF 3) has demonstrated good sensing performances for CRPC curing drugs in real human serum samples. Furthermore, the curing drug hydroxyflutamide has been combined with MOF 3, to construct a robust composite sensing platform MOF 3@hydroxyflutamide for highly efficient detection of CRPC biomarkers such as the androgen receptor (AR) and prostate-specific antigen (PSA). Finally, luminescence lifetime measurements, zeta potential measurements, and density functional theory (DFT) calculations were performed to gain insights into the sensing mechanism.

Scheme 1. Illustration of the detection process of (top) CRPC curing drugs based on MOF 3; (bottom) CRPC biomarkers with MOF 3@hydroxyflutamide.

Fig. 1. (a) Coordination environment of Eu ions in the structure of the Eu-MOF; (b) coordination mode of the H₂L linker in the Eu-MOF; (c) 3D framework network of Eu-MOF.

Fig. 2. (a) STEM-HAADF image of MOF 3 nanocrystals; (b)–(d) EDS mapping images in STEM mode of MOF 3 nanocrystals; (e) TEM image of MOF 3 along with the corresponding particle size distribution; (f) TEM image of the AR; (g) TEM image of PSA; (h) TEM image of a mixture of AR, MOF 3 and hydroxyflutamide; (i) TEM image of a mixture of PSA and MOF 3@hydroxyflutamide.

Fig. 3. (a) Quenching efficiency of CRPC effective drugs (abiraterone, bicalutamide, cabazitaxel, and hydroxyflutamide) towards MOF 3; (b) luminescence spectra of 3 before (blank) and after adding abiraterone, bicalutamide, cabazitaxel, and hydroxyflutamide, (excitation position: 250 nm) in the DMSO solution, test interval: 5 min.

Fig. 4. (a) PCA and (b) hierarchical cluster analysis (HCA) plot for the discrimination of the 13 analytes based on the relative luminescence quenching effect of the Ln-MOF sensor array. (c) A linear relationship between the concentration of hydroxyflutamide and the luminescence intensity ratio of MOF 3.

Fig. 5. (a) Optimized DFT geometry of the hydroxyflutamide molecule (ball and stick) interacting with the Eu-MOF cluster (stick). The characteristic interacting distances are reported in Å. Color code for all atoms: hydrogen (white), carbon (light grey), nitrogen (blue), oxygen (red), fluorine (cyan), and europium (turquoise); (b) the alpha and beta frontier molecular orbitals (HOMO (HOMO − 1) and LUMO (LUMO + 1)) diagrams for the MOF 1@hydroxyflutamide (stick). In the MOs, red and green colors indicate the negative and positive charges, respectively.

Fig. 6. (a) Luminescence spectra of MOF 3@hydroxyflutamide (0.15 pM) before (blank) and after adding phosphatase specific antigen (PSA), androgen receptor (AR), testosterone and l-lactate dehydrogenase, (excitation position: 250 nm) in human serum solution after 5 minutes of incubation; (b) quenching efficiency of CRPC biomarkers (PSA, AR, testosterone, and l-LDH) towards MOF 3@hydroxyflutamide. (c) Luminescence spectra of MOF 3@hydroxyflutamide after adding the AR at different concentrations (excitation: 250 nm); (d) linear relationship between concentration of the AR and relative luminescence intensity ratio of MOF 3@hydroxyflutamide; (e) luminescence spectra of MOF 3@hydroxyflutamide after adding PSA at different concentrations (excitation: 250 nm); (f) linear relationship between the concentration of PSA and relative luminescence intensity ratio of MOF 3@hydroxyflutamide.

Scheme 2. Sensing mechanism of MOF 3@hydroxyflutamide towards the AR and PSA (ET = energy transfer and Em = emission).