Codoping Enhanced Radioluminescence of Nanoscintillators for X-ray-Activated Synergistic Cancer Therapy and Prognosis Using Metabolomics

Abstract

Radio-and photodynamic therapies are the first line of cancer treatments but suffer from poor light penetration and less radiation accumulation in soft tissues with high radiation toxicity. Therefore, a multifunctional nanoplatform with diagnosis-assisted synergistic radio-and photodynamic therapy and tools facilitating early prognosis are urgently needed to fight the war against cancer. Further, integrating cancer therapy with untargeted metabolomic analysis would collectively offer clinical pertinence through facilitating early diagnosis and prognosis. Here, we enriched scintillation of CeF 3 nanoparticles (NPs) through codoping Tb 3+ and Gd 3+ (CeF 3 :Gd 3+ ,Tb 3+ ) for viable clinical approach in the treatment of deep-seated tumors. The codoped CeF 3 :Gd 3+ ,Tb 3+ scintillating theranostic NPs were then coated with mesoporous silica, followed by loading with rose bengal (CGTS-RB) for later computed tomography (CT)-and magnetic resonance image (MRI)-guided X-ray stimulated synergistic radio-and photodynamic therapy (RT+XPDT) using low-dose, one-time X-ray irradiation. The results corroborated an efficient tumor regression with synergistic RT+XPDT relative to single RT. Global untargeted metabolome shifts highlighted the mechanism behind this efficient tumor regression using RT, and synergistic RT+XPDT treatment is due to the starvation of nonessential amino acids involved in protein and DNA synthesis and energy regulation pathways necessary for growth and progression. Our study also concluded that tumor and serum metabolites shift during disease progression and regression and serve as robust biomarkers for early assessment of disease state and prognosis. From our results, we propose that codoping is an effective and extendable technique to other materials for gaining high optical yield and multifunctionality and for use in diagnostic and therapeutic applications. Critically, the integration of multifunctional theranostic nanomedicines with metabolomics has excellent potential for the discovery of early metabolic biomarkers to aid in better clinical disease diagnosis and prognosis.

Emerging Nanomedicine‐Enabled/Enhanced Nanodynamic Therapies beyond Traditional Photodynamics

“…Similarly, Tb 3+ and Gd 3+ co‐doped CeFe 3 (CeFe 3 :Gd 3+ ,Tb 3+ ) nanoparticles with enriched scintillation were introduced for X‐ray simulated RDT by activating FDA‐approved rose bengal as loaded in the surface‐coated mesoporous silica layer. [ 114 ] This co‐doping strategy with Tb 3+ and Gd 3+ improved the scintillation yield and further augmented the 1 O 2 production for tumor therapy. In addition, the rational combination of β‐NaGdF 4 :Tb 3+ nanoparticles with rose bengal acquired ultrahigh FRET efficiency of up to 99.739% for the massive production of 1 O 2 , inducing the inhibition rate of 90% on suppressing HepG2 tumor growth under the low X‐ray dose of 1.5 Gy.…”

Investigating the reactive oxygen species production of Rose Bengal and Merocyanine 540-loaded radioluminescent nanoparticles

“…Production of OHc and O 2 c À radicals can be explained by the cascade of Compton, photo, and Auger-electrons that are produced by the interaction of X-rays with lanthanide-doped RLNPs. [15][16][17] The electrons then react with an acceptor i.e. PS, water, DMSO, and oxygen, inducing ROS generation.…”

“…15,16 Recent studies highlight the development of different RLNPs as energy mediators for indirect activation of photosensitizers by using X-rays as an excitation source for PDT, in a process now known as X-PDT. 15,[17][18][19][20] Conventional PDT utilizes light of a specic wavelength to excite a photosensitizer molecule to its triplet excited state and leading to the production of cytotoxic singlet oxygen and other ROS, such as hydroxyl, hydrogen peroxides and superoxide anion radicals. ROS and singlet oxygen are powerful oxidants that can damage biomolecules such as lipids, proteins and nucleic acids, making PDT a successful treatment for supercial cancers, actinic keratoses, and macular degeneration.…”

Energy‐converting biomaterials for cancer therapy: Category, efficiency, and biosafety

“…(a) Biodistribution of the Au 10 (SG) 10 molecule (Reprinted with permission from Zhang et al (2014), Copyright 2014 Wiley‐VCH Verlag GmbH & Co. KGaA, Weinheim), (b) Schematic illustration of hierarchical multiplexing nanodroplets for multimodal imaging‐guided RT (Reprinted with permission from Jiang et al (2018), Copyright 2018 American Chemical Society), (c) Schematic illustration of Pd@Au bimetallic nanostructure to relieve tumor hypoxia (Reprinted with permission from Yang, Chen, and Shi (2019a), Copyright 2019 Wiley‐VCH Verlag GmbH & Co. KGaA, Weinheim), (d) Schematic illustration of X‐ray‐activated synergistic therapy (Reprinted with permission from Ahmad et al (2019), Copyright 2019 American Chemical Society), (e) Schematic illustration of the X‐ray‐controlled ONOO − generation for RT based on RBS‐T‐SCNPs (Reprinted with permission from Du et al (2018), Copyright 2018 Wiley‐VCH Verlag GmbH & Co. KGaA, Weinheim)…”

“…Therefore, Ce‐based radiation‐driven ROS‐ECBs, such as CeF 3 @VP (verteporfin), CeF 3 @ZnO, Ce‐doped TiO 2 , CeLaF 3 /LaF 3 @Chlorine e6, have been the most explored nanosystems for X‐ray‐induced RT/XPDT (Ren et al, 2018; Xie et al, 2019). For instance, Ahmad et al (2019) developed a rose bengal‐loaded and MSNs‐coated CeF 3 :Gd 3+ ,Tb 3+ (CGTSRB) for X‐ray‐activated synergistic therapy (Figure 2d). This nanosystem was explored as a radio‐sensitization agent for enhancing RT.…”