Microfluidic Synthesis of Theranostic Nanoparticles with Near-Infrared Scintillation: Toward Next-Generation Dosimetry in X-ray-Induced Photodynamic Therapy

Abstract

We developed a microfluidic synthesis to grow GdF 3 :Eu theranostic scintillating nanoparticles to simultaneously monitor the X-ray dose delivered to tumors during treatments with X-ray activated photodynamic therapy (X-PDT). The flow reaction was optimized to enhance scintillation emission from the Eu 3+ ions. The as-prepared ∼15 nm rhombohedral-shaped nanoparticles selfassembled into ∼100 nm mesoporous flower-like nanostructures, but the rhombohedral units remained intact and the scintillation spectra unaltered. The conjugation of the ScNPs with multilayers of methylene blue (MB) in a core−shell structure (GdF@MB) resulted in enhanced singlet oxygen ( 1 O 2 ) generation under X-ray irradiation, with maximum 1 O 2 production for nanoparticles with 4 MB layers (GdF@4MB). High 1 O 2 yield was further evidenced in cytotoxicity assays, demonstrating complete cell death only for the association of ScNPs with MB and X-rays. Because the scintillating Eu 3+ emission at 694 nm is within the therapeutic window and was only partially absorbed by the MB molecules, it was explored for getting in vivo dosimetric information. Using porcine skin and fat to simulate the optical and radiological properties of the human tissues, we showed that the scintillation light can be detected for a tissue layer of ∼16 mm, thick enough to be employed in radiotherapy treatments of breast cancers, for instance. Therefore, the GdF 3 :Eu ScNPs and the GdF@4MB nanoconjugates are strong candidates for treating cancer with X-PDT while monitoring the treatment and the radiation dose delivered, opening new avenues to develop a next-generation modality of real-time in vivo dosimetry.

Alternative Strategy to Optimize Cerium Oxide for Enhanced X-ray-Induced Photodynamic Therapy

“…Radiotherapy (RT) is one of the most prevalent anticancer treatment strategies in clinical practice. − Radiation resistance caused by the hypoxic property of cancer tissue limits the efficacy of RT and increases the side effects of RT. − Similarly, photodynamic therapy (PDT) is a temporal and spatial selective anticancer treatment strategy, which has attracted considerable attention in recent years. − However, the greatly limited tissue penetration depth of laser and the inherent hypoxia in malignant solid tumors are still the main reasons for its clinical application. − Inspired by the ionizing radiation of RT with enhanced tissue penetration depth, X-ray-induced photodynamic therapy (X-PDT) has been considered a potential alternative therapeutic strategy to overcome the above-mentioned issues by utilizing the higher energy and greater penetration depth of X-rays. − Despite some efforts have been made in the design and construction of some special photosensitizers (PSs) for X-PDT, they still fail to make satisfactory progress due to the energy mismatch between X-ray (KeV to MeV) and traditional PSs (eV). − Thus, the advanced PSs as energy transducers are urgently demanded for the high-efficiency X-PDT.…”

Hafnium (Hf)-Chelating Porphyrin-Decorated Gold Nanosensitizers for Enhanced Radio–Radiodynamic Therapy of Colon Carcinoma

“…High-Z element-containing materials, such as nanoparticles, , nanoclusters, , and metal–organic frameworks, , have been shown to significantly enhance radiotherapy. For instance, gold nanoparticles (AuNPs) have been widely utilized as radiosensitizers due to their excellent biocompatibility, facile preparation, versatile surface modification, and exceptional ability to deposit energy. − Hafnium (Hf 4+) ion has been demonstrated to be a promising high-Z metal that can readily chelate with certain ligands, such as photosensitizer, , phenolic agents, , etc.…”

Terbium-Rose Bengal Coordination Nanocrystals-Induced ROS Production under Low-Dose X-rays in Cultured Cancer Cells for Photodynamic Therapy

“…X-ray triggered scintillators (Sc) and photosensitizers (Ps) in recent studies have been implemented for X-ray induced photodynamic therapy (X-PDT) in deep tissue tumor destruction with low X-ray irradiation doses. − Sc generate photoluminescence (PL) with X-ray irradiation, which subsequently excites nearby Ps to produce reactive oxygen species (ROS). − Various pairs between Sc and Ps, including Au/verteporfin, Cu/cysteamine, and Eu/methylene blue (MB), have been studied to generate enough ROS under low X-ray doses. − Among them, terbium (Tb) and rose bengal (RB) are considered a classical pair for X-PDT − due to their widely overlapped excitation/absorption wavelength for donor–acceptor energy transfer. RB contains heavy atoms [chlorine and iodine (I)], which increase the lifetime of the dye’s triplet state and contribute high amounts of absorbance in the visible wavelength .…”