Local delivery of accutox® synergises with immune-checkpoint inhibitors at disrupting tumor growth.

BACKGROUND: The Accum® platform was initially designed to accumulate biomedicines in target cells by inducing endosomal-to-cytosol escape. Interestingly however, the use of unconjugated Accum® was observed to trigger cell death in a variety of cancer cell lines; a property further exploited in the development of Accum®-based anti-cancer therapies. Despite the impressive pro-killing abilities of the parent molecule, some cancer cell lines exhibited resistance. This prompted us to test additional Accum® variants, which led to the identification of the AccuTOX® molecule. METHODS: A series of flow-cytometry and cell-based assays were used to assess the pro-killing properties of AccuTOX® along with its ability to trigger the production of reactive oxygen species (ROS), endosomal breaks and antigen presentation. RNA-seq was also conducted to pinpoint the most prominent processes modulated by AccuTOX® treatment in EL4 T-cell lymphoma. Finally, the therapeutic potency of intratumorally-injected AccuTOX® was evaluated in three different murine solid tumor models (EL4, E0771 and B16) both as a monotherapy or in combination with three immune-checkpoint inhibitors (ICI). RESULTS: In total, 7 Accum® variants were screened for their ability to induce complete cell death in 3 murine (EL4, B16 and E0771) and 3 human (MBA-MD-468, A549, and H460) cancer cell lines of different origins. The selected compound (hereafter refereed to as AccuTOX®) displayed an improved killing efficiency (~ 5.5 fold compared to the parental Accum®), while retaining its ability to trigger immunogenic cell death, ROS production, and endosomal breaks. Moreover, transcriptomic analysis revealed that low dose AccuTOX® enhances H2-Kb cell surface expression as well as antigen presentation in cancer cells. The net outcome culminates in impaired T-cell lymphoma, breast cancer and melanoma growth in vivo especially when combined with anti-CD47, anti-CTLA-4 or anti-PD-1 depending on the animal model. CONCLUSIONS: AccuTOX® exhibits enhanced cancer killing properties, retains all the innate characteristics displayed by the parental Accum® molecule, and synergizes with various ICI in controlling tumor growth. These observations will certainly pave the path to continue the clinical development of this lead compound against multiple solid tumor indications.

Janus Micromotors for Photophoretic Motion and Photon Upconversion Applications Using a Single Near-Infrared Wavelength.

External stimuli can trigger changes in temperature, concentration, and momentum between micromotors and the medium, causing their propulsion and enabling them to perform different tasks with improved kinetic efficiencies. Light-activated micromotors are attractive systems that achieve improved motion and have the potential for high spatiotemporal control. Photophoretic swarming motion represents an attractive means to induce micromotor movement through the generation of temperature gradients in the medium, enabling the micromotors to move from cold to hot regions. The micromotors studied herein are assembled with Fe3O4 nanoparticles, and NaGdF4:Yb3+,Er3+/NaGdF4:Yb3+ and LiYF4:Yb3+,Tm3+ upconverting nanoparticles. The Fe3O4 nanoparticles were localized to one hemisphere to produce a Janus architecture that facilitates improved upconversion luminescence with the upconverting nanoparticles distributed throughout. Under 976 nm excitation, Fe3O4 nanoparticles generate the temperature gradient, while the upconverting nanoparticles produce visible light that is used for micromotor motion tracking and triggering of reactive oxygen species generation. As such, the motion and application of the micromotors are achieved using a single excitation wavelength. To demonstrate the practicality of this system, curcumin was adsorbed to the micromotor surface and degradation of Rhodamine B was achieved with kinetic rates that were over twice as fast as the static micromotors. The upconversion luminescence was also used to track the motion of the micromotors from a single image frame, providing a convenient means to understand the trajectory of these systems. Together, this system provides a versatile approach to achieving light-driven motion while taking advantage of the potential applications of upconversion luminescence such as tracking and detection, sensing, nanothermometry, particle velocimetry, photodynamic therapy, and pollutant degradation.

Achieving photostability in dye-sensitized upconverting nanoparticles and their use in Fenton type photocatalysis.

Dye sensitization is a promising approach to enhance the luminescence of lanthanide-doped upconverting nanoparticles. However, the poor photostability of near-infrared dyes hampers their use in practical applications. To address this, commercial IR820 was modified for improved photostability and covalently bonded to amine-functionalized silica-coated LnUCNPs. Two methods of covalent linking were investigated: linking the dye to the surface of the silica shell, and embedding the dye within the silica shell. The photostability of the dyes when embedded in the silica shell exhibited upconversion emissions from NaGdF4:Er3+,Yb3+/NaGdF4:Yb3+ nanoparticles for over four hours of continuous excitation with no change in intensity. To highlight this improvement, the photostable dye-embedded system was successfully utilized for Fenton-type photocatalysis, emphasizing its potential for practical applications. Overall, this study presents a facile strategy to circumvent the overlooked limitations associated with photodegradation, opening up new possibilities for the use of dye-sensitized lanthanide-doped upconverting nanoparticles in a range of fields.

The role of lanthanide luminescence in advancing technology.

Our society is indebted to the numerous inventors and scientists who helped bring about the incredible technological advances in modern society that we all take for granted. The importance of knowing the history of these inventions is often underestimated, although our reliance on technology is escalating. Lanthanide luminescence has paved the way for many of these inventions, from lighting and displays to medical advancements and telecommunications. Given the significant role of these materials in our daily lives, knowingly or not, their past and present applications are reviewed. A majority of the discussion is devoted to pointing out the benefits of using lanthanides over other luminescent species. We aimed to give a short outlook outlines promising directions for the development of the considered field. This review aims to provide the reader enough content to further appreciate the benefits that these technologies have brought into our lives, with the perspective of travelling among the past and latest advances in lanthanide research, aiming for an even brighter future.

Combining Pr3+-Doped Nanoradiosensitizers and Endogenous Protoporphyrin IX for X-ray-Mediated Photodynamic Therapy of Glioblastoma Cells.

Glioblastoma multiforme is an aggressive type of brain cancer with high recurrence rates due to the presence of radioresistant cells remaining after tumor resection. Here, we report the development of an X-ray-mediated photodynamic therapy (X-PDT) system using NaLuF4:25% Pr3+ radioluminescent nanoparticles in conjunction with protoporphyrin IX (PPIX), an endogenous photosensitizer that accumulates selectively in cancer cells. Conveniently, 5-aminolevulinic acid (5-ALA), the prodrug that is administered for PDT, is the only drug approved for fluorescence-guided resection of glioblastoma, enabling dual detection and treatment of malignant cells. NaLuF4:Pr3+ nanoparticles were synthesized and spectroscopically evaluated at a range of Pr3+ concentrations. This generated radioluminescent nanoparticles with strong emissions from the 1S0 excited state of Pr3+, which overlaps with the Soret band of PPIX to perform photodynamic therapy. The spectral overlap between the nanoparticles and PPIX improved treatment outcomes for U251 cells, which were used as a model for the thin tumor margin. In addition to sensitizing PPIX to induce X-PDT, our nanoparticles exhibit strong radiosensitizing properties through a radiation dose-enhancement effect. We evaluate the effects of the nanoparticles alone and in combination with PPIX on viability, death, stress, senescence, and proliferation. Collectively, our results demonstrate this as a strong proof of concept for nanomedicine.

Cooperative Sensitization Upconversion in Solution Dispersions of Co-Crystal Assemblies of Mononuclear Yb3+ and Eu3+ Complexes.

Lanthanide upconversion luminescence in nanoparticles has prompted continuous breakthroughs in information storage, temperature sensing, and biomedical applications, among others. Achieving upconversion luminescence at the molecular scale is still a critical challenge in modern chemistry. In this work, we explored the upconversion luminescence of solution dispersions of co-crystals composed of discrete mononuclear Yb(DBM)3 Bpy and Eu(DBM)3 Bpy complexes (DBM: dibenzoylmethane, Bpy: 2,2'-bipyridine). The 613 nm emission of Eu3+ was observed under excitation of Yb3+ at 980 nm. From the series of molecular assemblies studied, the most intense luminescence was obtained for a 1 : 1 molar ratio of Yb3+ : Eu3+ , resulting in a high quantum yield of 0.67 % at 2.1 W cm-2 . The structure and energy transfer mechanism of the assemblies were fully characterized. This is the first example of an Eu3+ -based upconverting system composed of two discrete mononuclear lanthanide complexes present as co-crystals in non-deuterated solution.

Biomolecules incorporated in halide perovskite nanocrystals: synthesis, optical properties, and applications.

Halide perovskite nanocrystals (HPNCs) have emerged at the forefront of nanomaterials research over the past two decades. The physicochemical and optoelectronic properties of these inorganic semiconductor nanoparticles can be modulated through the introduction of various ligands. The use of biomolecules as ligands has been demonstrated to improve the stability, luminescence, conductivity and biocompatibility of HPNCs. The rapid advancement of this field relies on a strong understanding of how the structure and properties of biomolecules influences their interactions with HPNCs, as well as their potential to extend applications of HPNCs towards biological applications. This review addresses the role of several classes of biomolecules (amino acids, proteins, carbohydrates, nucleotides, etc.) that have shown promise for improving the performance of HPNCs and their potential applications. Specifically, we have reviewed the recent advances on incorporating biomolecules with HP nanomaterials on the formation, physicochemical properties, and stability of HP compounds. We have also shed light on the potential for using HPs in biological and environmental applications by compiling some recent of proof-of-concept demonstrations. Overall, this review aims to guide the field towards incorporating biomolecules into the next-generation of high-performance HPNCs for biological and environmental applications.

Upconversion Luminescence through Cooperative and Energy-Transfer Mechanisms in Yb3+ -Metal-Organic Frameworks.

Lanthanide-doped metal-organic frameworks (Ln-MOFs) have versatile luminescence properties, however it is challenging to achieve lanthanide-based upconversion luminescence in these materials. Here, 1,3,5-benzenetricarboxylic acid (BTC) and trivalent Yb3+ ions were used to generate crystalline Yb-BTC MOF 1D-microrods with upconversion luminescence under near infrared excitation via cooperative luminescence. Subsequently, the Yb-BTC MOFs were doped with a variety of different lanthanides to evaluate the potential for Yb3+ -based upconversion and energy transfer. Yb-BTC MOFs doped with Er3+ , Ho3+ , Tb3+ , and Eu3+ ions exhibit both the cooperative luminescence from Yb3+ and the characteristic emission bands of these ions under 980 nm irradiation. In contrast, only the 497 nm upconversion emission band from Yb3+ is observed in the MOFs doped with Tm3+ , Pr3+ , Sm3+ , and Dy3+ . The effects of different dopants on the efficiency of cooperative luminescence were established and will provide guidance for the exploitation of Ln-MOFs exhibiting upconversion.

On the photostability and luminescence of dye-sensitized upconverting nanoparticles using modified IR820 dyes.

Dye sensitization is a promising route to enhance luminescence from lanthanide-doped upconverting nanoparticles (LnUCNPs) by improving the photon harvesting capability of LnUCNPs through the use of dye molecules, characterized by higher absorption coefficients. The literature does not fully address the poor photostability of NIR dyes, hindering solution-based applications. The improvements achieved by dye-sensitized LnUCNPs are usually obtained by comparison with non-dye sensitized LnUCNPs. This comparison results in exciting the LnUCNPs at different wavelengths with respect to the dye-sensitized LnUCNPs or at the same wavelengths, where, however, the non-dye sensitized LnUCNPs do not absorb. Both these comparisons are hardly conclusive for a quantification of the improvements achieved by dye-sensitization. Both shortcomings were addressed by studying the photodegradation via thorough spectroscopic evaluations of a 4-nitrothiophenol-modified and unmodified IR820-LnUCNP system. The modified IR820 dye system exhibits a 200% enhancement in the emission of NaGdF4:Er3+,Yb3+/NaGdF4:Yb3+ nanoparticles relative to the unmodified IR820-sensitized LnUCNPs and emits for over twice the duration, demonstrating a substantial improvement over previous dye-LnUCNP systems. Upconversion dynamics between the dyes and Er3+ establish the importance of back-transfer dynamics in modulating the dye-LnUCNP luminescence. Quantum yield measurements further illustrate the mechanism of sensitization and increased efficiency of this new nanosystem.

Energy Migration Control of Multimodal Emissions in an Er3+ -Doped Nanostructure for Information Encryption and Deep-Learning Decoding.

Modulating the emission wavelengths of materials has always been a primary focus of fluorescence technology. Nanocrystals (NCs) doped with lanthanide ions with rich energy levels can produce a variety of emissions at different excitation wavelengths. However, the control of multimodal emissions of these ions has remained a challenge. Herein, we present a new composition of Er3+ -based lanthanide NCs with color-switchable output under irradiation with 980, 808, or 1535 nm light for information security. The variation of excitation wavelengths changes the intensity ratio of visible (Vis)/near-infrared (NIR-II) emissions. Taking advantage of the Vis/NIR-II multimodal emissions of NCs and deep learning, we successfully demonstrated the storage and decoding of visible light information in pork tissue.

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

Radioluminescent nanomaterials have garnered significant attention in the past decade due to their potential to perform X-ray mediated photodynamic therapy (X-PDT). Many of these materials are assumed to produce singlet oxygen based on a single assay. Herein we demonstrate that multiple assays are required to confidently determine whether singlet oxygen or other reactive oxygen species are being produced through type I or type II PDT mechanisms. Rose Bengal and Merocyanine 540 photosensitizers were loaded into mesoporous silica-coated NaLuF4:Dy3+,Gd3+ nanoparticles and the combination of ABDA, DPBF, and NaN3 assays along with electron paramagnetic resonance were employed to determine that superoxide and hydroxyl radicals were exclusively produced from this system under X-ray excitation. Knowledge of the correct PDT mechanism is crucial for informing what types of disease may be best suited for treatment using PDT nanosystems.

On a local (de-)trapping model for highly doped Pr3+ radioluminescent and persistent luminescent nanoparticles.

Trivalent praseodymium exhibits a wide range of luminescent phenomena when doped into a variety of different materials. Herein, radioluminescent NaLuF4:20%Pr3+ nanoparticles are studied. Four different samples of this composition were prepared ranging from 400-70 nm in size. Kinetic studies of radioluminescence as a function of X-ray irradiation time revealed a decrease in the emissions originating from the 1S0 level, due to the formation or optical activation of defects during excitation, and a simultaneous increase in the visible emissions resulting from the lower optical levels. Thermoluminescence measurements elucidated that a local de-trapping mechanism was responsible for the increase in steady state emission and persistent luminescence originating from the lower optical levels. The results and mechanism described through this study serve to provide a novel nanoparticle composition with versatile luminescent properties and provides experimental evidence in favor of a local trapping model.

Evaluation of Lanthanide-Doped Upconverting Nanoparticles for in Vitro and in Vivo Applications.

Because of their unique physicochemical properties, lanthanide-doped upconverting nanoparticles (Ln-UCNPs) have exceptional potential for biological applications. However, the use in biological systems is hampered by the limited understanding of their bionano interactions. Our multidisciplinary study has generated these insights through in-depth and quantitative analyses. The Ln-UCNPs examined here are spherical, monodisperse, and stable in aqueous environments. We show that Ln-UCNPs were associated with HeLa (cervical cancer) and LLC-PK1 (renal proximal tubule) cells and were nontoxic over a wide concentration range. Multiple biomarkers were assessed to monitor the cellular homeostasis in Ln-UCNP-treated cells. To this end, we evaluated the nuclear lamina, nucleoli, and nuclear transport factors. Single-cell analyses quantified the impact on Nrf2 and NF-κB, two transcription factors that control stress and immune responses. Moreover, we measured Ln-UCNP-induced changes in the abundance of molecular chaperones. Collectively, in vitro studies confirmed that Ln-UCNPs are nontoxic and trigger minor cellular stress responses. This lack of toxicity was verified in vivo, using the model organism Caenorhabditis elegans. The compatibility with biological systems prompted us to assess Ln-UCNPs as potential contrast agents for magnetic resonance imaging. We demonstrated that the Ln-UCNPs examined here were especially suitable as T2 contrast agents; they clearly outperformed the clinically used Gadovist. Taken together, our interdisciplinary work provides robust evidence for the nontoxicity of Ln-UCNPs. This sets the stage for the translation of Ln-UCNP for use in complex biological systems.

Recent insights into upconverting nanoparticles: spectroscopy, modeling, and routes to improved luminescence.

The development of reliable and reproducible synthetic routes that produce monodisperse lanthanide-doped upconverting nanoparticles has resulted in an appreciable need to determine the mechanisms which govern upconversion luminescence at the nanoscale. New experimental and theoretical evidence explicates the quenching phenomena involved in the low luminescence efficiencies. A deeper understanding of the role of surfaces and defects in the quenching mechanisms and the properties of upconverting nanoparticles are of fundamental importance to develop nanomaterials with enhanced luminescence properties. Herein, we summarize the most recent spectroscopic investigations, which have enabled the scientific community to ascertain that the predominant source of quenching involved in the luminescence of lanthanide-doped upconverting nanoparticles can be attributed to surface-defects. Modeling of these mechanisms in nanomaterials supports the experimental findings and yields further insights into the surface phenomena, providing a predictive tool to improve the luminescent efficiencies in nanomaterials.

Luminescence dynamics and enhancement of the UV and visible emissions of Tm3+ in LiYF4:Yb3+,Tm3+ upconverting nanoparticles.

To maximize the intrinsic luminescence efficiency of the higher energy emissions of Tm3+ in LiYF4:Yb3+,Tm3+ upconverting nanoparticles, we investigated a specific range of Tm3+ dopant concentrations. Reported to be optimized at 25% Yb3+, 0.5% Tm3+, due to the multitude of Tm3+-to-Tm3+ interactions, the Tm3+ concentration commonly used may not be suitable for strong UV and visible emissions. Thus, we varied the concentration of Tm3+ in LiYF4 nanoparticles between 0.08 and 0.55% to elucidate the effect of moderate changes of the dopant concentration on the UV, visible and NIR emissions. We determined a new optimized concentration of 0.24% Tm3+ for maximal UV and visible emissions (nominally 0.2%). An extensive analysis of the luminescence spectra in the UV, visible and NIR regions and decay time measurements provides evidence for new luminescence mechanisms involving cross-relaxation pathways from the UV-emitting states of Tm3+. Furthermore, we performed studies on an azobenzene derivative to demonstrate the substantial enhancement of the UV emissions by the newly optimized composition as evidenced by an increase in the degree of trans-cis photoisomerization.

Perspective: lanthanide-doped upconverting nanoparticles.

In this perspective, we aim to present an overview of some important physical and chemical aspects of lanthanide-doped upconverting nanoparticle research to be considered, from synthesis considerations to bioapplications. To this end, we have reviewed several practical considerations and prepared several straightforward recommendations toward improved cohesion in the field, based on observed trends over the last decade of research.

A NIR-responsive azobenzene-based supramolecular hydrogel using upconverting nanoparticles.

To circumvent the need for direct UV excitation in a supramolecular hydrogel composed of an azobenzene-modified poly(acrylic acid) copolymer and deoxycholate-ß-cyclodextrin as a crosslinker, we modified this system for use with LiYF4:Tm3+/Yb3+ upconverting nanoparticles, which emit UV light upon NIR excitation. A complete gel-sol transition was observed in 60 minutes upon 980 nm irradiation. No change was observed under similar conditions of a control sample over the same period of time.