Li5Zn8Ga5Ge9O36: Cr3+, Ti4+: A Long Persistent Phosphor Excited in a Wide Spectral Region from UV to Red Light for Reproducible Imaging through Biological Tissue

Near‐infrared (NIR) long‐persistent phosphors (LPPs) have emerged as a potential solution for bio‐imaging applications over the past few years. However, there are enormous challenges regarding their in situ application based on their dependence on short‐wavelength excitation. In this paper, we report a multi‐spectral excited NIR LPP, Li₅Zn₈Ga₅Ge₉O₃₆: 1.5 % Cr³⁺, 0.5 % Ti⁴⁺, which overcomes the limitations of functional processes in biological tissues and other complex systems. This LPP exhibits a high luminescent intensity and a long emission duration in the NIR region (700–800 nm). The applicability of this phosphor to tissue imaging is demonstrated experimentally. Its persistent luminescence (PersL) can easily penetrate approximately 2 mm of pork flesh. More importantly, this phosphor can be re‐charged in situ using a red LED or laser diode array to provide renewed NIR PersL for biological tissues, which is beneficial for long‐term biological tissue imaging applications with high signal‐to‐noise ratios. Systematic investigations of the nature of energy traps and PersL mechanisms are also reported in this paper.     

Near-Infrared Light-Triggered Chlorine Radical (.Cl) Stress for Cancer Therapy

Free radicals with reactive chemical properties can fight tumors without causing drug resistance. Reactive oxygen species (ROS) has been widely used for cancer treatment, but regrettably, the common O₂ and H₂O₂ deficiency in tumors sets a severe barrier for sufficient ROS production, leading to unsatisfactory anticancer outcomes. Here, we construct a chlorine radical (^.Cl) nano-generator with SiO₂-coated upconversion nanoparticles (UCNPs) on the inside and Ag⁰/AgCl hetero-dots on the outside. Upon near-infrared (NIR) light irradiation, the short-wavelength emission UCNP catalyzes ^.Cl generation from Ag⁰/AgCl with no dependence on O₂/H₂O₂. ^.Cl with strong oxidizing capacity and nucleophilicity can attack biomolecules in cancer cells more effectively than ROS. This ^.Cl stress treatment will no doubt broaden the family of oxidative stress-induced antitumor strategies by using non-oxygen free radicals, which is significant in the development of new anticancer agents.     

Multifunctional Uniform Core–Shell Fe3O4@mSiO2 Mesoporous Nanoparticles for Bimodal Imaging and Photothermal Therapy

Multimodal imaging and simultaneous therapy is highly desirable because it can provide complementary information from each imaging modality for accurate diagnosis and, at the same time, afford an imaging‐guided focused tumor therapy. In this study, indocyanine green (ICG), a near‐infrared (NIR) imaging agent and perfect NIR light absorber for laser‐mediated photothermal therapy, was successfully incorporated into superparamagnetic Fe₃O₄@mSiO₂ core–shell nanoparticles to combine the merit of NIR/magnetic resonance (MR) bimodal imaging properties with NIR photothermal therapy. The resultant nanoparticles were homogenously coated with poly(allylamine hydrochloride) (PAH) to make the surface of the composite nanoparticles positively charged, which would enhance cellular uptake driven by electrostatic interactions between the positive surface of the nanoparticles and the negative surface of the cancer cell. A high biocompatibility of the achieved nanoparticles was demonstrated by using a cell cytotoxicity assay. Moreover, confocal laser scanning microscopy (CLSM) observations indicated excellent NIR fluorescent imaging properties of the ICG‐loaded nanoparticles. The relatively high r₂ value (171.6 mM ^?1 s^?1) of the nanoparticles implies its excellent capability as a contrast agent for MRI. More importantly, the ICG‐loaded nanoparticles showed perfect NIR photothermal therapy properties, thus indicating their potential for simultaneous cancer diagnosis as highly effective NIR/MR bimodal imaging probes and for NIR photothermal therapy of cancerous cells.     

A Multifunctional Biomaterial with NIR Long Persistent Phosphorescence,Photothermal Response and Magnetism

There are many reports on long persistent phosphors (LPPs) applied in bioimaging. However, there are few reports on LPPs applied in photothermal therapy (PTT), and an integrated system with multiple functions of diagnosis and therapy. In this work, we fabricate effective multifunctional phosphors Zn₃Ga₂SnO₈: Cr³⁺, Nd³⁺, Gd³⁺ with NIR persistent phosphorescence, photothermal response and magnetism. Such featured materials can act as NIR optical biolabels and magnetic resonance imaging (MRI) contrast agents for tracking the early cancer cells, but also as photothermal therapeutic agent for killing the cancer cells. This new multifunctional biomaterial is expected to open a new possibility of setting up an advanced imaging‐guided therapy system featuring a high resolution for bioimaging and low side effects for the photothermal ablation of tumors.     

Facile Synthesis of Fe3O4@Au/PPy-DOX Nanoplatform with Enhanced Glutathione Depletion and Controllable Drug Delivery for Enhanced Cancer Therapeutic Efficacy

The complex physiological environment and inherent self-healing function of tumors make it difficult to eliminate malignant tumors by single therapy. In order to enhance the efficacy of antitumor therapy, it is significant and challenging to realize multi-mode combination therapy by utilizing/improving the adverse factors of the tumor microenvironment (TME). In this study, a novel Fe₃O₄@Au/PPy nanoplatform loaded with a chemotherapy drug (DOX) and responsive to TME, near-infrared (NIR) laser and magnetic field was designed for the combination enhancement of eliminating the tumor. The Fe²⁺ released at the low pH in TME can react with endogenous H₂O₂ to induce toxic hydroxyl radicals (·OH) for chemodynamic therapy (CDT). At the same time, the generated Fe³⁺ could deplete overexpressed glutathione (GSH) at the tumor site to prevent reactive oxygen species (ROS) from being restored while producing Fe²⁺ for CDT. The designed Fe₃O₄@Au/PPy nanoplatform had high photothermal (PT) conversion efficiency and photodynamic therapy (PDT) performance under NIR light excitation, which can promote CDT efficiency and produce more toxic ROS. To maximize the cancer-killing efficiency, the nanoplatform can be successfully loaded with the chemotherapeutic drug DOX, which can be efficiently released under NIR excitation and induction of slight acidity at the tumor site. In addition, the nanoplatform also possessed high saturation magnetization (20 emu/g), indicating a potential magnetic targeting function. In vivo and in vitro results identified that the Fe₃O₄@Au/PPy-DOX nanoplatform had good biocompatibility and magnetic-targeted synergetic CDT/PDT/PTT/chemotherapy antitumor effects, which were much better than those of the corresponding mono/bi/tri-therapies. This work provides a new approach for designing intelligent TME-mediated nanoplatforms for synergistically enhancing tumor therapy.     

Design of Photostable,Activatable Near‐Infrared Photoacoustic Probes Using Tautomeric Benziphthalocyanine as a Platform

Near‐infrared (NIR) imaging techniques have attracted significant attention for biological and medicinal applications due to the ability of NIR to penetrate deeply into tissues. However, there are very few stable, activatable molecular probes that can utilize NIR light in the wavelength range beyond 800 nm. Herein, we report a new activatable NIR system for photoacoustic imaging based on tautomeric benziphthalocyanines (BPcs). We found that the existence of a free hydroxyl group is crucial for NIR absorption of BPcs. Synthesized water‐soluble hydroxy BPcs exhibited high photostability and no fluorescence, which are desirable features for photoacoustic imaging. We synthesized BPcs in which the free hydroxyl group was masked by an esterase‐labile or an H₂O₂‐labile group. The photoacoustic signals of these hydroxy‐masked BPcs were increased upon NIR excitation at 880 nm in the presence of esterase or H₂O₂, respectively. These are rare examples of activatable probes utilizing NIR light at around 900 nm.     

Design of Photostable,Activatable Near‐Infrared Photoacoustic Probes Using Tautomeric Benziphthalocyanine as a Platform

Near‐infrared (NIR) imaging techniques have attracted significant attention for biological and medicinal applications due to the ability of NIR to penetrate deeply into tissues. However, there are very few stable, activatable molecular probes that can utilize NIR light in the wavelength range beyond 800 nm. Herein, we report a new activatable NIR system for photoacoustic imaging based on tautomeric benziphthalocyanines (BPcs). We found that the existence of a free hydroxyl group is crucial for NIR absorption of BPcs. Synthesized water‐soluble hydroxy BPcs exhibited high photostability and no fluorescence, which are desirable features for photoacoustic imaging. We synthesized BPcs in which the free hydroxyl group was masked by an esterase‐labile or an H₂O₂‐labile group. The photoacoustic signals of these hydroxy‐masked BPcs were increased upon NIR excitation at 880 nm in the presence of esterase or H₂O₂, respectively. These are rare examples of activatable probes utilizing NIR light at around 900 nm.     

Synergistic Anticancer Therapy by Ovalbumin Encapsulation-Enabled Tandem Reactive Oxygen Species Generation

The anticancer efficacy of photodynamic therapy (PDT) is limited due to the hypoxic features of solid tumors. We report synergistic PDT/chemotherapy with integrated tandem Fenton reactions mediated by ovalbumin encapsulation for improved in vivo anticancer therapy via an enhanced reactive oxygen species (ROS) generation mechanism. O₂^.− produced by the PDT is converted to H₂O₂ by superoxide dismutase, followed by the transformation of H₂O₂ to the highly toxic ^.OH via Fenton reactions by Fe²⁺ originating from the dissolution of co-loaded Fe₃O₄ nanoparticles. The PDT process further facilitates the endosomal/lysosomal escape of the active agents and enhances their intracellular delivery to the nucleus—even for drug-resistant cells. Cisplatin generates O₂^.− in the presence of nicotinamide adenine dinucleotide phosphate oxidase and thereby improves the treatment efficiency by serving as an additional O₂^.− source for production of ^.OH radicals. Improved anticancer efficiency is achieved under both hypoxic and normoxic conditions.     

Reactive oxygen specie-induced photodynamic therapy activation by supramolecular strategy

Photodynamic therapy (PDT) agents may accumulate in skin and cause severe skin cytotoxicity. We report a pro-guest-based supramolecular strategy to selectively activate PDT in the reactive oxygen specie (ROS) overexpressed microenvironment, which is often existing in tumor and inflammatory tissues. PDT agents methylene blue (MB) and basic blue 17 (BB17) are used as model drugs. When encapsulated by acyclic cucurbit[n]uril (CB[n]), the efficacy of PDT agents is significantly inhibited. By contrast, in the presence of ROS (H₂O₂) and pro-guest, PDT agents are displaced and reactivated to show a dramatically enhanced PDT efficacy in cells.     

Monitoring Singlet Oxygen and Hydroxyl Radical Formation with Fluorescent Probes During Photodynamic Therapy

Singlet oxygen (¹O₂) is the primary oxidant generated in photodynamic therapy (PDT) protocols involving sensitizers resulting in type II reactions. ¹O₂ can give rise to additional reactive oxygen species (ROS) such as the hydroxyl radical (^?OH). The current study was designed to assess 3′‐p‐(aminophenyl) fluorescein (APF) and 3′‐p‐(hydroxyphenyl) fluorescein (HPF) as probes for the detection of ¹O₂ and ^?OH under conditions relevant to PDT. Cell‐free studies indicated that both APF and HPF were converted to fluorescent products following exposure to ¹O₂ generated by irradiation of a water‐soluble photosensitizing agent (TPPS) and that APF was 35‐fold more sensitive than HPF. Using the ¹O₂ probe singlet oxygen sensor green (SOSG) we confirmed that 1 mm NaN₃ quenched ¹O₂‐induced APF/HPF fluorescence, while 1% DMSO had no effect. APF and HPF also yielded a fluorescent product upon interacting with ^?OH generated from H₂O₂ via the Fenton reaction in a cell‐free system. DMSO quenched the fluorogenic interaction between APF/HPF and ^?OH at doses as low as 0.02%. Although NaN₃ was expected to quench ^?OH‐induced APF/HPF fluorescence, co‐incubating NaN₃ with APF or HPF in the presence of ^?OH markedly enhanced fluorescence. Cultured L1210 cells that had been photosensitized with benzoporphyhrin derivative exhibited APF fluorescence immediately following irradiation. Approximately 50% of the cellular fluorescence could be suppressed by inclusion of either DMSO or the iron‐chelator desferroxamine. Combining the latter two agents did not enhance suppression. We conclude that APF can be used to monitor the formation of both ¹O₂ and ^?OH in cells subjected to PDT if studies are performed in the presence and absence of DMSO, respectively. That portion of the fluorescence quenched by DMSO will represent the contribution of ^?OH. This procedure could represent a useful means for evaluating formation of both ROS in the context of PDT.     

Octahedron-dependent near-infrared luminescence in Cr3+-activated phosphors

Searching for broadband near-infrared (NIR) materials with high efficiency and excellent thermal luminescence stability is of great significance because of their widespread spectroscopic applications. Different element substitution can modulate the structure and crystal field of host lattice so as to regulate the luminescent properties. Herein, we report the octahedron-dependent NIR luminescence in Cr³⁺-doped KMP₂O₇ (M = Ga, Sc, In, and Lu) phosphors and investigate the effect of octahedral environment on luminescent properties, aiming to provide guidance for host material selection. The decreased crystal field strength leads to the apparent spectral red shift from 815 to 900 nm for the samples of M = Ga to Lu. The small Stokes shift as well as weak electron–phonon coupling effect decreases the non-radiative transition probability and thus gives rise to the highest emission intensity and excellent thermal stability of Cr³⁺-doped KGaP₂O₇. The optimal sample, KGa_0.89P₂O₇:0.11Cr³⁺, possesses an internal/external quantum efficiency of 55.8%/36.6%, and its integrated emission intensity at 423 K can maintain 68% of that at room temperature. Finally, we investigate the potential applications in non-destructive examination field by manufacturing a NIR phosphor-conversion light-emitting diode device.     

A Highly Efficient Chemiluminescence Probe for the Detection of Singlet Oxygen in Living Cells

Singlet oxygen is among the reactive oxygen species (ROS) with the shortest life‐times in aqueous media because of its extremely high reactivity. Therefore, designing sensors for detection of ¹O₂ is perhaps one of the most challenging tasks in the field of molecular probes. Herein, we report a highly selective and sensitive chemiluminescence probe ( SOCL‐CPP ) for the detection of ¹O₂ in living cells. The probe reacts with ¹O₂ to form a dioxetane that spontaneously decomposes under physiological conditions through a chemiexcitation pathway to emit green light with extraordinary intensity. SOCL‐CPP demonstrated promising ability to detect and image intracellular ¹O₂ produced by a photosensitizer in HeLa cells during photodynamic therapy (PDT) mode of action. Our findings make SOCL‐CPP the most effective known chemiluminescence probe for the detection of ¹O₂. We anticipate that our chemiluminescence probe for ¹O₂ imaging would be useful in PDT‐related applications and for monitoring ¹O₂ endogenously generated by cells in response to different stimuli.     

Gadolinium(III) Porpholactones as Efficient and Robust Singlet Oxygen Photosensitizers

Construction of Gd^III photosensitizers is important for designing theranostic agents owing to the unique properties arising from seven unpaired f electrons of the Gd³⁺ ion. Combining these with the advantages of porpholactones with tunable NIR absorption, we herein report the synthesis of Gd^III complexes Gd‐1 – 4 ( 1 , porphyrin; 2 , porpholactone; 3 and 4 , cis‐ and trans‐porphodilactone, respectively) and investigated their function as singlet oxygen (¹O₂) photosensitizers. These Gd complexes displayed ¹O₂ quantum yields (Φ_Δs) from 0.64–0.99 with the order Gd‐1 < Gd‐2 < Gd‐3 < Gd‐4 . The gradually enhanced ¹O₂ sensitization after β‐oxazolone moiety replacement was ascribed to the narrowing of the energy gap (ΔE) between the lowest triplet states (T₁) of the ligand and the energy level of the ¹Δ_g→³Σ_g transition of ¹O₂. In particular, Gd‐4 is capable of excitation in the visible to NIR region (400–700 nm) with a quantum yield near unity. These Gd complexes were first demonstrated as efficient photosensitizers in photocatalysis such as oxidative C?H bond functionalization of secondary or tertiary amines, and the oxygenation of the natural product cholesterol. Finally, after glycosylation, these water‐soluble Gd complexes showed potential applications in photodynamic therapy (PDT) in HeLa cells. This work revealed that Gd^III complexes of “bioinspired” β‐modified porpholactones are efficient NIR photosensitizers and form a chemical basis to construct appealing photocatalysts and theranostic agents based on lanthanides.     

Singlet Oxygen Luminescence Image in Blood Vessels During Vascular-Targeted Photodynamic Therapy

Singlet oxygen (¹O₂) is widely regarded as the main cytotoxic substance that induces the biological damage for photodynamic therapy (PDT). In this study, the previously developed near-infrared (NIR) optical imaging system was optimized for fast imaging of ¹O₂ luminescence. The optical imaging system enables direct imaging of ¹O₂ luminescence in blood vessels within 2 s during vascular-targeted PDT (V-PDT), which makes this system extremely practical for in vivo studies. The dependence of RB concentration on ¹O₂ luminescence image was investigated for V-PDT, and the data imply that 1270 nm signal is attributed to ¹O₂ luminescence. The imaging system operates with a field of view of 9.60 × 7.68 mm² and a spatial resolution of 30 μm, which holds the potential to elucidate the correlation between cumulative ¹O₂ luminescence and vasoconstriction for V-PDT.     

Theranostic Nanoplatform with Hydrogen Sulfide Activatable NIR Responsiveness for Imaging‐Guided On‐Demand Drug Release

NIR light responsive nanoplatforms hold great promise for on‐demand drug release in precision cancer medicine. However, currently available systems utilize “always‐on” photothermal transducers that lack target specificity, and thus inaccurately differentiate tumors from normal tissues. Developed here is a theranostic nanoplatform featuring H₂S‐mediated in situ production of NIR photothermal agents for imaging‐guided and photocontrolled drug release. The system targets H₂S‐rich cancers. This nanoplatform shows H₂S‐activatable NIR‐II emission and NIR light controllable release of the drug Camptothecin‐11. Upon administering the system to HCT116 tumor‐bearing mice, the tumor is greatly suppressed with minimal side effects, arising from the synergy of the cancer‐specific and NIR light activated therapy. This theranostic nanoplatform thus sheds light on precision medicine with guidance through NIR‐II imaging.     

Controllable Release and High‐Efficiency Collection of Hydrogen Peroxide: Application on the Quantitative Investigation of Biomolecule Oxidation Induced by Reactive Oxygen Species

Hydrogen peroxide and hydroxyl radical, both important members of the reactive oxygen species (ROS) family, can cause serious oxidative damages in biological systems. In order to proclaim and prevent oxidation stress, researches on the biomolecule oxidation induced by H₂O₂ or OH^. are in crucial need. However, due to the high reactivity of ROS, traditional methods are difficult to achieve the in situ quantitative investigations on those reactions involving ROS. In this work, using scanning electrochemical microscopy technique (SECM) in a tip generation‐substrate collection mode (TG‐SC), the controllable release and the high‐efficiency collection of electrogenerated H₂O₂ were achieved. Compared to ex situ fluorescence method, SECM improved the collection efficiency approximately two times larger. Based on it, SECM combined with surface plasmon resonance (SPR) was employed to in situ monitor the protein oxidation (taking Cu₁₂⁺? MT as a model) induced by H₂O₂. OH^., which was generated from the interaction between H₂O₂ and Cu₁₂⁺? MT, can attack the peptide chain and induced the unrepairable protein oxidation damage. The whole process was quantitatively characterized by SPR, and the linear relationship between SPR dip shift and the amounts of released H₂O₂ was successfully built. Our work proves that the combined SECM‐SPR technique can realize the in situ quantitative determinations of the biomolecule oxidation induced by ROS, which affords an avenue for further elucidation on the mechanisms of oxidation stress in organisms.     

Self-Amplified Photodynamic Therapy through the 1O2-Mediated Internalization of Photosensitizers from a Ppa-Bearing Block Copolymer

Nanocarriers are employed to deliver photosensitizers for photodynamic therapy (PDT) through the enhanced penetration and retention effect, but disadvantages including the premature leakage and non-selective release of photosensitizers still exist. Herein, we report a ¹O₂-responsive block copolymer (POEGMA-b-P(MAA-co-VSPpaMA) to enhance PDT via the controllable release of photosensitizers. Once nanoparticles formed by the block copolymer have accumulated in a tumor and have been taken up by cancer cells, pyropheophorbide a (Ppa) could be controllably released by singlet oxygen (¹O₂) generated by light irradiation, enhancing the photosensitization. This was demonstrated by confocal laser scanning microscopy and in vivo fluorescence imaging. The ¹O₂-responsiveness of POEGMA-b-P(MAA-co-VSPpaMA) block copolymer enabled the realization of self-amplified photodynamic therapy by the regulation of Ppa release using NIR illumination. This may provide a new insight into the design of precise PDT.     

Self‐Amplified Photodynamic Therapy through the 1O2‐Mediated Internalization of Photosensitizers from a Ppa‐Bearing Block Copolymer

Nanocarriers are employed to deliver photosensitizers for photodynamic therapy (PDT) through the enhanced penetration and retention effect, but disadvantages including the premature leakage and non‐selective release of photosensitizers still exist. Herein, we report a ¹O₂‐responsive block copolymer (POEGMA‐b‐P(MAA‐co‐VSPpaMA) to enhance PDT via the controllable release of photosensitizers. Once nanoparticles formed by the block copolymer have accumulated in a tumor and have been taken up by cancer cells, pyropheophorbide a (Ppa) could be controllably released by singlet oxygen (¹O₂) generated by light irradiation, enhancing the photosensitization. This was demonstrated by confocal laser scanning microscopy and in vivo fluorescence imaging. The ¹O₂‐responsiveness of POEGMA‐b‐P(MAA‐co‐VSPpaMA) block copolymer enabled the realization of self‐amplified photodynamic therapy by the regulation of Ppa release using NIR illumination. This may provide a new insight into the design of precise PDT.     

A mini review of nanomaterials on photodynamic therapy

In this account, the reactive oxygen species (ROS) in photodynamic therapy (PDT) were deliberately reviewed. First, the specific definition of ROS and PDT were readily clarified. Afterward, this review focuses on the fundamental principles and applications of PDT. Due to strong oxidation ability of radicals (e.g., •OH and O₂^•-) and non-radical (e.g., ¹O₂ and H₂O₂), these ROS would attack the in vitro and in vivo tumor cells, thus achieving the goal of cancer treatment. Then, ROS in PDT for cancer treatment was thoroughly reviewed, including the mechanism and photosensitizer (PS) selection (i.e., nanomaterials). Ultimately, emphasis was made on the challenges, research gap, and prospects of ROS in cancer treatment and critically discussed. Hopefully, this review can offer detailed theoretical guidance for the researchers who participate in the study regarding ROS in PDT.     

Pheophytin Derived Near‐Infrared‐Light Responsive Carbon Dot Assembly as a New Phototheranotic Agent for Bioimaging and Photodynamic Therapy

Carbon dots (CDs), a kind of phototheranostic agent with the capability of simultaneous bioimaging and phototherapy [i.e., photodynamic therapy (PDT) or photothermal therapy (PTT)], have received considerable attention because of their remarkable properties, including flexibility for surface modification, high biocompatibility, low toxicity and photo‐induced activity for malignant tumor cells. Among numerous carbon sources, it has been found that natural biomass are good candidates for the preparation of CD phototheranostic agents. In this study, pheophytin, a type of Mg‐free chlorophyll derivative and also a natural product with low toxicity, was used as a raw carbon source for the synthesis of CDs by using a microwave method. The obtained hydrophobic CDs exhibited a maximum near‐infrared (NIR) emission peak at approximately 680 nm, and high singlet oxygen (¹O₂) generation with a quantum yield of 0.62. The self‐assembled CDs from the as‐prepared CDs with DSPE‐mPEG2000 retained efficient ¹O₂ generation. The obtained carbon dot assembly was not only an efficient fluorescence (FL) imaging agent but also a smart PDT agent. Our studies indicated that the obtained hydrophilic CD assembly holds great potential as a new phototheranostic agent for cancer therapy. This work provides a new route for synthesis of CDs and proposes a readily available candidate for tumor treatment.