Integration of TADF Photosensitizer as "Electron Pump" and BSA as "Electron Reservoir" for Boosting Type I Photodynamic Therapy.

Type I photosensitization provides an effective solution to the problem of unsatisfactory photodynamic therapeutic (PDT) effects caused by the tumor hypoxia. The challenge in the development of Type I mode is to boost the photosensitizer's own electron transfer capacity. Herein, we found that the use of bovine serum albumin (BSA) to encapsulate a thermally activated delayed fluorescence (TADF) photosensitizer PS can significantly promote the Type I PDT process to generate a mass of superoxide anions (O2•-). This Type I photosensitization opened a new strategy by employing BSA as "electron reservoir" and TADF photosensitizer as "electron pump". We integrated these roles of BSA and PS in one system by preparing nanophotosensitizer PS@BSA. The Type I PDT performance was demonstrated with tumor cells under hypoxic conditions. Furthermore, PS@BSA took full advantage of the tumor-targeting role of BSA and achieved efficient PDT for tumor-bearing mice in the in vivo experiments. This work provides an effective route to improve the PDT efficiency of hypoxic tumors.

Jointly Depleting Glutathione Based on Self-Assembled Nanomicelles for Enhancing Photodynamic Therapy.

Photodynamic therapy (PDT) is one common ROS-generating therapeutic method with high tumor selectivity and low side effects. But the GSH-upregulation often alleviates its therapeutic efficiency. Here, we proposed a new strategy of jointly depleting GSH to enhance the therapeutic effect of PDT by preparing a nanomicelle by self-assembly method from GSH-activated photosensitizer DMT, curcumin, and amphiphilic polymer TPGS.

Self-assembly-integrated tumor targeting and electron transfer programming towards boosting tumor type I photodynamic therapy.

Type I photodynamic therapy (PDT) is attracting increasing interest as an effective solution to the poor prognosis of patients with hypoxic tumors. The development of functional type I photosensitizers is limited by a lack of feasible strategies to systematically modulate electron transfer (ET) in photosensitization. Herein, we present an easily accessible approach for the preparation of nanophotosensitizers with self-assembly-integrated tumor-targeting and ET programming towards boosting tumor type I PDT. Specifically, a dual functional amphiphile PS-02 was designed with a ligand (6-NS) that had the ability to not only target tumor cell marker carbonic anhydrase IX (CAIX) but also regulate the ET process for type I PDT. The amphiphile PS-02 tended to self-assemble into PS-02 nanoparticles (NPs), which exhibited a local "ET-cage effect" due to the electron-deficient nature of 6-NS. It is noteworthy that when PS-02 NPs selectively targeted the tumor cells, the CAIX binding enabled the uncaging of the inhibited ET process owing to the electron-rich characteristic of CAIX. Therefore, PS-02 NPs integrated tumor targeting and CAIX activation towards boosting type I PDT. As a proof of concept, the improved PDT performance of PS-02 NPs was demonstrated with tumor cells under hypoxic conditions and solid tumor tissue in mouse in vivo experiments. This work provides a practical paradigm to develop versatile type I PDT nano-photosensitizers by simply manipulating ET and easy self-assembling.

An unexpected strategy to alleviate hypoxia limitation of photodynamic therapy by biotinylation of photosensitizers.

The most common working mechanism of photodynamic therapy is based on high-toxicity singlet oxygen, which is called Type II photodynamic therapy. But it is highly dependent on oxygen consumption. Recently, Type I photodynamic therapy has been found to have better hypoxia tolerance to ease this restriction. However, few strategies are available on the design of Type I photosensitizers. We herein report an unexpected strategy to alleviate the limitation of traditional photodynamic therapy by biotinylation of three photosensitizers (two fluorescein-based photosensitizers and the commercially available Protoporphyrin). The three biotiylated photosensitizers named as compound 1, 2 and 3, exhibit impressive ability in generating both superoxide anion radicals and singlet oxygen. Moreover, compound 1 can be activated upon low-power white light irradiation with stronger ability of anion radicals generation than the other two. The excellent combinational Type I / Type II photodynamic therapy performance has been demonstrated with the photosensitizers 1. This work presents a universal protocol to provide tumor-targeting ability and enhance or trigger the generation of anion radicals by biotinylation of Type II photosensitizers against tumor hypoxia.

Naphthofluorescein-based organic nanoparticles with superior stability for near-infrared photothermal therapy.

Photothermal agents (PTAs) based on organic small molecules with near-infrared (NIR) absorption (700-900 nm) have attracted increasing attention in cancer photothermal therapy (PTT). However, NIR organic PTAs often suffer from poor stability. Fluorescein and its derivatives have been widely used in biological imaging and sensing due to their minimal cytotoxicity. But fluorescein and its derivatives have not been used in PTT because most of them don't have NIR absorption. In this work, two NIR naphthofluorescein derivatives, namely NFOM-1 and NFOM-2, were synthesized. In contrast to NFOM-1, NFOM-2 possesses an intramolecular hydrogen bonding network, which extends the absorption to the NIR region and significantly improves the photostability. NFOM-2 was encapsulated into an amphiphilic polymer (DSPE-mPEG2000) to obtain NFOMNPs as PTAs. Compared to the organic molecule NFOM-2, the absorption of NFOMNPs is broadened and further red-shifted to fit an 808 nm light source. Moreover, NFOMNPs exhibit good photothermal conversion efficiency (PCE, 40.4%, 808 nm, 1.0 W cm-2), remarkable photostability and physiological stability, and significant PTT efficacy in vitro and in vivo was achieved. In other words, this study provides an intramolecular hydrogen bond network strategy and a fluorescein-based molecular platform to construct ultra-stable PTAs for efficient NIR PTT.

Liposome-Based Nanoencapsulation of a Mitochondria-Stapling Photosensitizer for Efficient Photodynamic Therapy.

Mitochondria-targeting photodynamic therapy (PDT) can block mitochondrial function and trigger the inherent proapoptotic cascade signal of mitochondria, which has been considered to have the potential to amplify the efficiency of PDT. However, the dynamic change of mitochondrial membrane potential (MMP) makes most cationic photosensitizers easily fall off from the mitochondria, which greatly limits the efficiency of PDT. Here, we have developed a smart liposome encapsulation method based on a mitochondria-stapling photosensitizer for efficient theranostic photodynamic therapy. The stapling photosensitizer can be covalently bound inside mitochondria via two reaction sites without a falloff effect, regardless of the change of MMP. As a result, the liposome-based nanophotosensitizer showed a high efficiency of PDT (IC50 = 0.98 µM) under 630 nm light. At the same time, the nanophotosensitizer had fluorescence imaging-guided ability to monitor abnormal mitochondrial morphology during PDT. Importantly, the results of mice experiments also showed that the liposome-based nanophotosensitizer possessed excellent antitumor PDT activity because the released photosensitizer can stay inside mitochondria during the whole process of PDT.

A Dual-Nanozyme-Catalyzed Cascade Reactor for Enhanced Photodynamic Oncotherapy against Tumor Hypoxia.

Tumor hypoxia is a typical characteristic of tumor microenvironment (TME), which seriously compromises the therapeutic effect of photodynamic therapy (PDT). The development of nanozymes with oxygen-generation ability is a promising strategy to overcome the oxygen-dependent of PDT but remained a great challenge. Herein, a dual-nanozymes based cascade reactor HAMF is proposed to alleviate tumor hypoxia for enhanced PDT. The hollow mesoporous silica nanoparticles (HMSNs) are constructed as an excellent nanocarrier to load ultra-small gold nanoparticles (Au NPs) and manganese dioxide (MnO2 ) shell via in situ reduction method, and further coordination with an efficient photosensitizer 4-DCF-MPYM (4-FM), a thermally activated delayed fluorescence (TADF) fluorescein derivative. With the response to TME, MnO2 can catalyze endogenous H2 O2 into O2 and subsequently accelerating glucose oxidation by Au NPs to produce additional H2 O2 , which is reversely used as the substrate for MnO2 -catalyzed reaction, thereby constantly producing singlet oxygen (1 O2 ) for enhanced PDT upon light irradiation. This work proposed a cascade reactor based on dual-nanozyme to relieve tumor hypoxia for effective tumor suppression, which may enrich the application of multi-nanozymes in biomedicine.

Constructing a Local Hydrophobic Cage in Dye-Doped Fluorescent Silica Nanoparticles to Enhance the Photophysical Properties.

Aggregation-caused quenching (ACQ) and poor photostability in aqueous media are two common problems for organic fluorescence dyes which cause a dramatic loss of fluorescence imaging quality and photodynamic therapy (PDT) failure. Herein, a local hydrophobic cage is built up inside near-infrared (NIR) cyanine-anchored fluorescent silica nanoparticles (FSNPs) in which a hydrophobic silane coupling agent (n-octyltriethoxysilane, OTES) is doped into FSNPs for the first time to significantly inhibit the ACQ effect and inward diffusion of water molecules. Therefore, the obtained optimal FSNP-C with OTES-modification can provide hydrophobic repulsive forces to effectively inhibit the π-π stacking interaction of cyanine dyes and simultaneously reduce the formation of strong oxidizing species (•OH and H2O2) in reaction with H2O, resulting in the best photostability (fluorescent intensity remained at 90.1% of the initial value after 300 s of laser scanning) and a high PDT efficiency on two- and three-dimensional (spheroids) HeLa cell culture models. Moreover, through molecular engineering (including increasing covalent anchoring sites and steric hindrance groups of cyanine dyes), FSNP-C exhibits the highest fluorescent intensity both in water solution (12.3-fold improvement compared to free dye) and living cells due to the limitation of molecular motion. Thus, this study provides an effectively strategy by combining a local hydrophobic cage and molecular engineering for NIR FSNPs in long-term bright fluorescence imaging and a stable PDT process.

Red-to-blue photon up-conversion with high efficiency based on a TADF fluorescein derivative.

A new photon up-conversion system with a TADF fluorescein derivative as a photosensitizer was developed to achieve a quite large anti-Stokes shift from red to blue with a fairly high up-conversion emission quantum yield. This TADF photosensitizer has a very small ΔEST to provide a 207 nm anti-Stokes shift photon up-conversion. Meanwhile, it has a quite long triplet state lifetime (22.11 µs) and a large molar extinction coefficient to assure a high up-conversion efficiency of 11.2%. These results fully demonstrated the potential of the TADF fluorescein derivative as the photosensitizer used in photon up-conversion for the first time.

Achieving long-lived thermally activated delayed fluorescence in the atmospheric aqueous environment by nano-encapsulation.

Fluorescent silica nanoparticles, which encapsulated dye DCF-BYT with thermally activated delayed fluorescence (TADF) were fabricated by a simple synthetic method. Even in the atmospheric aqueous environment, the obtained DCF-BYT nanoparticles exhibited extremely long TADF lifetime up to 9.33 ms, which imparts these nanoparticles with great potential in biological applications, like time-resolved fluorescence imaging.

A dual-targeted theranostic photosensitizer based on a TADF fluorescein derivative.

Specific diagnosis and therapy of cancer is still a challenge in biomedical research. Photodynamic therapy (PDT) has emerged as a novel therapeutic modality for cancer treatment. However, the traditional PDT photosensitizers often exhibit low specific selectivity. In this study, we have reported a dual-targeted theranostic photosensitizer FL-RGD by covalently conjugating tumor marker cyclic arginine-glycine-aspartic acid tripeptide (RGD) and a fluorescein derivative FL which has a property of thermally activated delayed fluorescence (TADF) and a long triplet lifetime for efficient PDT. The FL-RGD can target tumor tissues and further locate lysosomes of tumor cells to concurrently achieve the cancers' specific diagnosis and efficient treatment. The mechanism of its highly efficient PDT was attributed to the damage of lysosome via 1O2. Besides, FL-RGD has the potential to be utilized in depth imaging and treatment by two-photon excitation. The actual diagnosis performance of FL-RGD was proved by fluorescence imaging of living cells and tumor bearing mice. The therapy performance was proved by MTT assays, fluorescence-activated cell sorting (FACS) analysis and PDT experiments on tumor bearing mice. The research obviously exhibited the potential of FL-RGD for tumor theranostics in vivo and in vitro.