Tannic Acid-Based Self-Assembling Nanocarriers with Antiphotobleaching and Controlled Releasing Properties for Collaborative Near-Infrared Photothermal/Photodynamic Therapy.

Near-infrared (NIR) organic materials have been widely developed for tumor phototherapy due to their deep tumor penetration, good biodegradability, and high photothermal conversion (PCE). However, most of the NIR organic dyes are easily destroyed by photooxidation due to their big and long conjugated structures, such as cyanine dyes. Under light irradiation, the reactive oxygen species (ROS) produced by these NIR dyes can easily break their conjugated skeleton, resulting in a dramatic decrease in phototherapeutic efficiency. Herein, an NIR organic dye cyanine dye (CyS) and a photosensitizer methylene blue (MB) were chosen to prepare nanocarrier CMTNPs by facile self-assembling with a natural antioxidant, tannic acid (TA). TA can greatly enhance the stability of NIR cyanine dyes by scavenging ROS. Furthermore, CMTNPs have a character of pH/thermal dual response, allowing for controlled release of MB in the slightly acidic tumor environment during photothermal therapy. The released MB can turn on both fluorescence and photodynamic therapy effects. In vitro and in vivo experiments demonstrated the remarkable tumor ablation ability of CMTNPs. Thus, our study provided an antiphotobleaching and controlled release photosensitizer strategy through the introduction of antioxidant TA into the nanocarrier for efficient collaborative photothermal/photodynamic therapy.

Type-I Photodynamic Therapy Induced by Pt-Coordination of Type-II Photosensitizers into Supramolecular Complexes.

Platinum supramolecular complexes based on photosensitizers have garnered great interest in photodynamic therapy (PDT) due to Pt (II) centers as chemotherapeutic agents to eliminate tumor cells completely, which greatly improve the antitumor efficacy of PDT. However, in comparison to precursor photosensitizer ligand, the formed platinum supramolecular complexes typically exhibit inferior outcomes in terms of reactive oxygen species (ROS) generation. How to boost ROS generation in the formed platinum supramolecular complexes for enhanced PDT is an enticing yet highly challenging task. Here we report a Pt-coordination-based dimeric photosensitizer complex (Cz-BTZ-Py)2Pt(OTf)2. It is found that comparing with photosensitizer ligand Cz-BTZ-Py, the formed supramolecular complex exhibit redshifts of absorption wavelength as well as enhanced ROS generation efficiency. Moreover, type-I ROS generation (O2⋅-) is produced in the formed platinum supramolecular complexes mainly due to a reduced energy gap ΔEST resulting from exciton coupling between two photosensitizer ligands. And type-I ROS (O2⋅-) generation significantly amplifies the photodynamic therapy (PDT) outcomes. In vitro evaluation shows excellent photochemotherapy performance of (Cz-BTZ-Py)2Pt(OTf)2 nanoparticles. We anticipate this work would provide a novel approach to design type-I photosensitizers for efficient PDT.

Configuration-mediated excited-state energy dissipation in metal-bridged dimeric D-A fluorophores for enhanced photothermal therapy.

Photothermal agents (PTAs) based on donor (D)-acceptor (A) NIR fluorophores show great promise in photothermal therapy due to their accessible molecular engineering to mediate excitation energy for high photothermal conversion. Except for molecular structural modification of D-A fluorophores, intermolecular arrangement in space greatly influences their excitation energy dissipation as well. But how to mediate their intermolecular arrangement is still challenging. Here we control the intermolecular orientation of chromophores via metal coordination to form Pt-bridged dimeric D-A fluorophores with different geometries. The formed configuration isomers show different intermolecular exciton coupling behaviors involving charge transfer (CT) evolution and internally limited molecular rotation, which greatly affect excited-energy dissipation. Compared with folded configuration with intense NIR emission (quantum yields (QYs) = 15.62 %), linear configuration favors non-radiative decays with low QYs (6.99 %) but enhanced photothermal conversion efficiency (PCE = 41.57 %). The self-assembled nanoparticles combining Pt-bridged dimeric D-A fluorophores with DSPE-PEG2000-RGD reveal superior photothermal therapeutic features with desirable biosafety. This research provides a new designing concept to mediate excited-state energy dissipation pathways at a sub-nano level for enhanced photothermal conversion. STATEMENT OF SIGNIFICANCE: D-A fluorophores as photothermal agents attract great attention in photothermal therapy due to their accessible molecular engineering. Besides molecular engineering of D-A fluorophores, the intermolecular packing manner is proven to greatly affect their excitation energy dissipation. But how to control intermolecular arrangement is still challenging. Here we control the intermolecular orientation of chromophores via metal coordination to form Pt-bridged dimeric D-A fluorophores with different geometries. Compared to the folded configuration, linear configuration facilitates charge transfer (CT) evolution and molecular rotation, which promotes non-radiative decays of excited energy for enhanced photothermal therapy.

Metal-Coordination-Mediated H-Aggregates of Cyanine Dyes for Effective Photothermal Therapy.

Integration of cyanine dyes and metal ions into one nanoplatform via metal-coordination interactions is an effective strategy to build multimodality phototheranostics. The multifunctionalities of the formed nanoscale metal-organic particles (NMOPs) have been widely explored. However, the effect of metal-coordination interaction on the aggregation behavior of cyanine dyes is rarely reported. Herein, we reported the H-aggregation behavior of cyanine dye Cy-3COOH induced by different metal ions M (Fe2+ or Mn2+ ). Moreover, the extent of H-aggregates varied with different metal-coordination interactions. Upon NIR irradiation, H-aggregates of Cy-3COOH remarkably promoted photothermal conversion efficiency. Interestingly, we also find that H-aggregates of Cy-3COOH induced by metal ions can generate the reactive oxygen species (ROS) involving singlet oxygen (1 O2 ) and superoxide anion radical (O2 - ⋅) upon light irradiation. In addition, the ROS efficiency varies depending on the extent of H-aggregates. Additionally, the photoinduced ROS could disassemble aggregates and decompose cyanine dye Cy-3COOH, which limits the photothermal capability of Cy-3COOH/M NPs. Therefore, the photothermal performance of Cy-3COOH/M NPs could be manipulated by the degree of H-aggregation. This would provide a new insight to develop efficient phototheranostics NMOPs for cancer treatment.

A Selenium-Substituted Heptamethine Cyanine Photosensitizer for Near-Infrared Photodynamic Therapy.

Photodynamic therapy (PDT) is a relatively safe approach to cancer treatment without significant systemic side effects or drug resistance. However, the current PDT efficiency is unsatisfactory due to the lack of near-infrared (NIR) photosensitizers. Heptamethine cyanine (Cy7) dyes are well-known NIR fluorophores and are also used as photosensitizers. But their singlet oxygen quantum yields (ΦΔ ) are not ideal. Herein, we developed an NIR photosensitizer with a long-lived excited triplet state (τ=4.3 µs) by introducing a selenium atom into the structure of a Cy7 dye. The new NIR photosensitizer exhibits a significantly high singlet oxygen quantum yield (ΦΔ =0.11). Its good PDT effect was demonstrated in the living cells. Considering that the selenium-substituted photosensitizer has a very low dark cytotoxicity and good chemical stability, we conclude that it will have a promising future in biomedical and clinical applications.

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.

Rational design of a small organic photosensitizer for NIR-I imaging-guided synergistic photodynamic and photothermal therapy.

Developing a small molecular photosensitizer to achieve multimodal phototherapy has recently garnered attention as a promising strategy for efficient cancer treatment. However, synthesis of a multifunctional small molecular photosensitizer has remained challenging. Here we report an aggregation-induced-emission (AIE)-featured luminogen (AIEgen) TPA-BTZ decorated with long and branched alkyl chains. TPA-BTZ shows long-wavelength emission at ca. 800 nm in the NIR-I region. Moreover, upon laser irradiation, TPA-BTZ could produce O2˙- and 1O2via both type I and type II mechanisms for enhanced photodynamic therapy (PDT). The propeller-like structure triphenylamine (TPA) rotators not only endow TPA-BTZ with AIE characteristics but also facilitate heat generation by intramolecular rotation for photothermal therapy (PTT). More importantly, long and branched alkyl chains can create intermolecular spatial isolation in the fabricated TPA-BTZ@PEG2000 nanoparticles (NPs) to allow sufficient intramolecular motion for photothermal conversion. Due to these unique features, in vitro and in vivo evaluations demonstrate that the TPA-BTZ@PEG2000 NPs exhibited long-term NIR-imaging ability, superior tumoricidal activity, and suppressed tumor growth. This research provides new insights for developing new AIEgens for NIR imaging-guided multimodal phototherapy.

Open-Source and Reduced-Expenditure Nanosystem with ROS Self-Amplification and Glutathione Depletion for Simultaneous Augmented Chemodynamic/Photodynamic Therapy.

Reactive oxygen species (ROS)-induced cell apoptosis has emerged as an efficient strategy for cancer therapy. However, tumor hypoxia and insufficient amounts of endogenous hydrogen peroxide (H2O2) in the tumor microenvironment are currently the main limitations of photodynamic therapy (PDT) and chemodynamic therapy (CDT). Moreover, the glutathione (GSH) scavenging effect on ROS further hinders the efficiency of ROS-mediated therapy. Here, a CaO2-based nanosystem (named as CF@CO@HC) with ROS self-amplification and GSH-depletion abilities was developed by a bottom-up approach. This hybrid nanoparticle consisted of a photosensitizer-doped calcium peroxide (CaO2) core (CaO2-FM), a hybrid organosilica framework (Cu-ONS) incorporated with Fenton reagents (Cu2+) and tetrasulfide groups, and a local hydrophobic cage (HC) shell. The photosensitizer was fluorescein derivative 4-FM with a thermally activated delayed fluorescence (TADF) property. The HC shell was built to protect the CaO2 and the photosensitizer from being attacked by water. Upon being internalized into cancer cells, the nanosystem was decomposed through the reduction reactions of Cu2+ and the tetrasulfide bond-doped silica shell by GSH, thus releasing Cu+ for Cu+-mediated CDT. Meanwhile, the exposed CaO2-FM can react with H2O to liberate photosensitizer 4-FM and generate H2O2 and O2 to overcome barriers in CDT and PDT. Thus, our study provided an open-source and reduced-expenditure strategy via GSH depletion and ROS self-amplification behaviors for ROS generation and significantly achieved an improved synergistic PDT/CDT for cancers.

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.

A highly selective sequential recognition probe for Zn2+ and HSO4-/H2PO4- based on a diarylethene chemosensor.

A novel diarylethene derivative chemosensor DTP-o connected to Schiff base unit for fluorescent detection of Zn2+ and relay-detection of HSO4-/H2PO4- was designed and synthesized successfully. DTP-o displayed excellent photochromism and fluorometric sensing toward Zn2+ to form DTP-o-Zn2+ complex in acetonitrile with the detection limit of 5.62 × 10-7 M. And the form of DTP-o combined with Zn2+ could further be verified by Job's plot titrations and mass spectrometry analysis. Furthermore, the complex of DTP-o-Zn2+ showed an excellent characteristic of fluorescent relay-response toward HSO4- and H2PO4- with high sensitivity and selectivity. The detection limits for HSO4- and H2PO4- were as low as 3.04 × 10-8 M and 3.41 × 10-8 M, respectively. Moreover, the sensor DTP-o could also be applied to detect Zn2+ on practical samples and test strips with high accuracy.