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.

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.

Au@mSiO2 core-shell nanoparticles loaded with fluorescent dyes: synthesis and application for imaging performance.

Here, Au@mSiO2 core-shell nanoparticles were easily synthesized by a one-pot method. Positively charged alkyl chains with different lengths were modified on the surface of the particles. Thus composite nanoparticles with different potentials and hydrophilic interface properties were prepared. Based on the charge properties of the shell surface, the process of loading dyes was simplified by the strong electrostatic adsorption between the particle surface and the heterogeneous negatively charged dyes. The fluorescence intensity and fluorescence lifetime of the loaded fluorescent dyes showed that the dyes could not produce effective tunneling in the mesoporous materials, which was limited to the surface of the particles, which is beneficial for the subsequent research on the loading or release of nanoparticles. After loading, the nanoparticles still exhibit a high fluorescence intensity, enabling dual-mode microscopic imaging (TEM and fluorescence).

A Novel D-A-D Photosensitizer for Efficient NIR Imaging and Photodynamic Therapy.

Photodynamic therapy (PDT) has attracted great interest in cancer theranostics owing to its minimal invasiveness and low side effect. In PDT, photosensitizers are indispensable components that generate cytotoxic reactive oxygen species (ROS). Tremendous efforts have been devoted to optimizing the photosensitizer with enhanced ROS efficiency. However, to improve the precision and controllability for PDT, developing NIR imaging-guided photosensitizers are still urgent and challenging. Here, we have designed a novel photosensitizer 2Cz-BTZ which integrated with intense NIR emission and photoinduced singlet oxygen 1 O2 generation capabilities. Moreover, after loading the photosensitizers 2Cz-BTZ into biocompatible amphiphilic polymers F127, the formed 2Cz-BTZ@F127 nanoparticles (NPs) exhibited good photoinduced therapy as well as long-term in vivo imaging capabilities. Under these merits, the 2Cz-BTZ@F127 NPs showed NIR imaging-guided PDT, which paves a promising way for spatiotemporally precise tumor theranostics.

Porphyrin-based metal coordination polymers with self-assembly pathway-dependent properties for photodynamic and photothermal therapy.

Porphyrin-based metal coordination polymers (MCPs) have attracted significant attention due to their great promise for applications in phototherapy, including photodynamic therapy (PDT) and photothermal therapy (PTT). However, the detailed self-assembly process of porphyrin-based MCPs is still poorly understood. This work provides a detailed study of the self-assembly process of MCPs constructed from Mn2+ and TCPP (TCPP: 5,10,15,20-tetrakis(4'-carboxyphenyl)porphyrin) in aqueous solution. Unlike the traditional nucleation and growth mechanism, we discover that there is a metastable metal-organic intermediate which is kinetically favored in the self-assembly process. And the metastable metal-organic intermediate nanotape structures could convert into thermodynamically favored nanosheets through disassembling into monomers followed by a reassembling process. Moreover, the two structurally different assemblies exhibit distinct photophysical performances. The intermediate Mn-TCPP aggregates show good light-induced singlet oxygen 1O2 generation for PDT while the thermodynamically favored stable Mn-TCPP aggregates exhibit an excellent photothermal conversion ability as photothermal agents (PTAs). This study could facilitate the control of the self-assembly pathway to fabricate complex MCPs with desirable applications.

Self-Assembled Platinum Supramolecular Metallacycles Based on a Novel TADF Photosensitizer for Efficient Cancer Photochemotherapy.

Recently, supramolecular coordination complexes (SCCs) based on photosensitizers as bridging ligands have attracted great attention in cancer therapy owing to their synergistic effect between photodynamic therapy (PDT) and chemotherapy. Herein, a highly emissive supramolecular platinum triangle BTZPy-Pt based on a novel type of photosensitizer BTZPy with thermally activated delayed fluorescence (TADF) was fabricated. The BTZPy and BTZPy-Pt exhibited strong luminescence emission in the visible range with high quantum yields (quantum yields (QYs) for BTZPy and BTZPy-Pt were about 78 and 62% in ethanol solutions, respectively). Additionally, BTZPy had been proved to be an excellent photosensitizer with superior 1O2 generation capability (the 1O2 generation quantum yield reached up to ca. 95%) for PDT. By the combination of the excellent phototoxicity of BTZPy and the antitumor activity of the Pt center, the platinum triangle BTZPy-Pt demonstrated a highly efficient anticancer performance toward HeLa cells (IC50: 0.5 µg mL-1). This study not only provides a blueprint to fabricate new types of photosensitizers but also paves a way to design novel SCCs for efficient PDT.

Recent development of amorphous metal coordination polymers for cancer therapy.

Nanoscale metal coordination polymers (NCPs), built from metal ions and organic ligands, have attracted tremendous interest in biomedical applications. This is mainly due to their mesoporous structure, tunable size and morphology and versatile functionality. NCPs can be further divided into nanoscale metal-organic frameworks (NMOFs) and amorphous coordination polymer particles (ACPPs) depending on their structural crystallinity. NMOFs as nanocarriers have been extensively reviewed. However, the highlights of ACPPs as theranostic nanoplatforms are still limited. In this review, the recent progress of ACPPs as theranostic nanoplatforms is summarized based on what types of organic linkers used. The ACPPs are divided into three main parts: photosensitizers-based ACPPs, chemical drugs-based ACPPs, and biomolecules-based ACPPs. Finally, the prospects and challenges of the ACPPs for enhanced biomedical applications are also discussed. STATEMENT OF SIGNIFICANCE: Over the last decades, amorphous metal coordination polymers (ACPPs), constructed by metal ions and organic linkers, have attracted enormous interest in cancer treatment owing to their high drug loading capability, facile synthetic procedures, low long-term toxicity, and mild preparation conditions. In this review, we highlight the recent progress of ACPPs for biomedical application based on different types of organic building blocks including photosensitizers, chemical drugs, and biomolecules. Moreover, the prospects and challenges of ACPPs for clinical application are also discussed. We hope this review entitled "Recent development of amorphous metal coordination polymers for cancer therapy" would arise the researchers' interest in this field to accelerate their clinical application in cancer therapy.

Recent Development of Photothermal Agents (PTAs) Based on Small Organic Molecular Dyes.

Photothermal therapy (PTT) has attracted great attention due to its noninvasive and effective use against cancer. Various photothermal agents (PTAs) including organic and inorganic PTAs have been developed in the last decades. Organic PTAs based on small-molecule dyes exhibit great potential for future clinical applications considering their good biocompatibility and easy chemical modification or functionalization. In this review, we discuss the recent progress of organic PTAs based on small-molecule dyes for enhanced PTT. We summarize the strategies to improve the light penetration of PTAs, methods to enhance their photothermal conversion efficiency, how to optimize PTAs' delivery into deep tumors, and how to resist photobleaching under repeated laser irradiation. We hope that this review can rouse the interest of researchers in the field of PTAs based on small-molecule dyes and help them to fabricate next-generation PTAs for noninvasive cancer therapy.

Histone deacetylase gene PtHDT902 modifies adventitious root formation and negatively regulates salt stress tolerance in poplar.

Histone deacetylases (HDACs) regulate gene transcription, and play a critical role in plant growth, development and stress responses. HD2 proteins are plant specific histone deacetylases. In woody plants, functions of HD2s are not known. In this study, we cloned an HD2 gene PtHDT902 from Populus trichocarpa and investigated its sequence, expression, subcellular localization, and functions in root development and salt stress responses. Our findings indicated that PtHDT902 was a nuclear protein and its expression was regulated by abiotic stresses. The over-expression of PtHDT902 in both Arabidopsis and poplar increased the expression levels of gibberellin (GA) biosynthetic genes. The expression of PtHDT902 in Arabidopsis enhanced primary root growth, and its over-expression in poplar inhibited adventitious root formation. These phenotypes resulted from over-expression of PtHDT902 were consistent with the GA-overproduction phenotypes. In addition, the poplar plants over-expressing PtHDT902 exhibited lower tolerance to salt than non-transgenic plants. These findings indicated that PtHDT902 worked as an important regulator in adventitious root formation and salt stress tolerance in poplar.

Thyroid function and decabromodiphenyl ethane (DBDPE) exposure in Chinese adults from a DBDPE manufacturing area.

Polybrominated diphenyl ethers (PBDEs), which are persistent organic pollutants, affect thyroid function. Human exposure to decabromodiphenyl ethane (DBDPE), which has a similar structure to PBDEs, has recently increased, and the health effects of DBDPE have not been well studied. The objective of this study was to determine whether human exposure to DBDPE was associated with thyroid hormone levels in adults from a DBDPE manufacturing area. Three hundred-two blood samples were collected from two populations in the largest DBDPE manufacturing area located in North China: 133 DBDPE occupationally exposed workers from a DBDPE manufacturing plant and 169 non-DBDPE occupationally exposed residents from a nearby food processing plant. The levels of DBDPE, and thyroid function parameters [total thyroxine (TT4), free T4 (FT4), total triiodothyronine (TT3), free T3 (FT3), thyroid-stimulating-hormone (TSH), thyroglobulin antibody (TG-Ab), and thyroid peroxidase antibody (TPO-Ab)] were measured in serum samples. Serum concentrations of DBDPE ranged from 3.148 to 54,360 ng g-1 lipid weight (lw), with a geometric mean of 332.6 ng g-1 lw. A 10-fold increase in the DBDPE concentration was associated with increase of 4.73 nmol L-1 [95% confidence interval (CI): 2.75, 6.71] TT4 and 0.046 nmol L-1 TT3 [95% CI: 0.012, 0.081], corresponding to increases of approximately of 4.73% (95% CI: 2.75%-6.71%) and 2.38% (95% CI: 0.62%-4.20%), respectively. DBDPE in serum was also significantly and positively associated with the concentrations of TG-Ab and TPO-Ab. Our study found that exposure to DBDPE was associated with changes in thyroid activity in adults exposed to a high concentration of DBDPE, mainly increases of TT4, TT3, TPO-Ab, and TG-Ab. The association between DBDPE exposure and thyroid homeostasis requires further investigation because increasing DBDPE exposure has emerged in recent years.

Histone deacetylases and their functions in plants.

Histone deacetylases (HDACs) mediate histone deacetylation and act in concert with histone acetyltransferases to regulate dynamic and reversible histone acetylation which modifies chromatin structure and function, affects gene transcription, thus, controlling multiple cellular processes. HDACs are widely distributed in almost all eukaryotes, and there have been many researches focusing on plant HDACs recently. An increasing number of HDAC genes have been identified and characterized in a variety of plant species and the functions of certain HDACs have been studied. The present studies indicate that HDACs play a key role in regulating plant growth, development and stress responses. This paper reviews recent findings on HDACs and their functions in plants, especially their roles in development and stress responses.