Photo-Induced Disproportionation-Mediated Photodynamic Therapy: Simultaneous Oxidation of Tetrahydrobiopterin and Generation of Superoxide Radicals.

We herein present an approach of photo-induced disproportionation for preparation of Type-I photodynamic agents. As a proof of concept, BODIPY-based photosensitizers were rationally designed and prepared. The photo-induced intermolecular electron transfer between homotypic chromophores leads to the disproportionation reaction, resulting in the formation of charged intermediates, cationic and anionic radicals. The cationic radicals efficiently oxidize the cellularimportant coenzyme, tetrahydrobiopterin (BH4 ), and the anionic radicals transfer electrons to oxygen to produce superoxide radicals (O2 - ⋅). One of our Type-I photodynamic agents not only self-assembles in water but also effectively targets the endoplasmic reticulum. It displayed excellent photocytotoxicity even in highly hypoxic environments (2 % O2 ), with a half-maximal inhibitory concentration (IC50 ) of 0.96 µM, and demonstrated outstanding antitumor efficacy in murine models bearing HeLa tumors.

Ultra-Small Nano-Assemblies as Tumor-Targeted and Renal Clearable Theranostic Agent for Photodynamic Therapy.

It is a challenge to design photosensitizers to balance between the tumor-targeting enrichment for precise treatment and efficient clearance within a reasonable timescale for reducing side effects. Herein, an ultra-small nano-photosensitizer 1a with excellent tumor-specific accumulation and renal clearance is reported. It is formed from the self-assembly of compound 1 bearing three triethylene glycol (TEG) arms and two pyridinium groups in water. The positively charged surface with neutral TEG coating enables 1a to efficiently target the tumor, with the signal-to-background ratio reaching as high as 11.5 after tail intravenous injection. The ultra-small size of 1a with an average diameter of 5.6 nm allows its fast clearance through kidney. Self-assembly also endows 1a with an 18.2-fold enhancement of reactive oxygygen species generation rate compared to compound 1 in organic solution. Nano-PS 1a manifests an excellent photodynamic therapy efficacy on tumor-bearing mouse models. This work provides a promising design strategy of photosensitizers with renal clearable and tumor-targeting ability.

Supramolecular Photosensitizer Enables Oxygen-Independent Generation of Hydroxyl Radicals for Photodynamic Therapy.

The highly oxygen-dependent nature of photodynamic therapy (PDT) limits its therapeutic efficacy against hypoxic solid tumors in clinics, which is an urgent problem to be solved. Herein, we develop an oxygen-independent supramolecular photodynamic agent that produces hydroxyl radical (•OH) by oxidizing water in the presence of intracellularly abundant pyruvic acid under oxygen-free conditions. A fluorene-substituted BODIPY was designed as the electron donor and coassembled with perylene diimide as the electron acceptor to form the quadruple hydrogen-bonded supramolecular photodynamic agent. Detailed mechanism studies reveal that intermolecular electron transfer and charge separation upon light irradiation result in an efficient generation of radical ion pairs. Under oxygen-free conditions, the cationic radicals directly oxidize water to generate highly cytotoxic •OH, and the anionic radicals transfer electrons to pyruvic acid, realizing the catalytic cycle. Thus, this photodynamic agent exhibited superb photocytotoxicity even under severe hypoxic environments and excellent in vivo antitumor efficacy on HeLa-bearing mouse models. This work provides a strategy for constructing oxygen-independent photodynamic agents, which opens up an avenue for effective PDT against hypoxic tumors.

Supramolecular photodynamic agents for simultaneous oxidation of NADH and generation of superoxide radical.

Given that Type-I photosensitizers (PSs) have hypoxia tolerance, developing general approaches to prepare Type-I PSs is of great importance, but remains a challenge. Here, we report a supramolecular strategy for the preparation of Type-I photodynamic agents, which simultaneously generate strong oxidizing cationic radicals and superoxide radicals, by introducing electron acceptors to the existing Type-II PSs. As a proof-of-concept, three electron acceptors were designed and co-assembled with a classical PS to produce quadruple hydrogen-bonded supramolecular photodynamic agents. The photo-induced electron transfer from the PS to the adjacent electron acceptor occurs efficiently, leading to the generation of a strong oxidizing PS+• and an anionic radical of the acceptor, which further transfers an electron to oxygen to form O2-•. In addition, these photodynamic agents induce direct photocatalytic oxidation of NADH with a turnover frequency as high as 53.7 min-1, which offers an oxygen-independent mechanism to damage tumors.

A host-guest strategy for converting the photodynamic agents from a singlet oxygen generator to a superoxide radical generator.

Type-I photosensitizers (PSs) generate cytotoxic oxygen radicals by electron transfer even in a hypoxic environment. Nevertheless, the preparation of type-I PSs remains a challenge due to the competition of triplet-triplet energy transfer with O2 (type-II process). In this work, we report an effective strategy for converting the conventional type-II PS to a type-I PS by host-guest complexation. Electron-rich pillar[5]arenes are used as an electron donor and macrocyclic host to produce a host-guest complex with the traditional electron-deficient type-II PS, an iodide BODIPY-based guest. The host-guest complexation promotes intermolecular electron transfer from the pillar[5]arene moiety to BODIPY and then to O2 by the type-I process upon light-irradiation, leading to efficient generation of the superoxide radical (O2 -˙). The results of anti-tumor studies indicate that this supramolecular PS demonstrates high photodynamic therapy efficacy even under hypoxic conditions. This work provides an efficient method to prepare type-I PSs from existing type-II PSs by using a supramolecular strategy.

Circularly polarized luminescence from helical N,O-boron-chelated dipyrromethene (BODIPY) derivatives.

We report N,O-boron-chelated dipyrromethene derivatives exhibiting circularly polarized luminescence (CPL) in the red/near-infrared region, both in solution and the aggregated state. The CPL is originated from the helical chirality through intramolecular substitution of fluorine by an alkenolic substituent. The self-assembly of the fluorophores significantly enhances the |glum| values from 10-4 to 10-2.

BODIPY-Based Photodynamic Agents for Exclusively Generating Superoxide Radical over Singlet Oxygen.

Developing Type-I photosensitizers is considered as an efficient approach to overcome the deficiency of traditional photodynamic therapy (PDT) for hypoxic tumors. However, it remains a challenge to design photosensitizers for generating reactive oxygen species by the Type-I process. Herein, we report a series of α,ß-linked BODIPY dimers and a trimer that exclusively generate superoxide radical (O2-. ) by the Type-I process upon light irradiation. The triplet formation originates from an effective excited-state relaxation from the initially populated singlet (S1 ) to triplet (T1 ) states via an intermediate triplet (T2 ) state. The low reduction potential and ultralong lifetime of the T1 state facilitate the efficient generation of O2-. by inter-molecular charge transfer to molecular oxygen. The energy gap of T1 -S0 is smaller than that between 3 O2 and 1 O2 thereby precluding the generation of singlet oxygen by the Type-II process. The trimer exhibits superior PDT performance under the hypoxic environment.

Rational design of a "dual lock-and-key" supramolecular photosensitizer based on aromatic nucleophilic substitution for specific and enhanced photodynamic therapy.

Photosensitizing agents are essential for precise and efficient photodynamic therapy (PDT). However, most of the conventional photosensitizers still suffer from limitations such as aggregation-caused quenching (ACQ) in physiological environments and toxic side-effects on normal tissues during treatment, leading to reduced therapeutic efficacy. Thus, integrating excellent photophysical properties and accurate carcinoma selectivity in a photosensitizer system remains highly desired. Herein, a "dual lock-and-key" supramolecular photosensitizer BIBCl-PAE NPs for specific and enhanced cancer therapy is reported. BIBCl-PAE NPs are constructed by encapsulating a rationally designed glutathione (GSH)-activatable photosensitizer BIBCl in a pH-responsive diblock copolymer. In normal tissues, BIBCl is "locked" in the hydrophobic core of the polymeric micelles due to ACQ. Under the "dual key" activation of low pH and high levels of GSH in a tumor microenvironment, the disassembly of micelles facilitates the reaction of BIBCl with GSH to release water-soluble BIBSG with ideal biocompatibility, enabling the highly efficient PDT. Moreover, benefiting from the Förster resonance energy transfer effect of BIBSG, improved light harvesting ability and 1O2 production are achieved. In vitro and vivo experiments have demonstrated that BIBCl-PAE NPs are effective in targeting and inhibiting carcinoma. BIBCl-PAE NPs show superior anticancer efficiency relative to non-activatable controls.

Correction: Rational design of a "dual lock-and-key" supramolecular photosensitizer based on aromatic nucleophilic substitution for specific and enhanced photodynamic therapy.

[This corrects the article DOI: 10.1039/D0SC01122C.].

An unexpected coupling-reduction tandem reaction for the synthesis of alkenyl-substituted BODIPYs.

We report an unexpected coupling-reduction tandem reaction as a general and efficient one-pot synthesis of alkenyl-substituted boron dipyrromethene (BODIPY) from chlorinated-BODIPY and alkyne. This unique synthesis combined the Sonogashira coupling reaction and reduction reaction without adding an additional reagent, which shows higher yields, broader substrate scope and faster reaction rate compared with the conventional methods of the Knoevenagel reaction and Heck coupling reaction.

Dual stimuli-responsive bispillar[5]arene-based nanoparticles for precisely selective drug delivery in cancer cells.

Paclitaxel-loaded nanoparticles based on a bispillar[5]arene compound were successfully developed using a microemulsion method for the first time. The nanoparticles exhibited dual stimuli-responsiveness towards both spermine and glutathione, allowing precisely selective drug release in lung cancer cells that overexpress both stimuli.

Supramolecular Polymer-Based Fluorescent Microfibers for Switchable Optical Waveguides.

We report the switchable optical waveguide microfibers based on fluorescent supramolecular polymer for the first time. The pillar[5]arene-based supramolecular polymeric microfibers were prepared easily from the viscous solution of bispillar[5]arene host (bisP5A) and diphenylanthracene-derived guest (GD). The resulting microfibers  act as an active optical waveguide material with long propagation distance (400 µm) and low optical propagation loss (0.01 dB/µm). When photoresponsive dithienylethene-derived guest (GDTE) was added, the resulting ternary microfibers show switchable optical waveguide by the noninvasive control of UV/vis light with negligible fatigue over four cycles. This convenient preparation method is also applied for the quadruple-hydrogen-bonded fluorescent supramolecular polymeric microfibers which imply good light propagation property with an optical loss coefficient of 0.02 dB/µm.

Fungistatic intensity of agricultural soil against fungal agents and phylogenetic analysis on the actinobacteria involved.

A total of 287 agricultural soil samples collected from 26 provinces or autonomous regions of China were tested on their ability to suppress the conidial germination of nine biocontrol fungal agents. These soil samples showed great differences in the degree to inhibit the germination of conidia (22.8% < mean inhibition rate < 97.5%), but all exhibited fungistatic activities above the moderate levels (mean inhibition rate > 50%) to most of tested fungi. Ten soil samples that have stronger fungistatic intensity (germination inhibition rate > 68.3%) to the target fungi, Trichoderma viride and Paecilomyces lilacinus, were selected to evaluate their soil actinobacteria involved fungistasis in soil. Of the 1,000 isolates from those soil samples, 345 actinobacteria exhibited fungistatic activity to conidial germination of T. viride and P. lilacinus with germination inhibition rates higher than 10%. Sequences encoding 16S rRNA gene of the 345 actinobacteria were analyzed by ARDRA and resulted 44 different ARDRA types. Fifty-six isolates, at least one from each unique ARDRA type, were selected for 16S rDNA sequencing and phylogenetic analysis. Results indicated that the actinobacteria involved in the soil fungistasis had close phylogenetic relationship with the members of Sterptomycetaceae, Microbacteriaceae, Micrococcaceae, and Nocardiacea.