A TME-enlightened protein-binding photodynamic nanoinhibitor for highly effective oncology treatment.

The efficiency of photodynamic therapy (PDT) is greatly dependent on intrinsic features of photosensitizers (PSs), but most PSs suffer from narrow diffusion distances and short life span of singlet oxygen (1O2). Here, to conquer this issue, we propose a strategy for in situ formation of complexes between PSs and proteins to deactivate proteins, leading to highly effective PDT. The tetrafluorophenyl bacteriochlorin (FBC), a strong near-infrared absorbing photosensitizer, can tightly bind to intracellular proteins to form stable complexes, which breaks through the space-time constraints of PSs and proteins. The generated singlet oxygen directly causes the protein dysfunction, leading to high efficiency of PSs. To enable efficient delivery of PSs, a charge-conversional and redox-responsive block copolymer POEGMA-b-(PAEMA/DMMA-co-BMA) (PB) was designed to construct a protein-binding photodynamic nanoinhibitor (FBC@PB), which not only prolongs blood circulation and enhances cellular uptake but also releases FBC on demand in tumor microenvironment (TME). Meanwhile, PDT-induced destruction of cancer cells could produce tumor-associated antigens which were capable to trigger robust antitumor immune responses, facilitating the eradication of residual cancer cells. A series of experiments in vitro and in vivo demonstrated that this multifunctional nanoinhibitor provides a promising strategy to extend photodynamic immunotherapy.

Tumor Microenvironment-Triggered Self-Adaptive Polymeric Photosensitizers for Enhanced Photodynamic Therapy.

Photodynamic therapy (PDT) employs photosensitizers to convert nearby oxygen into toxic singlet oxygen (1O2) upon laser light irradiation, showing great potential as a noninvasive approach for tumor ablation. However, the therapeutic efficacy of PDT is essentially impeded by π-π stacking and the aggregation of photosensitizers. Herein, we propose a tumor microenvironment-triggered self-adaptive nanoplatform to weaken the aggregation of photosensitizers by selenium-based oxidation at the tumor site. The selenide units in a selenium-based porphyrin-containing amphiphilic copolymer (PSe) could be oxidized into hydrophilic selenoxide units, leading to the nanoplatform self-expansion and stretching of the distance between intramolecular porphyrin units. This process could provide a better switch to greatly reduce the aggregation of photosensitive porphyrin units, generating more 1O2 upon laser irradiation. As verified in a series of in vitro and in vivo studies, PSe could be efficiently self-adapted at tumor sites, thus significantly enhancing the PDT therapeutic effect against solid tumors and minimizing side effects.

Monotropein Protects Mesenchymal Stem Cells from Lipopolysaccharide-Induced Impairments and Promotes Fracture Healing in an Ovariectomized Mouse Model.

Monotropein is one of the active ingredients in Morinda Officinalis, which has been used for the treatment in multiple bone and joint diseases. This study aimed to observe the in vitro effects of Monotropein on osteogenic differentiation of lipopolysaccharide treated bone marrow mesenchymal stem cells (bMSCs), and the in vivo effects of local application of Monotropein on bone fracture healing in ovariectomized mice. Lipopolysaccharide was used to set up the inflammatory model in bMSCs, which were treated by Monotropein. Molecular docking analysis was performed to evaluate the potential interaction between Monotropein and p65. Transverse fractures of middle tibias were established in ovariectomized mice, and Monotropein was locally applied to the fracture site using injectable hydrogel. Monotropein enhanced the ability of primary bMSCs in chondro-osteogenic differentiation. Furthermore, Monotropein rescued lipopolysaccharide-induced osteogenic differentiation impairment and inhibited lipopolysaccharide-induced p65 phosphorylation in primary bMSCs. Docking analysis showed that the binding activity of Monotropein and p65/14-3-3 complex is stronger than the selective inhibitor of NF-κB (p65), DP-005. Local application of Monotropein partially rescued the decreased bone mass and biomechanical properties of callus or healed tibias in ovariectomized mice. The expressions of Runx2, Osterix and Collagen I in the 2-week callus were partially restored in Monotropein-treated ovariectomized mice. Taking together, local application of Monotropein promoted fracture healing in ovariectomized mice. Inhibition of p65 phosphorylation and enhancement in osteogenesis of mesenchymal stem cells could be partial of the effective mechanisms.

Expanded single-color barcoding in microspheres with fluorescence anisotropy for multiplexed biochemical detection.

Single-color barcoding strategies could break the limits of spectral crosstalk in conventional intensity-based fluorescence barcodes. Fluorescence anisotropy (FA), a self-referencing quantity able to differentiate spectrally similar fluorophores, is highly attractive in designing fluorescent barcodes within a limited emission window. In this study, FA-based encoding of polystyrene (PS) microspheres was realized for the first time. The FA signals of fluorophores were stabilized inside PS microspheres owing to hampered rotational motion. Fluorescent labels were incorporated with similar emission but different structures, symmetries, and lifetimes. On the one hand, Förster Resonance Energy Transfer (FRET) including homo-FRET and hetero-FRET resulted in a decrease of steady-state FA with increasing dye loading, converting conventional intensity-based codes into FA-based codes. On the other hand, mixing dyes with different intrinsic FA values generated different FA values at the same fluorescence intensity level. Single color 5-plex FA-encoded microspheres were demonstrated and decoded on a homemade microscopic FA imaging platform in real time. The FA-encoded microspheres were successfully applied to detect the oligonucleotide of the foodborne bacterium, Bacillus cereus, without spectral crosstalk between the encoding and reporting dyes. Overall, FA-based encoding with an expanded coding capacity in the FA dimension holds great potential in multiplexed high-throughput chemical and biological analyses.

A hybrid erbium(III)-bacteriochlorin near-infrared probe for multiplexed biomedical imaging.

Spectrally distinct fluorophores are desired for multiplexed bioimaging. In particular, monitoring biological processes in living mammals needs fluorophores that operate in the 'tissue-transparent' near-infrared (NIR) window, that is, between 700 and 1,700 nm. Here we report a fluorophore system based on molecular erbium(III)-bacteriochlorin complexes with large Stokes shift (>750 nm) and narrowband NIR-to-NIR downconversion spectra (full-width at half-maximum ≤ 32 nm). We have found that the fast (2 × 109 s-¹) and near-unity energy transfer from bacteriochlorin triplets to the erbium(III) 4I13/2 level overcomes the notorious vibrational overtones quenching, resulting in bright and long-lived (1.73 µs) 1,530 nm luminescence in water. We demonstrate the excitation/emission-multiplexed capability of the complexes in the visualization of dynamic circulatory and metabolic processes in living mice, and through skull tracking of cancer cell metastases in mouse brain. This hybrid probe system facilitates robust multiplexed NIR imaging with high contrast and spatial resolution for applications ranging from fluorescence-guided surgery, diagnostics and intravital microscopy.

Highly Antibacterial and Adhesive Hyaluronic Acid Hydrogel for Wound Repair.

Bacterial infections accompanied with wound healing often lead to more serious health hazards to patients. Therefore, it is urgent to explore a wound dressing that can promote wound repair while possessing antibacterial capability. Here, we constructed a multifunctional hydrogel dressing by a redox-initiated cross-linking reaction of methacrylated hyaluronic acid (HAMA), 5,10,15,20-tetra (4-methacrylate phenyl) porphyrin (TPP), and dopamine methacrylamide (DMA), named HAMA-TPP-DMA, with broad-spectrum photodynamic antibacterial capability, where the aggregation of TPP photosensitizer units could be greatly inhibited to produce more singlet oxygen. The hydrogel has excellent biodegradability and biocompatibility, providing favorable conditions for wound healing. Furthermore, the incorporation of dopamine into the hydrogel gives the wound dressing with enhanced adhesiveness, benefiting for the wound repair. More importantly, the antibacterial experiments in vitro and mice wound models in vivo showed that the HAMA-TPP-DMA hydrogel can significantly resist bacteria and accelerate the wound healing in mice (the closure rate > 98% after 15 days). Thus, this hydrogel dressing with superior antibacterial infection and wound healing capability provides a promising strategy in wound repair.

Water-Soluble Polymers with Appending Porphyrins as Bioinspired Catalysts for the Hydrogen Evolution Reaction.

Molecular design to improve catalyst performance is significant but challenging. In enzymes, residue groups that are close to reaction centers play critical roles in regulating activities. Using this bioinspired strategy, three water-soluble polymers were designed with appending Co porphyrins and different side-chain groups to mimic enzyme reaction centers and activity-controlling residue groups, respectively. With these polymers, high hydrogen evolution efficiency was achieved in neutral aqueous media for electro- (turnover frequency >2.3×104  s-1 ) and photocatalysis (turnover number >2.7×104 ). Porphyrin units are surrounded and protected by polymer chains, and more importantly, the activity can be tuned with different side-chain groups. Therefore, instead of revising molecular structures that is difficult from both design and synthesis points of view, polymers can be used to improve molecular solubility and stability and simultaneously regulate activity by using side-chain groups.

Self-Amplified Photodynamic Therapy through the 1 O2 -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 1 O2 -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 (1 O2 ) generated by light irradiation, enhancing the photosensitization. This was demonstrated by confocal laser scanning microscopy and in vivo fluorescence imaging. The 1 O2 -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.

Precise Self-Assembly and Controlled Catalysis of Thermoresponsive Core-Satellite Multicomponent Hybrid Nanoparticles.

The construction of multicomponent hybrid nanomaterials with well-controlled architecture, especially bearing an ordered homogeneity and distribution of the subunits with tunable functions, is a key challenge in chemistry and material science. Herein, we reported a versatile and novel strategy to fabricate core-satellite multicomponent nanostructures with tunable interparticle distances and catalysis properties by the combination of surface-initiated reversible addition-fragmentation chain transfer (SI-RAFT) polymerization and self-assembly. The arrangement and interparticle distance of gold satellites could be precisely tuned by the SI-RAFT polymerization process and the feeding ratio of gold nanoparticles (AuNPs) and the core nanoparticle. It is worth to note that multilayered core-satellite nanostructures have been fabricated by a high-feeding ratio of AuNPs and magnetite NP (MNP)@SiO2-PNIPAm. Notably, the core-satellite MNP@SiO2-PNIPAm-Au nanoparticles exhibited excellent thermoresponsive behaviors with the change of temperature. Furthermore, the catalytic efficiency of MNP@SiO2-PNIPAm-Au nanoparticles via the reduction of 4-nitrophenol to 4-aminophenol can be well modulated by the nanoparticle size, temperature, and polymer feed ratio. This strategy for precise construction of core-satellite nanostructures would open a new pathway to construct multicomponent functional nanostructures.

NIR-Activated "OFF/ON" Photodynamic Therapy by a Hybrid Nanoplatform with Upper Critical Solution Temperature Block Copolymers and Gold Nanorods.

Photodynamic therapy (PDT) is a promising treatment modality for cancer treatment owing to its minimally invasive nature and negligible drug resistance. However, the disadvantages of conventional photosensitizers including universal aggregation-caused quenching (ACQ) effect or nonselective activation are still major hurdles for PDT clinical application. Herein, a new strategy for flexible manipulating photosensitizers in effective quenching and quick recovery of photoactivation is presented by introducing porphyrin units into upper critical solution temperature (UCST) block copolymer decorated gold nanorods (AuNR-P(AAm-co-AN-co-TPP)-b-PEG). The UCST block copolymer can achieve a self-quenching effect to make the porphyrin photosensitizers in the "Off" state by π-π stacking and hydrogen bonding interactions at physiological temperature, which greatly minimizes the nonselective phototoxicity of the photosensitizers to meet the requirement of phototherapy protected from sunlight. After the immigration of AuNR-P(AAm-co-AN-co-TPP)-b-PEG nanoparticles into the tumor tissue and the internalization by cancer cells, the UCST polymer chains can be extended under the local heating of AuNRs by NIR light irradiation, and then porphyrin photosensitizers are turned "On" to dramatically boost the PDT efficiency. Therefore, the process of PDT could be well manipulated in the "Off/On" state by the hybrid nanoplatform with UCST block copolymers and AuNRs, which will open new horizons for clinical treatments of PDT.

NIR-Activated Polymeric Nanoplatform with Upper Critical Solution Temperature for Image-Guided Synergistic Photothermal Therapy and Chemotherapy.

Premature and incomplete drug release is the typical bottleneck of drug release in traditional chemotherapy. Synergistic therapies are highly desirable in medicine and biology because they can compensate for the drawbacks of single therapy and significantly enhance the therapeutic efficacy. Herein, a novel near infrared (NIR)-activated polymeric nanoplatform with upper critical solution temperature (UCST) was constructed for image-guided synergistic photothermal therapy (PTT) and chemotherapy. UCST-responsive amphiphilic block copolymers were synthesized by reversible addition-fragmentation chain-transfer (RAFT) polymerization and then co-assembled with IR780 and cabazitaxel (Cab) to form spherical nanoparticles (NPs). IR780/Cab dual-loaded UCST polymeric NPs can produce local heating upon NIR laser irradiation and further lead to the dissociation of cargo-loaded NPs and controlled release of Cab. IR780 plays the role of both a heating generator and an activator for "on-demand" drug release. The investigation of in vivo fluorescence and photothermal imaging clearly demonstrated tumor targeting. Notably, both in vitro and in vivo studies illustrated that the synergistic PTT and chemotherapy presented better anticancer efficacy than that of PTT and chemotherapy simplely combined. Thus, the well-defined polymeric nanoplatform opens a versatile and effective path to develop image-guided synergistic therapies for tumor treatment.

Sensitization of Hypoxic Tumor to Photodynamic Therapy via Oxygen Self-Supply of Fluorinated Photosensitizers.

Photodynamic therapy (PDT) utilizes photosensitizers to convert innoxious oxygen to cytotoxic reactive oxygen species under an appropriate light, thus inducing cancer cells necrosis. However, PDT performs in an oxygen-dependent method to destroy cells while hypoxia is a feature for most solid tumors. To effectively improve the PDT effect against solid tumors, an oxygen self-supplying and pH-sensitive therapeutic nanoparticle (PTFC) has been developed by the self-assembly of a tetrakis(pentafluorophenyl) chlorin (TFPC)-conjugated block copolymer (POEGMA-b-P(DEAEMA-co-GMA)). PTFC nanoparticles can transport oxygen to a tumor site with their accumulation in the tumor on account of the good oxygen solubility, therefore relieving the oxygen deficiency of a solid tumor and enhancing the PDT efficacy. It is worth noting that the oxygen loading was realized by the fluorinated photosensitizer itself. In addition, the phototoxicity of PTFC nanoparticles is greatly improved in an acidic aqueous environment due to the DEAEMA unit protonation, which not only enhanced the cellular uptake of nanoparticles but also weakened the aggregation of photosensitizers. Taking the hypoxia and acidic microenvironment of solid tumors, PTFC nanoparticles could be efficiently taken up and disassembled to release oxygen upon accumulation at tumor sites, thus significantly improving the PDT efficacy against solid tumors.

NIR-Triggered Multifunctional and Degradable Nanoplatform Based on an ROS-Sensitive Block Copolymer for Imaging-Guided Chemo-Phototherapy.

Imaging-guided chemo-phototherapy based on multifunctional nanocarriers has emerged as a promising and high-efficient cancer treatment because of the inevitable limitations of single therapy. Herein, a near-infrared (NIR) light-activated degradable polymeric nanoplatform was fabricated for chemo-phototherapy. An NIR photosensitizer, IR780, and a chemotherapeutic drug, doxorubicin (DOX), were efficiently coloaded within a reactive oxygen species (ROS)-sensitive polymeric micelle based on an amphiphilic copolymer with degradable thioketal (TK) linkages. The obtained spherical nanoparticles (denoted as (IR780/DOX)@PTK) exhibited a notable photodynamic and photothermal effect upon NIR light exposure. Furthermore, due to the rapid cleavage of TK linkers induced by ROS generated from NIR-activated IR780, (IR780/DOX)@PTK also showed an NIR light-induced degradable feature, which can be used for light-triggered tumor-specific drug release and lead to ignorable systematic toxicity after biodegradation and drug delivery. Under the guidance of NIR fluorescence and photothermal dual modal imaging, (IR780/DOX)@PTK exhibited excellent tumor accumulation after intravenously injection into 4T1-tumor-bearing mice. As verified in both in vitro and in vivo study, (IR780/DOX)@PTK presented a significant tumor suppression effect by synergistic chemo-phototherapy.

A Redox Stimulation-Activated Amphiphile for Enhanced Photodynamic Therapy.

The development of more efficient photosensitizers with minimal damage to surrounding normal tissues has been a valuable and challenging subject during photodynamic therapy (PDT). Herein, a stimuli-activated porphyrinic photosensitizer (PEG-TPP-DNB; PEG = poly(ethylene glycol); TPP = 5,10,15,20-tetraphenylporphyrin; DNB = 2,4-dinitrobenzene) with capabilities of fluorescence and, remarkably, singlet oxygen quenching was prepared successfully for photodynamic therapy with high efficiency and biosecurity. The amphiphilic PEG-TPP-DNB could be self-assembled into nanomicelles in aqueous media and dissociated in response to reductive thiol such as glutathione. Meanwhile, the fluorescence and singlet oxygen generation of porphyrinic photosensitizer would be activated to regenerate. Moreover, the intracellular uptake and localization effectively confirmed the redox-responsive and activated behavior of PEG-TPP-DNB micelles. The cytotoxicity in vitro revealed that the micelles had low dark toxicity and great phototoxicity, and in vivo bioimaging and antitumor evaluation further indicated that the micelles possessed selective tumor imaging and targeted PDT antitumor effect as well as low systemic toxicity. Overall, this tumor microenvironment-activated photosensitizer system may provide a useful strategy for precise photodynamic therapy.

Fabrication of a Dual-Stimuli-Responsive Supramolecular Micelle from a Pillar[5]arene-Based Supramolecular Diblock Copolymer for Photodynamic Therapy.

A pH and thermo dual-responsive supramolecular diblock copolymer is constructed by host-guest recognition of pillar[5]arene and viologen salt. The host polymer, poly(N,N-dimethylaminoethyl methacrylate) bearing pillar[5]arene as the terminal group (P[5]A-PDMAEMA) is synthesized by atom transfer radical polymerization (ATRP). Guest polymer, ethyl viologen-ended poly(N-isopropylacrylamide) (EV-PNIPAM) is prepared by reversible addition-fragmentation chain transfer polymerization. The supramolecular diblock copolymer can be self-assembled into stable supramolecular nanoparticles in aqueous solution at 40 °C, which show excellent pH and thermo responsiveness. The nanoparticles are further applied in the encapsulation of photosensitizers (pyropheophorbide-a, PhA) for photodynamic therapy (PDT). The dual-responsive nanoparticles can efficiently release PhA in acidic environment at 25 °C. Based on the result of cell experiments, PhA-loaded nanomicelles exhibit excellent PDT efficacy and low dark toxicity toward A549 cells. Thus, this supramolecular diblock copolymer enriches the methodology of constructing stimuli-responsive drug carriers and presents a great potential in PDT.

Enhancing the Efficacy of Photodynamic Therapy through a Porphyrin/POSS Alternating Copolymer.

Aggregation-induced quenching (AIQ) of photosensitizers greatly reduces the quantum yield of singlet oxygen generation and mitigates the efficacy of photodynamic therapy (PDT). We have prepared an alternating copolymer starting from 4-vinylbenzyl-terminated tetraphenylporphyrin (VBTPP) and maleimide isobutyl polyhedral oligomeric silsesquioxane (MIPOSS), via alternating reversible addition-fragmentation chain transfer (RAFT) polymerization. Porphyrin and POSS are installed on the amphiphilic block copolymers backbone in an alternating fashion and POSS completely inhibits the aggregation of porphyrin units via stacking. The amphiphilic block copolymer can self-assemble into nanoparticles and its application in PDT treatment was tested. These porphyrin-containing polymeric nanoparticles display high photochemical yield and phototoxicity in vitro and in vivo, providing a novel strategy to enhance the PDT efficacy.

Enhancing Photochemical Internalization of DOX through a Porphyrin-based Amphiphilic Block Copolymer.

Drug resistance is a primary obstacle that seriously reduces the therapy efficiency of most chemotherapeutic agents. To address this issue, the photochemical internalization (PCI) was employed to help the anticancer drug escape from lysosome and improve their translocation to the nucleus. A pH-sensitive porphyrin-based amphiphilic block copolymer (PEG113-b-PCL54-a-porphyrin) was synthesized, which was acted not only as a carrier for the delivery of DOX but also as a photosensitizer for PCI. PEG113-b-PCL54-a-porphyrin as a drug carrier exhibited a higher drug loading capacity, entrapment efficiency, and DOX release content. The PCI effect of PEG113-b-PCL54-a-porphyrin was studied by confocal laser scanning microscopy, and the results showed that most of DOX could be translocated into the nucleus for DOX-loaded PEG113-b-PCL54-a-porphyrin micelles. Moreover, the IC50 of pH-sensitive DOX-loaded PEG113-b-PCL54-a-porphyrin micelles was much lower than that of its counterpart without pH-responsiveness, DOX-loaded PEG113-b-PCL54-porphyrin micelles. Therefore, this drug delivery system based on pH-sensitive porphyrin-containing block copolymer would act as a potential vehicle for overcoming drug resistance in chemotherapy.

Characterization of Fractional Polysaccharides from Gleditsia sinensis and Gleditsia microphylla Gums.

The seeds of Gleditsia sinensis and Gleditsia microphylla, widespread in China, are an important source of galactomannans. G. sinensis gum (GSG) and G. microphylla gum (GMG) were purified and precipitated using different concentrations of ethanol and isopropanol. The GSG and GMG, precipitated in different stages, presented different characteristics, including polymer recovery, mannose/galactose ratio, chemical composition, molecular weight, and morphological appearance. The galactomannan recovery of GSG and GMG in 33.3% ethanol was 81.7% and 82.5%, respectively, while that in 28.8% isopropanol was 81.3% and 82.9%, respectively. To achieve similar precipitation efficiency, the amount of isopropanol should be lower than that of ethanol because of the lower dielectric constant of isopropanol (20 vs. 25 for ethanol). The precipitation behavior of galactomannans in polar organic solvents was dependent on the molecular structures and properties of the solvent. A higher mannose/galactose ratio and a higher molecular weight was obtained in a lower concentration of alcohols.

Morphology-controlled self-assembly of an organic/inorganic hybrid porphyrin derivative containing polyhedral oligomeric silsesquioxane (POSS).

An organic/inorganic hybrid porphyrin derivative, namely, metal-free tetrakisphenyl porphyrin-polyhedral oligomeric silsesquioxanes (H2 TPP-POSS) was synthesized by azide-alkyne click chemistry. The self-assembly behavior of H2 TPP-POSS was systematically studied in CHCl3 at different concentrations and in solvents with different polarities. Novel nanovesicles could be obtained through the self-assembly of H2 TPP-POSS in CHCl3 at a concentration lower than 10(-4) m. Diffuse microrods formed at a concentration higher than 10(-4) M. Additionally, the polarity of the solvent also greatly influenced the assembled morphologies, and a series of assembled morphologies, including crescent-shaped micelles, spherical micelles, doughnut-shaped vesicles, and ordered square sheets, could form in solvents with different polarities.