Synergistic chemotherapy/PTT/oxygen enrichment by multifunctional liposomal polydopamine nanoparticles for rheumatoid arthritis treatment

Amultifunctional liposomal polydopamine nanoparticle(MPM@Lipo)was designed in this study,to combine chemotherapy,photothermal therapy(PTT)and oxygen enrichment to clear hyperproliferating inflammatory cells and improve the hypoxic microenvironment for rheumatoid arthritis(RA)treatment.MPM@Lipo significantly scavenged intracellular reactive oxygen species and relieved joint hypoxia,thus contributing to the repolarization of M1 macrophages into M2 phenotype.Furthermore,MPM@Lipo could accumulate at inflammatory joints,inhibit the production of inflammatory factors,and protect cartilage in vivo,effectively alleviating RA progression in a rat adjuvant-induced arthritis model.Moreover,upon laser irradiation,MPM@Lipo can elevate the temperature to not only significantly obliterate excessively proliferating inflammatory cells but also accelerate the production of methotrexate and oxygen,resulting in excellent RA treatment effects.Overall,the use of synergistic chemotherapy/PTT/oxygen enrichment therapy to treat RA is a powerful potential strategy.

Emerging Strategies in Enhancing Singlet Oxygen Generation of Nano-Photosensitizers Toward Advanced Phototherapy

The great promise of photodynamic therapy(PDT) has thrusted the rapid progress of developing highly effective photosensitizers(PS) in killing cancerous cells and bacteria. To mitigate the intrinsic limitations of the classical molecular photosensitizers, researchers have been looking into designing new generation of nanomaterial-based photosensitizers(nano-photosensitizers) with better photostability and higher singlet oxygen generation(SOG) efficiency, and ways of enhancing the performance of existing photosensitizers. In this paper, we review the recent development of nano-photosensitizers and nanoplasmonic strategies to enhance the SOG efficiency for better PDT performance. Firstly, we explain the mechanism of reactive oxygen species generation by classical photosensitizers, followed by a brief discussion on the commercially available photosensitizers and their limitations in PDT. We then introduce three types of new generation nanophotosensitizers that can effectively produce singlet oxygen molecules under visible light illumination, i.e., aggregation-induced emission nanodots, metal nanoclusters (< 2 nm), and carbon dots. Different design approaches to synthesize these nano-photosensitizers were also discussed. To further enhance the SOG rate of nano-photosensitizers, plasmonic strategies on using different types of metal nanoparticles in both colloidal and planar metal-PS systems are reviewed. The key parameters that determine the metal-enhanced SOG(ME-SOG) efficiency and their underlined enhancement mechanism are discussed. Lastly, we highlight the future prospects of these nanoengineering strategies, and discuss how the future development in nanobiotechnology and theoretical simulation could accelerate the design of new photosensitizers and ME-SOG systems for highly effective image-guided photodynamic therapy.

Oxygen Radical Generation as an Index of Neurotoxic Damage

Biochemical, anatomical, and physiological characteristics of the brain make it especially vulnerable to insult. Specifically, some of these characteristics such as myelin and a high energy requirement provide for the introduction of free radical-induced insult. Recently, the biochemistry of free radicals has received considerable attention. It also has become increasingly suggestive that many drug and chemical-induced toxicities may be evoked via free radicals and oxidative stress. Major points addressed in this work are the regulation of neural-free radical generation by antioxidants and protective enzymes, xenobiotic-induced disruption of cerebral redox status, and specific examples of neurotoxic agent-induced alterations in free radicals as measured by the fluorescent probe dichlorofluorescein. This article considers that free radical mechanisms may contribute significantly to the properties of several diverse neurotoxic agents and proposes that free radicals may be common phenomena of neurotoxicity.

Synthesis,Characterization,and Linear and Nonlinear Optical Properties of Phenylene-vinylene Based Chromophores for Singlet Oxygen Generation

A series of symmetrical and unsymmetrical phenylene-vinylene （PV） based chro- mophores with the molecular configuration of donor-π-donor （D-g-D） were prepared and characterized. Iodine was first introduced into the Jr-conjugation backbone of the PV based chromophores in order to study the heavy atom effect on their linear absorption, two-photon absorption （TPA） properties, as well as singlet oxygen generation properties. TPA cross-sections of these chromophores were investigated by using the two-photon excited fluorescence method. The unsymmetrical chromophores were found to have larger TPA cross-section values compared to their symmetrical counterparts. For one of the unsymmetrical chromophores with the iodine incorporation, a large TPA cross section value with quenched emission was found. The decreased fluorescence quantum yield of a molecule can be ascribed to the increased intersystem crossing, which is favorable for enhancing the singlet oxygen generation. Therefore, the unsymmetrical PV based chromophores with heavy atom incorporation are promising singlet oxygen sensitizers for the photodynamic therapy application.

Efficient singlet oxygen generation by excitonic energy transfer on ultrathin g-C_(3)N_(4) for selective photocatalytic oxidation of methyl-phenyl-sulfide with O_(2)

Efficient generation of singlet oxygen(1 O_(2)) by an excitonic ene rgy transfer process is highly desired on a semiconductor photocatalyst for selective oxidation of methyl phenyl sulfide(MPS).Herein,it is demonstrated that a large amount of 1 O_(2) is produced on pristine graphitic carbon nitride(CN) nanosheet compared with bismuth oxybromide(BiOBr) and comme rcial P25 titanium dioxide(TiO_(2)).This leads to a certain photoactivity of CN for MPS oxidation.The observed ~77% selectivity for CN depends on the competitive results of excitonic energy transfer for 1 O_(2) formation and charge carrier separation for superoxide radical(O_(2)·) production,which are based on the phosphorescence spectra and electron paramagnetic resonance signals,respectively.Moreover,ultrathin CN nanosheets are synthesized by thermal treatment with the cyanuric acid-melamine hydrogen bonded aggregates as precursors.It is confirmed that the amount of produced 1 O_(2) could be increased by decreasing the thickness of resultant CN nanosheets.The optimized ultrathin CN nanosheet(~4 nm) exhibits excellent photoactivity with high selectivity(~99%).It is suggested that the excitonic energy transfer for 1 O_(2) formation is close related to the intrinsic exciton binding energy and the two-dimensional quantum confinement effect.This work establishes a basic mechanistic understanding on the excitonic processes in CN,and develops a feasible route to design CN-based photocatalysts for efficient 1 O_(2) generation.

Experimental study on ceramic membrane technology for onboard oxygen generation

The ceramic membrane oxygen generation technology has advantages of high concentration of produced oxygen and potential nuclear and biochemical protection capability. The present paper studies the ceramic membrane technology for onboard oxygen generation. Comparisons are made to have knowledge of the effects of two kinds of ceramic membrane separation technologies on oxygen generation, namely electricity driven ceramic membrane separation oxygen generation technology (EDCMSOGT) and pressure driven ceramic membrane separation oxygen generation technology (PDCMSOGT). Experiments were conducted under different temperatures, pressures of feed air and produced oxygen flow rates. On the basis of these experiments, the flow rate of feed air, electric power provided, oxygen recovery rate and concentration of produced oxygen are compared under each working condition. It is concluded that the EDCMSOGT is the oxygen generation means more suitable for onboard conditions. (C) 2016 Chinese Society of Aeronautics and Astronautics. Production and hosting by Elsevier Ltd.

Bone microenvironment regulative hydrogels with ROS scavenging and prolonged oxygen-generating for enhancing bone repair

Large bone defects resulting from fractures and disease are a major clinical challenge,being often unable to heal spontaneously by the body’s repair mechanisms.Lines of evidence have shown that hypoxia-induced overproduction of ROS in bone defect region has a major impact on delaying bone regeneration.However,replenishing excess oxygen in a short time cause high oxygen tension that affect the activity of osteoblast precursor cells.Therefore,reasonably restoring the hypoxic condition of bone microenvironment is essential for facilitating bone repair.Herein,we designed ROS scavenging and responsive prolonged oxygen-generating hydrogels(CPP-L/GelMA)as a“bone microenvironment regulative hydrogel”to reverse the hypoxic microenvironment in bone defects region.CPP-L/GelMA hydrogels comprises an antioxidant enzyme catalase(CAT)and ROS-responsive oxygen-releasing nanoparticles(PFC@PLGA/PPS)co-loaded liposome(CCP-L)and GelMA hydrogels.Under hypoxic condition,CPP-L/GelMA can release CAT for degrading hydrogen peroxide to generate oxygen and be triggered by superfluous ROS to continuously release the oxygen for more than 2 weeks.The prolonged oxygen enriched microenvironment generated by CPP-L/GelMA hydrogel significantly enhanced angiogenesis and osteogenesis while inhibited osteoclastogenesis.Finally,CPP-L/GelMA showed excellent bone regeneration effect in a mice skull defect model through the Nrf2-BMAL1-autophagy pathway.Hence,CPP-L/GelMA,as a bone microenvironment regulative hydrogel for bone tissue respiration,can effectively scavenge ROS and provide prolonged oxygen supply according to the demand in bone defect region,possessing of great clinical therapeutic potential.

IR780 loaded hollow MnO_(2) nanoparticles for dual-mode imaging and enhanced photodynamic therapy of oral squamous cell carcinoma

Photodynamic therapy(PDT)has emerged as a novel therapeutic modality for cancer treatment,but its therapeutic efficacy is severely limited by the hypoxic tumor microenvironment(TME).Here we designed an innovative multifunctional nano-platform which consists of a hollow MnO_(2) shell and internal photosensitizer IR780.It is not only used for multimodal imaging of oral squamous cell carcinoma(OSCC),but also for adjustment hypoxic TME to enhance cancer treatment.Hollow MnO_(2) can promote decomposition of tumor endogenous H2O2 to relieve tumor hypoxia,thereby enhancing the effect of photodynamic therapy.Photosensitizer IR780 generates singlet oxygen under laser irradiation to kill tumor cells,playing photodynamic effect,can also act as the contrast agents for photoacoustic and fluorescence multiple imaging,providing potential imaging capability for cancer therapeutic guidance and monitoring.Our research results in this article show that HMnO_(2)-IR780 nanocomposite exhibits good biocompatibility and nontoxicity,strong PA/FL imaging contrast,excellent oxygen production capacity and outstanding photodynamic therapy effect.This finding provides a new idea for multimodal imaging-guided nanotherapy for OSCC.

Orthogonal carbazole-perylene bisimide pentad:a photoconversion-tunable photosensitizer with diversified excitation and excited-state relaxation pathways

Integrating multiple photosensitive properties into an“all-in-one”photosensitizer(PS)shows great promise for the treatment of cancers owing to synergistic effect among them.However,the development of such PSs,especially those that need a single laser source,remains a challenge.Herein,we report an orchestration of electron donors and acceptors in a propeller-like pentad,PBI-4Cz,where four carbazole(Cz)units are covalently linked to the ortho-positions of the perylene bisimide(PBI)core.Strong intramolecular donor-acceptor interaction significantly quenches the luminescence and largely extends the absorption spectra to near-infrared region.Excited-state dynamics investigated via femto-and nano-second transient absorption spectroscopy revealed exclusive charge separation of the PBI-4Cz within initial 0.5 ps when photoexcited regardless of which intermediate is involved.Energy dissipation of the resulting charge-separated state(PBI^(•−)-4Cz^(•−))is subjected to the toggle between intersystem-crossing toward excited triplet states and charge recombination toward ground states.Relative importance of the two pathways can be tuned by micro-environmental polarity,which endows PBI-4Cz remarkable performances of singlet-oxygen generation(>90.0%)in toluene and photothermal conversion(∼28.6%)in DMSO.Harnessing intrinsic photostability and excited-state processes of heavy-atom-free PBI derivatives not only holds a promise for multifunctional phototheranostics,but also provides a prototype for designing high-performance PSs with tunable photoconversion pathways.

Tumor microenvironment-responsive MnSiO_(3)-Pt@BSA-Ce6 nanoplatform for synergistic catalysis-enhanced sonodynamic and chemodynamic cancer therapy

Compared with traditional photodynamic therapy(PDT),ultrasound(US)triggered sonodynamic therapy(SDT)has a wide application prospect in tumor therapy because of its deeper penetration depth.Herein,a novel MnSiO_(3)-Pt(MP)nanocomposite composed of Mn Si O_(3)nanosphere and noble metallic Pt was successfully constructed.After modification with bovine serum albumin(BSA)and chlorine e6(Ce6),the multifunctional nanoplatform Mn SiO_(3)-Pt@BSA-Ce6(MPBC)realized the magnetic resonance imaging(MRI)-guided synergetic SDT/chemodynamic therapy(CDT).In this nanoplatform,sonosensitizer Ce6 can generate singlet oxygen(^(1)O_(2))to kill cancer cells under US irradiation.Meanwhile,the loaded Pt has the ability to catalyze the decomposition of overexpressed hydrogen peroxide(H_(2)O_(2))in tumor microenvironment(TME)to produce oxygen(O_(2)),which can conquer tumor hypoxia and promote the SDT-induced^(1)O_(2)production.In addition,MP can degrade in mildly acidic and reductive TME,causing the release of Mn^(2+).The released Mn^(2+) not only can be used for MRI,but also can generate hydroxyl radical(^·OH)for CDT by Fenton-like reaction.The multifunctional nanoplatform MPBC has high biological safety and good anticancer effect,which displays the great latent capacity in biological application.

Metal-polyphenol-network coated CaCO_(3)as pH-responsive nanocarriers to enable effective intratumoral penetration and reversal of multidrug resistance for augmented cancer treatments

Construction of multifunctional stimuli-responsive nanotherapeutics enabling improved intratumoral penetration of therapeutics and reversal of multiple-drug resistance(MDR)is potent to achieve effective cancer treatment.Herein,we report a general method to synthesize pH-dissociable calcium carbonate(CaCO_(3))hollow nanoparticles with amorphous CaCO_(3)as the template,gallic acid(GA)as the organic ligand,and ferrous ions as the metallic center via a one-pot coordination reaction.The obtained GA–Fe@CaCO_(3)exhibits high loading efficiencies to both oxidized cisplatin prodrug and doxorubicin,yielding drug loaded GA-Fe@CaCO_(3)nanotherapeutics featured in pH-responsive size shrinkage,drug release,and Fenton catalytic activity.Compared to nonresponsive GA-Fe@silica nanoparticles prepared with silica nanoparticles as the template,such GA-Fe@CaCO_(3)confers significantly improved intratumoral penetration capacity.Moreover,both types of drug-loaded GA–Fe@CaCO_(3)nanotherapeutics exhibit synergistic therapeutic efficacies to corresponding MDR cancer cells because of the GA–Fe mediated intracellular oxidative stress amplification that could reduce the efflux of engulfed drugs by impairing the mitochondrial-mediated production of adenosine triphosphate(ATP).As a result,it is found that the doxorubicin loaded GA-Fe@CaCO_(3)exhibits superior therapeutic effect towards doxorubicin-resistant 4T1 breast tumors via combined chemodynamic and chemo-therapies.This work highlights the preparation of pH-dissociable CaCO_(3)-based nanotherapeutics to enable effective tumor penetration for enhanced treatment of drug-resistant tumors.

Dual excited state deactivation pathways in TPZ2:A centrosymmetric dye with both high fluorescence and triplet state quantum yield

In this letter, excited state dynamics of TPZ2, a centrosymmetric PRODAN dye, has been studied by using several time-resolved spectroscopy techniques. Fluorescence quantum yield of TPZ2 is found to be 0.50 in both acetonitrile and ethanol solution. The radiative decay rate of the excited state of TPZ2 is determined to be 2.0×10^8 s^-1. Meanwhile, highly efficient triplet state and singlet oxygen generation have been observed in TPZ2 and the intersystem crossing（ISC） rate is determined to be 2.0×10^8s^-1. The almost identical ISC and non-radiative decay rates indicate that ISC is the only non-radiative decay pathway in TPZ2. Thus, dual excited state（S1） deactivation mechanism（50/50, fluorescence/ISC） of TPZ2 is proposed.Because of this unique property, TPZ2 has the potential to be used as biocompatible imaging and photodynamic therapy agent in the same time.