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mRNA vaccines for cancer immunotherapy are commonly delivered using lipid nanoparticles (LNPs), which, when administered intravenously, may accumulate in the liver, potentially limiting their therapeutic efficacy. To overcome this challenge, the study introduces an oral mRNA vaccine formulation tailored for efficient uptake by immune cells in the gastrointestinal (GI) tract, known for its high concentration of immune cells, including dendritic cells (DCs). This formulation comprises mRNA complexed with ß-glucans (ßGlus), a potential adjuvant for vaccines, encapsulated within LNPs (ßGlus/mRNA@LNPs). The ßGlus/mRNA complexes within the small compartments of LNPs demonstrate a distinctive ability to partially dissociate and reassociate, responding to pH changes, effectively shielding mRNA from degradation in the harsh GI environment. Upon oral administration to tumor-bearing mice, ßGlus/mRNA@LNPs are effectively taken up by intestinal DCs and local nonimmune cells, bypassing potential liver accumulation. This initiates antigen-specific immune responses through successful mRNA translation, followed by drainage into the mesenteric lymph nodes to stimulate T cells and trigger specific adaptive immune responses, ultimately enhancing antitumor effects. Importantly, the vaccine demonstrates safety, with no significant inflammatory reactions observed. In conclusion, the potential of oral ßGlus/mRNA@LNPs delivery presents a promising avenue in cancer immunotherapy, offering needle-free and user-friendly administration for widespread adoption and self-administration.
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Vacinas Anticâncer , Imunoterapia , Nanopartículas , RNA Mensageiro , beta-Glucanas , Animais , beta-Glucanas/química , Administração Oral , Concentração de Íons de Hidrogênio , Camundongos , Vacinas Anticâncer/química , Vacinas Anticâncer/imunologia , RNA Mensageiro/genética , Nanopartículas/química , Células Dendríticas/imunologia , Lipídeos/química , Vacinas de mRNA , Linhagem Celular Tumoral , Neoplasias/terapia , Neoplasias/imunologia , Camundongos Endogâmicos C57BL , Humanos , LipossomosRESUMO
A convenient method for the synthesis of perdeuterated alkyl amides/amines is disclosed. Perdeuterated acetyl amides can be achieved by a hydrogen-deuterium (H/D) exchange protocol with Pt/C as a catalyst and D2O as a deuterium source under mild conditions. After removal or reduction of the acetyl group, this protocol can provide perdeuterated primary, secondary, and tertiary amines, which are difficult to achieve via other methods.
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Addressing the critical requirement for real-time monitoring of tumor progression in cancer care, this study introduces an innovative wearable platform. This platform employs a thermoplastic polyurethane (TPU) film embedded with hafnium oxide nanoparticles (HfO2 NPs) to facilitate dynamic tracking of tumor growth and regression in real time. Significantly, the synthesized HfO2 NPs exhibit promising characteristics as effective sonosensitizers, holding the potential to efficiently eliminate cancer cells through ultrasound irradiation. The TPU-HfO2 film, acting as a dielectric elastomer (DE) strain sensor, undergoes proportional deformation in response to changes in the tumor volume, thereby influencing its electrical impedance. This distinctive behavior empowers the DE strain sensor to continuously and accurately monitor alterations in tumor volume, determining the optimal timing for initiating HfO2 NP treatment, optimizing dosages, and assessing treatment effectiveness. Seamless integration with a wireless system allows instant transmission of detected electrical impedances to a smartphone for real-time data processing and visualization, enabling immediate patient monitoring and timely intervention by remote medical staff. By combining the dynamic tumor monitoring capabilities of the TPU-HfO2 film with the sonosensitizer potential of HfO2 NPs, this approach propels cancer care into the realm of telemedicine, representing a significant advancement in patient treatment.
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Nanopartículas , Neoplasias , Dispositivos Eletrônicos Vestíveis , Humanos , Neoplasias/diagnóstico por imagem , Neoplasias/terapia , Ondas UltrassônicasRESUMO
HYPOTHESIS: The formation of distorted lamellar phases, distinguished by their arrangement of crumpled, stacked layers, is frequently accompanied by the disruption of long-range order, leading to the formation of interconnected network structures commonly observed in the sponge phase. Nevertheless, traditional scattering functions grounded in deterministic modeling fall short of fully representing these intricate structural characteristics. Our hypothesis posits that a deep learning method, in conjunction with the generalized leveled wave approach used for describing structural features of distorted lamellar phases, can quantitatively unveil the inherent spatial correlations within these phases. EXPERIMENTS AND SIMULATIONS: This report outlines a novel strategy that integrates convolutional neural networks and variational autoencoders, supported by stochastically generated density fluctuations, into a regression analysis framework for extracting structural features of distorted lamellar phases from small angle neutron scattering data. To evaluate the efficacy of our proposed approach, we conducted computational accuracy assessments and applied it to the analysis of experimentally measured small angle neutron scattering spectra of AOT surfactant solutions, a frequently studied lamellar system. FINDINGS: The findings unambiguously demonstrate that deep learning provides a dependable and quantitative approach for investigating the morphology of wide variations of distorted lamellar phases. It is adaptable for deciphering structures from the lamellar to sponge phase including intermediate structures exhibiting fused topological features. This research highlights the effectiveness of deep learning methods in tackling complex issues in the field of soft matter structural analysis and beyond.
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The formulation of a drug using high-energy emulsification commonly causes drug deterioration. Exploiting the well-known Diet Coke-Mentos reaction (DCMR), a U-shaped tube reactor that can generate an eruption of bubbly flow that can serve as a low-energy emulsification platform, is proposed. The liquid in the U-tube reactor is a supersaturated solution of aqueous CO2, which mimics Diet Coke. When glass beads with rough surfaces, mimicking Mentos, are dropped into the carbonated water, an eruptive bubbly flow is spontaneously created, mediating effective emulsification at a compound water-oil interface. Experimental results demonstrate that DCMR-mediated bubbly flow may provide a versatile platform for the production of "oil-in-water" or "water-in-oil" droplets and Pickering emulsion composite particles as drug carriers. The DCMR-derived bubbly flow is generated without significant temperature elevation, so the activity of the drug to be emulsified is unaffected. In vivo results reveal the feasibility of using this low-energy emulsification platform to formulate an emulsion system that contains catalase, a temperature-sensitive oxidoreductase, to mitigate an experimentally formed paw inflammation in mice. The as-proposed emulsification platform is attractive for formulating numerous drug delivery systems on a small-scale in a customized manner to meet the needs of each individual for personalized medicine.
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Coque , Portadores de Fármacos , Camundongos , Animais , Emulsões , Água , DietaRESUMO
The prognosis in cases of pancreatic ductal adenocarcinoma (PDAC) with current treatment modalities is poor owing to the highly desmoplastic tumor microenvironment (TME). Herein, a ß-glucans-functionalized zinc-doxorubicin nanoparticle system (ßGlus-ZnD NPs) that can be orally administered, is developed for targeted PDAC therapy. Following oral administration in PDAC-bearing mice, ßGlus-ZnD NPs actively target/transpass microfold cells, overcome the intestinal epithelial barrier, and then undergo subsequent phagocytosis by endogenous macrophages (ßGlus-ZnD@MÏ). As hitchhiking cellular vehicles, ßGlus-ZnD@MÏ transits through the intestinal lymphatic system and enters systemic circulation, ultimately accumulating in the tumor tissue as a result of the tumor-homing and "stealth" properties that are conferred by endogenous MÏ. Meanwhile, the MÏ that hitchhikes ßGlus-ZnD NPs is activated to produce matrix metalloproteinases, destroying the desmoplastic stromal barrier, and differentiates toward the M1 -like phenotype, modulating the TME and recruiting effector T cells, ultimately inducing apoptosis of the tumor cells. The combination of ßGlus-ZnD@MÏ and immune checkpoint blockade effectively inhibits the growth of the primary tumor and suppresses the development of metastasis. It thus represents an appealing approach to targeted PDAC therapy.
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Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , beta-Glucanas , Animais , Camundongos , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/genética , Macrófagos/patologia , Carcinoma Ductal Pancreático/tratamento farmacológico , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/patologia , Microambiente Tumoral , Neoplasias PancreáticasRESUMO
Carbohydrates are key building blocks for advanced functional materials owing to their biological functions and unique material properties. Here, we propose a star-shaped discrete block co-oligomer (BCO) platform to access carbohydrate nanostructures in bulk and thin-film states via the microphase separation of immiscible carbohydrate and hydrophobic blocks (maltooligosaccharides with 1-4 glucose units and solanesol, respectively). BCOs with various star-shaped architectures and saccharide volume fractions were synthesized using a modular approach. In the bulk, the BCOs self-assembled into common lamellar, cylindrical, and spherical carbohydrate microdomains as well as double gyroid, hexagonally perforated lamellar, and Fddd network morphologies with domain spacings of â¼7 nm. In thin films, long-range-ordered periodic carbohydrate microdomains were fabricated via spin coating. Such controlled spatial arrangements of functional carbohydrate moieties on the nanoscale have great application potential in biomedical and nanofabrication fields.
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Nanoestruturas , Carboidratos , Nanoestruturas/químicaRESUMO
The in situ transformation of low-toxicity precursors into a chemotherapeutic agent at a tumor site to enhance the efficacy of its treatment has long been an elusive goal. In this work, a zinc-based zeolitic imidazolate framework that incorporates pharmaceutically acceptable precursors is prepared as a nanoreactor (NR) system for the localized synthesis of an antitumor drug. The as-prepared NRs are administered intratumorally in a tumor-bearing mouse model and then irradiated with ultrasound (US) to activate the chemical synthesis. The US promotes the penetration of the administered NRs into the tumor tissue to cover the lesion entirely, although some NRs leak into the surrounding normal tissue. Nevertheless, only the tumor tissue, where the H2O2 concentration is high, is adequately exposed to the as-synthesized antitumor drug, which markedly impedes development of the tumor. No significant chemical synthesis is detected in the surrounding normal tissue, where the local H2O2 concentration is negligible and the US irradiation is not directly applied. The as-proposed tumor-specific in situ synthesis of therapeutic molecules induces hardly any significant in vivo toxicity and, thus, is potentially a potent biocompatible approach to precision chemotherapy.
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Antineoplásicos , Neoplasias , Zeolitas , Camundongos , Animais , Portadores de Fármacos/química , Peróxido de Hidrogênio/química , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Antineoplásicos/química , Neoplasias/diagnóstico por imagem , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Zeolitas/química , NanotecnologiaRESUMO
We outline a machine learning strategy for quantitively determining the conformation of AB-type diblock copolymers with excluded volume effects using small angle scattering. Complemented by computer simulations, a correlation matrix connecting conformations of different copolymers according to their scattering features is established on the mathematical framework of a Gaussian process, a multivariate extension of the familiar univariate Gaussian distribution. We show that the relevant conformational characteristics of copolymers can be probabilistically inferred from their coherent scattering cross sections without any restriction imposed by model assumptions. This work not only facilitates the quantitative structural analysis of copolymer solutions but also provides the reliable benchmarking for the related theoretical development of scattering functions.
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The innate cartilage extracellular matrix is avascular and plays a vital role in innate chondrocytes. Recapping the crucial components of the extracellular matrix in engineered organs via polymeric gels and bioinspired approaches is promising for improving the regenerative aptitude of encapsulated cartilage/chondrocytes. Conventional gel formation techniques for polymeric materials rely on employing oxidative crosslinking, which is constrained in this avascular environment. Further, poor mechanical properties limit the practical applications of polymeric gels and reduce their therapeutic efficacy. Herein, the purpose of this study was to develop a bioadhesive gel possessing dual crosslinking for engineering cartilage. Tyramine (TYR) was first chemically conjugated to the alginate (ALG) backbone to form an ALG-TYR precursor, followed by the addition of calcium peroxide (CaO2); calcium ions of CaO2 physically crosslink with ALG, and oxygen atoms of CaO2 chemically crosslink TYR with tyrosinase, thus enabling dual/enhanced crosslinking and possessing injectability. The ALG-TYR/tyrosinase/CaO2 gel system was chemically, mechanically, cellularly, and microscopically characterized. The gel system developed herein was biocompatible and showed augmented mechanical strength. The results showed, for the first time, that CaO2 supplementation preserved cell viability and enhanced the crosslinking ability, bioadhesion, mechanical strength, chondrogenesis, and stability for cartilage regeneration.
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Alginatos , Monofenol Mono-Oxigenase , Alginatos/química , Cartilagem , Condrócitos , Condrogênese , Hidrogéis/química , Peróxidos , Engenharia Tecidual/métodos , Alicerces Teciduais/química , TiraminaRESUMO
DNA-templated metallization is broadly investigated in the fabrication of metallic structures by virtue of the unique DNA-metal ion interaction. However, current DNA-templated synthesis is primarily carried out based on pure DNA in an aqueous solution. In this study, we present in situ synthesis of metallic structures in a natural DNA complex bulk film by UV light irradiation, where the growth of silver particles is resolved by in situ time-resolved small-angle X-ray scattering and dielectric spectroscopy. Our studies provide physical insights into the kinetics and mechanisms of natural DNA metallization, in correlation with the multi-stage switching operations in the bulk phase, paving the way towards the development of versatile biomaterial composites with tunable physical properties for optical storage, plasmonics, and catalytic applications.
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The skin possesses an epithelial barrier. Delivering growth factors to deeper wounds is usually rather challenging, and these typically restrict the therapeutic efficacy for chronic wound healing. Efficient healing of chronic wounds also requires abundant blood flow. Therefore, addressing these concerns is crucial. Among presently accessible biomedical materials, tailored hydrogels are favorable for translational medicine. However, these hydrogels display insufficient mechanical properties, hampering their biomedical uses. Cold-atmospheric plasma (CAP) has potent cross-linking/polymerizing abilities. The CAP was characterized spectroscopically to identify excited radiation and species (hydroxyl and UV). CAP was used to polymerize pyrrole (creating Ppy) and crosslink hybrid polymers (Ppy, hyaluronic acid (HA), and gelatin (GEL)) as a multimodal dressing for chronic wounds (CAP-Ppy/GEL/HA), which were used to incorporate therapeutic platelet proteins (PPs). Herein, the physicochemical and biological features of the developed CAP-Ppy/GEL/HA/PP complex were assessed. CAP-Ppy/GEL/HA/PPs had positive impacts on wound healing in vitro. In addition, the CAP-Ppy/GEL/HA complex has improved mechanical aspects, therapeutics sustained-release/retention effect, and near-infrared (NIR)-driven photothermal-hyperthermic effects on lesions that drive the expression of heat-shock protein (HSP) with anti-inflammatory properties for boosted restoration of diabetic wounds in vivo. These in vitro and in vivo outcomes support the use of CAP-Ppy/GEL/HA/PPs for diabetic wound regeneration.
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Gases em Plasma , Polímeros , Regeneração , Ciência Translacional Biomédica , CicatrizaçãoRESUMO
Patients with irregular, huge burn wounds require time-consuming healing. The skin has an epithelial barrier mechanism. Hence, the penetration and retention of therapeutics across the skin to deep lesion is generally quite difficult and these usually constrain the delivery/therapeutic efficacies for wound healing. Effective burn wound healing also necessitates proper circulation. Conventional polymeric dressing usually exhibits weak mechanical behaviors, obstructing their load-bearing applications. Cold atmospheric plasma (CAP) was used as an efficient, environmentally friendly, and biocompatible process to crosslink methylcellulose (MC) designed for topical administration such as therapeutic substances of platelets (SP) and polyethyleneimine-polypyrrole nanoparticle (PEI-PPy NP)-laden MC hydrogel carriers, and wound dressings. The roles of framework parameters for CAP-treated SP-PEI-PPy NP-MC polymeric complex system; chemical, physical, and photothermal effects; morphological, spectroscopical, mechanical, rheological, and surface properties; in vitro drug release; and hydrophobicity are discussed. Furthermore, CAP-treated SP-PEI-PPy NP-MC polymeric complex possessed augmented mechanical properties, biocompatibility, sustainable drug release, drug-retention effects, and near-infrared (NIR)-induced hyperthermia effects that drove heat-shock protein (HSP) expression with drug permeation to deep lesions. This work sheds light on the CAP crosslinking polymeric technology and the efficacy of combining sustained drug release with photothermal therapy in burn wound bioengineering carrier designs.
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Plaquetas/efeitos dos fármacos , Queimaduras/terapia , Metilcelulose/química , Metilcelulose/efeitos da radiação , Gases em Plasma/farmacologia , Cicatrização/efeitos dos fármacos , Animais , Fenômenos Químicos , Humanos , Camundongos , Ratos , Análise EspectralRESUMO
Blending with homopolymer offers a facile approach for tuning the microdomain morphology of block copolymer, provided that the homopolymer chains are uniformly solubilized in the corresponding microdomain to swell the junction point separation. Here we studied the solubilization behavior of poly(4-vinyl pyridine) homopolymer (h-P4VP) in the lamellar microdomain formed by its blends with a poly(ethylene oxide)-block-poly(4-vinyl pyridine) (PEO-b-P4VP) showing the feature of lower critical ordering transition (LCOT) in terms of weaker segregation strength at lower temperature. We revealed that, while the conventional criterion of homopolymer-to-block molecular weight ratio for attaining uniform solubilization was applicable to LCOT blend, there was an excess swelling of junction point separation upon the addition of homopolymer, leading to a decrease of interdomain distance with increasing homopolymer composition. This anomalous phenomenon was attributed to the reduction of interfacial free energy due to the incorporation of P4VP homopolymer into the microdomain interface.
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Electrostatic compaction of double stranded DNA induced by a positively charged poly(amidoamine) (PAMAM) dendrimer of generation four (G4) was found to produce two unique types of DNA mesophases, in which the DNA bent into superhelices packed in a tetragonal or hexagonal lattice. The structure formed at a lower dendrimer charge density was three-dimensionally (3D) ordered, as characterized by the P41212 space group with a 41 screw axis in a tetragonal arrangement, showing that the weakly bent DNA superhelices with a pitch length of ca. 5.0 nm possessed both identical handedness and phase conservation. The 3D ordered structure transformed into a 2D mesophase at a higher dendrimer charge density, wherein the strongly bent superhelices with a pitch length of ca. 4.0 nm organized in a hexagonal lattice without lateral coherence of helical trajectory. The counterion valency of the protonic acid that is used to charge the dendrimer was found to influence the phase diagram. Under a given dendrimer charge density, the complex with a multivalent acid-protonated dendrimer tended to form structures with less curved DNA, attesting that the driving force of charge matching was reduced by increasing the counterion valency of the dendrimer.
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Dendrímeros , Cristais Líquidos , DNA , DNA Super-Helicoidal , Eletricidade EstáticaRESUMO
Gene therapy is one of the most important developments for modern medicine. As such methods for the compaction and delivery of nucleic acids bearing therapeutic sequences is essential. The quest for non-viral carriers of nucleic acids has produced a number of possible candidates with dendrimer being among the most promising. Their hyper-branched structure and well-defined size together with low cytotoxicity has found success in both ex-vivo and in-vivo studies. The compaction of DNA with dendrimer has produced a rich array of different structures depending on the physiochemical conditions. Mechanisms that drive the compaction have been shown to be a number of physical interactions that reduce the large polymeric entity from 100s of nanometers to some tens of nanometers to fit into the cell nucleus. The mechanisms driving the compaction of DNA will be discussed in detail while the focus will be directed to tuning the structural properties of the complexes and their structural characterization using small-angle scattering techniques.
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Dendrímeros , Ácidos Nucleicos , DNA , Terapia GenéticaRESUMO
The columnar mesophase, in which the molecular or supramolecular building blocks with rod-like geometry pack into two-dimensional (2D) lattices, is an important class of mesomorphic structure having been found in various liquid crystalline materials for practical applications. The cylindrical micelles assembled by amphiphilic surfactants may also form columnar mesophases with the micelle packing symmetry being tunable by the molecular characteristics of the surfactants. In this study, we demonstrate that a positively charged tree-like polymer, poly(amidoamine) (PAMAM) G4 dendrimer, acted as an effective structure-directing agent for the columnar mesophase of a common anionic surfactant, sodium dodecyl sulfate (SDS), via their electrostatic interaction. By adjusting the dendrimer charge density and the nominal binding ratio (Xn) of SDS to dendrimer, the electrostatic complexes self-assembled to form a body-centered cubic (BCC) sphere phase, wherein the dendrimers were staggered between the interspaces of the SDS spherical micelles packed in the BCC lattice. Four types of 2D columnar mesophase composed of SDS cylindrical micelles and dendrimers were accommodated within the interstitial tunnels, including the hexagonal columnar phase (Colhex), simple rectangular columnar phase (Colsr), oblique columnar phase (Colob) and centered rectangular columnar phase (Colcr). A detailed analysis of the geometry of the dendrimer in the columnar mesophases revealed that the structural transition was governed by the interplay among the lateral and axial deformations of the dendrimer, and the deformation of the SDS micelle cross section for achieving effective charge matching and accommodation of the dendrimer. The present study demonstrated the power of the dendrimer in directing the long-range ordered packing of oppositely charged cylinders to yield a rich structural polymorphism of the columnar mesophase that may be exploited for the development of functional materials.
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A series of novel photo-switchable [2]rotaxanes (i.e., Rot-A-SP and Rot-B-SP before and after shuttling controlled by acid-base, respectively) containing one spiropyran (SP) unit (as a photochromic stopper) on the axle and two tetraphenylethylene (TPE) units on the macrocycle were synthesized via click reaction. Upon UV/visible light exposure, both mono-fluorophoric rotaxanes Rot-A-SP and Rot-B-SP with the closed form (i.e., non-emissive SP unit) could be transformed into the open form (i.e., red-emissive merocyanine (MC) unit) to acquire their respective bi-fluorophoric Rot-A-MC and Rot-B-MC reversibly. The aggregation-induced emission (AIE) properties of bi-fluorophoric TPE combined with MC AIEgens of these designed rotaxanes and mixtures in semi-aqueous solutions induced interesting ratiometric photoluminescence (PL) and Förster resonance energy transfer (FRET) behaviors, which were further investigated and verified by dynamic light scattering (DLS), X-ray diffraction (XRD), and time-resolved photoluminescence (TRPL) measurements along with theoretical studies. Accordingly, in contrast to the model axle (Axle-MC) and the analogous mixture (Mixture-MC, containing the axle and macrocycle components in a 1:1 molar ratio), more efficient FRET behaviors and stronger red PL emissions were obtained from dual-AIEgens between a blue-emissive TPE donor (PL emission at 468 nm) and a red-emissive MC acceptor (PL emission at 668 nm) in both novel photo-switchable [2]rotaxanes Rot-A-MC and Rot-B-MC under various external modulations, including water content, UV/Vis irradiation, pH value, and temperature. Furthermore, the reversible fluorescent photo-patterning applications of Rot-A-SP in a powder form and a solid film with excellent photochromic and fluorescent behaviors are first investigated in this report.