Construction of Core-Shell NanoMOFs@microgel for Aqueous Lubrication and Thermal-Responsive Drug Release.

The construction of porous nanocarriers with good lubricating performance and stimuli-responsive drug release is significant for the synergetic therapy of osteoarthritis (OA). Although metal-organic framework nanoparticles (nanoMOFs) as carriers can support drug delivery, achieving the synergy of aqueous lubrication and stimuli-responsive drug release is challenging. In this work, a core-shell nanoMOFs@poly(N-isopropylacrylamide) (PNIPAm) microgel hybrid via one-pot soap-free emulsion polymerization is developed. Programmable growth of the PNIPAm microgel layer on the surface of nanoMOFs is achieved by tuning the concentration of the monomer and the crosslinker in the reaction. Reversible swelling-collapsing behaviors of the hybrid are realized by tuning the temperature below and above the lower critical solution temperature. When used as water lubrication additives, the hybrid enables reductions in both the coefficient of friction and wear volume. In vitro thermal-responsive drug release is demonstrated on the diclofenac sodium-loaded hybrid by controlling the swelling and collapsing states of the PNIPAm nanolayer. Moreover, the good biocompatibility of the hybrid is verified by culturing toward HeLa and BEAS-2B cells. These results establish a nanoMOFs@microgel hybrid that can achieve friction and wear reduction and thermal-responsive drug release.

Mussel-inspired hydrogels: from design principles to promising applications.

Mussel-inspired chemistry, owing to its unique and versatile functions to manipulate dynamic molecular-scale interactions, has emerged as a powerful tool for the rational design and synthesis of new hydrogels. In particular, possessing a myriad of unique advantages that are otherwise impossible by conventional counterparts, mussel-inspired hydrogels have been widely explored in numerous fields such as biomedical engineering, soft electronics and actuators, and wearable sensors. Despite great excitement and vigor, a comprehensive and timely review on this emerging topic is missing. In this review, we discuss (1) the fundamental interaction mechanisms underpinning the spectacular wet adhesion in natural mussels and mussel-inspired materials; (2) the key routes to engineering hydrogels by leveraging on the interactions of mussel-inspired building blocks; (3) the emerging applications of mussel-inspired hydrogels, especially in the areas of flexible electronics and biomedical engineering; (4) the future perspectives and unsolved challenges of this multidisciplinary field. We envision that this review will provide an insightful perspective to stimulate new thinking and innovation in the development of next-generation hydrogels and beyond.

Aminobenzofuran-fused rhodamine dyes with deep-red to near-infrared emission for biological applications.

Aminobenzofuran-fused rhodamine dyes (AFR dyes) containing an amino group were constructed by an efficient condensation based on 3-coumaranone derivatives. AFR dyes exhibited significantly improved properties, including deep-red and near-infrared emissions, a large Stokes shift, good photostability, and wide pH stability. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium assay experiments show that these AFR dyes are biocompatible for their low cytotoxicity to both A549 and HeLa cells. Cell imaging data reveal that AFR1, AFR1E, and AFR2 are mainly located in the mitochondria, while AFR3 is a lysosome tracker. As far as we know, NIR AFR3 is the longest fluorescent rhodamine derivative containing the amino group. These amino group-containing AFR dyes hold great potential in fluorogenic detection, biomolecule labeling, and cell imaging.

Fabrication of versatile lignocellulose nanofibril/polymerizable deep eutectic solvent hydrogels with anti-swelling, adhesive and low-temperature resistant properties via a one-pot strategy.

Lignocellulosic nanofibril (LCNF) is indispensable in numerous potential applications because of its unsurpassed quintessential characteristics. While it still remains a challenge to assemble LCNF in a facile and environmental economy-first manner. In this work, a simple and green one-step synthetic approach was reported to prepare a series of LCNF-containing versatile hydrogels using deep eutectic solvent (DES). In particular, the LCNF5% hydrogel (namely LCNF5%-gel) in this work perfectly integrated superior stretchability (∼643 %), and displayed a dramatically improved anti-swelling ability (25 %) compared to the control sample (neat DES hydrogel, 2252 %). Simultaneously, the LCNF5% hydrogel presented underwater adhesiveness and outstanding long-term low-temperature resistance (stable at -25 °C for a month). This novel multifunctional hydrogel, prepared by a facile and eco-friendly strategy, is potentially useful in wet adhesion or underwater applications.

Dual-functional MOFs-based hybrid microgel advances aqueous lubrication and anti-inflammation.

This paper demonstrates the hybridization of copolymer microgel with drug-loaded metal-organic frameworks nanoparticles that can achieve excellent aqueous lubricating performance and anti-inflammatory effect for synergistic treatment of osteoarthritis (OA). Poly(ethylene glycol)-graft-poly(N-isopropylacrylamide) (PEG-g-PNIPAm) microgel layer is grown on the MIL-101(Cr) surface via one-pot soap-free emulsion polymerization method. The lower critical solution temperature of the MIL-101(Cr)@PEG-g-PNIPAm hybrid is raised significantly by incorporating PEG chains into the PNIPAm microgel matrix, which greatly enhances the high-temperature aqueous dispersion stability. The hybrid microgel demonstrated reversibly thermo-sensitive swelling-collapsing behavior to modulate the optical properties and hydrodynamic size. Using as aqueous lubricating additives, the hybrid reduces over 64% and 97% in friction coefficient and wear volume. Also, the hybrid supports desirable temperature-controlled lubrication modulation due to their reversible thermo-responsive behavior, which is benefit to joint lubrication of OA. After encapsulating anti-inflammatory diclofenac sodium (DS), the DS-MIL-101(Cr)@PEG-g-PNIPAm shows thermo-responsive drug release in aqueous media, which can improve the drug-delivery efficiency. By co-culturing the DS-loaded hybrid with human normal chondrocytes, we demonstrate good biocompatibility and anti-inflammatory effect on the chondrocytes with inflammation by regulating the expression of OA-related genes and proteins. Our work establishes multifunctional MOFs-based hybrid microgel systems for advanced colloids modulation and biomedical application.

A snowboard-inspired lubricating nanosystem with responsive drug release for osteoarthritis therapy.

Most of present works of osteoarthritis (OA) therapy are focusing on reducing friction and improving drug loading capacity, while little attention is paid to realizing long-time lubrication and on-demand drug release. In this study, inspired by snowboards with good solid-liquid interface lubrication, a fluorinated graphene based nanosystem with dual functions of long-time lubrication and thermal-responsive drug release was constructed for OA synergetic therapy. An aminated polyethylene glycol bridging strategy was developed to enable covalent grafting of hyaluronic acid on fluorinated graphene. This design not only greatly increased the nanosystem's biocompatibility, but also reduced the coefficient of friction (COF) by 83.3 % compared to H2O. The nanosystem showed long-time and steady aqueous lubrication behavior even after more than 24,000 times of friction tests, and a low COF of 0.13 was obtained with over 90% wear volume reduction. Diclofenac sodium was controllably loaded and sustained drug release was tuned by near-infrared light. Moreover, anti-inflammation results showed that the nanosystem had good protective effect on inhibiting OA deterioration, which could up-regulate cartilage anabolic genes of Col2α and aggrecan while down-regulating catabolic proteases genes of TAC1 and MMP1. This work constructs a novel dual-functional nanosystem that realizes friction and wear reduction with long lubrication life, and shows thermal-responsive on-demand drug release with good synergistic therapeutic effect of OA.

Copolythiophene-derived colorimetric and fluorometric sensor for visually supersensitive determination of lipopolysaccharide.

3-Phenylthiophene-based water-soluble copolythiophenes (CPT1) were designed for colorimetric and fluorometric detection of lipopolysaccharide (LPS). The sensor (CPT1-C) shows a high selectivity to LPS in the presence of other negatively charged bioanalytes as well an extreme sensitivity with the detection limit at picomolar level, which is the lowest ever achieved among all synthetic LPS sensors available thus far. Significantly, the sensing interaction can be apparently observed by the naked eyes, which presents a great advantage for its practical applications. The appealing performance of sensor was demonstrated to originate from the multiple electrostatic and hydrophobic cooperative interactions, synergetic with signal amplification via the conformational change of the 3-phenylthiophene-based copolymer main chain. As a straightforward application, CPT1-C is capable of rapidly discriminating the Gram-negative bacteria (with LPS in the membrane) from Gram-positive bacteria (without LPS).

A novel hypocrellin-based assembly for sonodynamic therapy against glioblastoma.

The non-invasive treatment of glioblastoma (GBM) is of great significance and can greatly reduce the complications of craniotomy. Sonodynamic therapy (SDT) is an emerging tumor therapeutic strategy that overcomes some fatal flaws of photodynamic therapy (PDT). Different from PDT, SDT has deep tissue penetration and can be applied in the non-invasive treatment of deep-seated tumors. However, effective sonosensitizers that can be used for SDT of GBM are still very rare. Herein, we have prepared a suitable assembly based on a hypocrellin derivative (CTHB) with good biocompatibility. Excitedly, the hypocrellin-based assembly (CTHB NPs) can effectively produce reactive oxygen species under ultrasound stimulation. The inherent fluorescence and photoacoustic imaging characteristics of the CTHB NPs are conducive to the precise positioning of the tumors. It has been proved both in subcutaneous and in intracranial tumor models that CTHB NPs can be used as an effective sonosensitizer to inhibit tumor growth under ultrasound irradiation. This hypocrellin-based assembly has a good clinical prospect in the non-invasive treatment of GBM.

Switching water droplet adhesion using responsive polymer brushes.

Two stimuli-responsive polymers, poly(N-isopropylacrylamide) (PNIPAM) and poly(dimethylamino)ethyl methacrylate (PDMAEMA), were grafted from initiator-modified anodized alumina substrates with irregular micro/nanoscale surface topography. The resulting polymer-coated surfaces exhibited highly unusual wettability properties, as spherical water/acid/alkali/salt droplets could be reversibly switched between pinned states and rolling states due to the changes of temperature, pH, and electrolytes. The key to this effect is the combination of a mixed monolayer which provides initiator points for brush growth as well as a permanently hydrophobic substrate and a surface roughness.

Adaptive control in lubrication, adhesion, and hemostasis by Chitosan-Catechol-pNIPAM.

Bio-inspired wet adhesives attract considerable attention in the biomedical field. However, achieving reversible and controllable wet adhesion still remains a challenging issue. In this study, we report a new thermo-responsive polysaccharide wet adhesive conjugate named Chitosan-Catechol-poly(N-isopropyl acrylamide) (Chitosan-Catechol-pNIPAM), where catechol, the wet adhesive moiety, and pNIPAM, the thermal responsive group, are chemically tethered to a chitosan backbone. The as-synthesized Chitosan-Catechol-pNIPAM presents a reversible sol-gel transition behavior when the temperature is cycled below and above the lower critical solution temperature (LCST, 35 °C), along with dynamic switching between lubrication and wet adhesion on various materials. Based on these excellent features, Chitosan-Catechol-pNIPAM can realize controllable attachment/detachment behavior over the skin through heating/cooling processes. Due to its good biocompatibility, the Chitosan-Catechol-pNIPAM coated syringe needles exhibit instant hemostasis after removing the needles from the punctured sites of mouse veins. Overall, the as-synthesized Chitosan-Catechol-pNIPAM is expected to be used as a new intelligent adhesive in various biomedical settings.

Photosensitizers for Photodynamic Therapy.

As an emerging clinical modality for cancer treatment, photodynamic therapy (PDT) takes advantage of the cytotoxic activity of reactive oxygen species (ROS) that are generated by light irradiating photosensitizers (PSs) in the presence of oxygen (O2 ). However, further advancements including tumor selectivity and ROS generation efficiency are still required. Substantial efforts are devoted to design and synthesize smart PSs with optimized properties for achieving a desirable therapeutic efficacy. This review summarizes the recent progress in developing intelligent PSs for efficient PDT, ranging from single molecules to delicate nanomaterials. The strategies to improve ROS generation through optimizing photoinduced electron transfer and energy transfer processes of PSs are highlighted. Moreover, the approaches that combine PDT with other therapeutics (e.g., chemotherapy, photothermal therapy, and radiotherapy) and the targeted delivery in cancer cells or tumor tissue are introduced. The main challenges for the clinical application of PSs are also discussed.

High Strength Astringent Hydrogels Using Protein as the Building Block for Physically Cross-linked Multi-Network.

Integrating proteins into a hydrogel network enables its good bioactivity as an ECM environment in biorelative applications. Although extensive studies on preparing protein hydrogels have been carried out, the reported systems commonly present very low mechanical strength and weak water-rentention capacity. Learning from the astringent mouthfeel, we report here a protein engineered multinetwork physical hydrogel as TA-PVA/BSA. In a typical case, the BSA protein-integrated poly(vinyl alcohol) (PVA) solution is treated by the freeze-thaw method and forms the first hydrogel network, and tannic acid (TA) then cross-links with BSA proteins and PVA chains to form the secondary hydrogel network based on the noncovalent interaction (hydrogen bond and hydrophobic interaction). The as-prepared TA-PVA/BSA composite hydrogel is a pure physically cross-linking network and possesses ultrahigh tensile strength up to ∼9.5 MPa but is adjustable, relying on the concentration of TA and BSA. Moreover, its mechanical strength is further improved by prestretching induced anisotropy of mechanical performance. Because of its controllable and layered structure as skin, the composite hydrogel presents good water-retention capacity compared to traditional high strength hydrogels. This work demonstrates a novel method to design high mechanical strength but layered physical cross-linking hydrogels and enables us to realize their biorelative applications.

Biodegradable hypocrellin derivative nanovesicle as a near-infrared light-driven theranostic for dually photoactive cancer imaging and therapy.

Photoactive agents based on natural products have attracted substantial attention in clinical applications because of their distinct biological activity, molecular structure multiformity, and low biotoxicity. Herein, we initially modify hypocrellin B (HB) with 1,2-diamino-2-methyl propane to form near-infrared (NIR) light (>700 nm)-responsive amino-substituted HB derivative (DPAHB). The DPAHB exhibit broad absorption (400-800 nm), NIR emission (maximum emission peak at 710 nm), and high singlet oxygen (1O2) quantum yield (∼0.33) under NIR light (721 nm) irradiation. After self-assembly by using DPAHB with PEG-PLGA, the as-prepared nanovesicles (DPAHB NVs) retain efficient 1O2 generation, more interestingly, show high photothermal conversion efficiency (∼0.24) under NIR light (721 nm) irradiation for synergistic photodynamic therapy (PDT) and photothermal therapy toward hypoxic tumor. The DPAHB NVs can not only be as a fluorescence/photoacoustic imaging agent but also exhibit an even stronger PDT efficiency than that of chlorin e6 (a widely used classic photosensitizer). In vitro and in vivo studies demonstrate that DPAHB NVs possess high photothermal stability, enhanced tumor accumulation, and suitable biodegradation rate, thus, show a highly promising clinical potential as a new photoactive agent for cancer therapy.

Severe Bone Marrow Suppression Accompanying Pulmonary Infection and Hemorrhage of the Digestive Tract Associated with Leflunomide and Low-dose Methotrexate Combination Therapy.

A 60-year-old male patient developed hyperpyrexia, cough, expectoration with blood-stained sputum, mouth ulcers, and suppurative tonsillitis after receiving 35 days of combination treatment with leflunomide (LEF) and low-dose methotrexate (MTX) for active rheumatoid arthritis. On admission, routine blood tests showed severe thrombocytopenia, agranulocytosis, and decreased hemoglobin concentration compared with the relatively normal results of 1 month previously during the first hospitalization. Chest radiography revealed inflammation in both lungs, and a fecal occult blood test was positive. Given this presentation, severe bone marrow suppression accompanying pulmonary infection and hemorrhage of the digestive tract associated with LEF and MTX combination therapy was diagnosed. After 28 days of symptomatic treatment, the patient's complications subsided gradually. This case highlighted that bone marrow suppression associated with MTX and LEF combination therapy could be very serious, even at a normal dose or especially at the beginning of treatment. MTX and LEF combination therapy should be used with caution or be limited in those with a history of pulmonary disease, hemorrhage of the digestive tract, or other relevant diseases.

Polymer-based precipitation preserves biological activities of extracellular vesicles from an endometrial cell line.

Extracellular vesicles (EVs) are membrane-bound vesicles released by cells and act as media for transfer of proteins, small RNAs and mRNAs to distant sites. They can be isolated by different methods. However, the biological activities of the purified EVs have seldom been studied. In this study, we compared the use of ultracentrifugation (UC), ultra-filtration (UF), polymer-based precipitation (PBP), and PBP with size-based purification (PBP+SP) for isolation of EVs from human endometrial cells and mouse uterine luminal fluid (ULF). Electron microscopy revealed that the diameters of the isolated EVs were similar among the tested methods. UF recovered the highest number of EVs followed by PBP, while UC and PBP+SP were significantly less efficient (P<0.05). Based on the number of EVs-to-protein ratios, PBP had the least protein contamination, significantly better than the other methods (P<0.05). All the isolated EVs expressed exosome-enriched proteins CD63, TSG101 and HSP70. Incubation of the trophoblast JEG-3 cells with an equal amount of the fluorescence-labelled EVs isolated by the studied methods showed that many of the PBP-EVs treated cells were fluorescence positive but only a few cells were labelled in the UC- and UF-EVs treated groups. Moreover, the PBP-EVs could transfer significantly more miRNA to the recipient cells than the other 3 methods (P<0.05). The PBP method could isolate EVs from mouse ULF; the diameter of the isolated EVs was 62±19 nm and expressed CD63, TSG101 and HSP70 proteins. In conclusion, PBP could best preserve the activities of the isolated EVs among the 4 methods studied and was able to isolate EVs from a small volume of sample. The simple setup and low equipment demands makes PBP the most suitable method for rapid EV assessment and isolation of EVs in clinical and basic research settings.

Biocompatible Iron Phthalocyanine-Albumin Assemblies as Photoacoustic and Thermal Theranostics in Living Mice.

Exploring novel and versatile nanomaterials for the construction of personalized multifunctional phototheranostics with significant potentials in bioimaging-guided tumor phototherapies has attracted considerable attention. Herein, the phototheranostic agent human serum albumin-iron (II) phthalocyanine FePc nanoparticles (HSA-FePc NPs) were fabricated for photoacoustic (PA) imaging-guided photothermal therapy (PTT) of cancer in vivo. The prepared HSA-FePc NPs exhibited high stability, efficient NIR absorption, good capability and stability of photothermal behavior with a high photothermal conversion efficiency of ∼44.4%, high contrast and spatial resolution of PA imaging, efficient cancer therapy, and low long-term toxicity. This potent multifunctional phototheranostic is, therefore, very promising and favorable for effective, precise, and safe antitumor treatment in clinical application.

Versatile Polymer Nanoparticles as Two-Photon-Triggered Photosensitizers for Simultaneous Cellular, Deep-Tissue Imaging, and Photodynamic Therapy.

Clinical applications of current photodynamic therapy (PDT) photosensitizers (PSs) are often limited by their absorption in the UV-vis range that possesses limited tissue penetration ability, leading to ineffective therapeutic response for deep-seated tumors. Alternatively, two-photon excited PS (TPE-PS) using NIR light triggered is one the most promising candidates for PDT improvement. Herein, multimodal polymer nanoparticles (PNPs) from polythiophene derivative as two-photon fluorescence imaging as well as two-photon-excited PDT agent are developed. The prepared PNPs exhibit excellent water dispersibility, high photostability and pH stability, strong fluorescence brightness, and low dark toxicity. More importantly, the PNPs also possess other outstanding features including: (1) the high 1 O2 quantum yield; (2) the strong two-photon-induced fluorescence and efficient 1 O2 generation; (3) the specific accumulation in lysosomes of HeLa cells; and (4) the imaging detection depth up to 2100 µm in the mock tissue under two-photon. The multifunctional PNPs are promising candidates as TPE-PDT agent for simultaneous cellular, deep-tissue imaging, and highly efficient in vivo PDT of cancer.

Water-Soluble Polythiophene for Two-Photon Excitation Fluorescence Imaging and Photodynamic Therapy of Cancer.

Positively charged water-soluble polythiophene (PT0) that could self-assemble into nanoparticles in pure water solution was designed and synthesized. PT0 exhibited high photostabilities and pH stabilities, excellent biocompatibility, strong 1O2 generation capability, and large two-photon absorption cross sections. Moreover, we showed that the fluorescence of PT0 was unaffected by the interference of biomolecules and metal ions. As an example application, PT0 was demonstrated to be capable of simultaneous cell imaging and photodynamic therapy under either one-photon or two-photon excitation modes.

Photothermally actuated interfacial hydration for fast friction switch on hydrophilic polymer brush modified PDMS sheet incorporated with Fe3O4 nanoparticles.

A near-infrared light triggered fast interfacial friction switch was achieved with polyelectrolyte brush grafted PDMS embedded with Fe3O4 nanoparticles, where the in situ heating up of the photothermal Fe3O4 nanoparticles in the polymer matrix changes the interface humidity and thereafter alters the hydration level of the interfacial polymer brushes.