Mitochondria-Targeting and Multiresponsive Nanoplatform Based on AIEgens for Synergistic Chemo-Photodynamic Therapy and Enhanced Immunotherapy.

Although photodynamic therapy (PDT) has become an attractive strategy for cancer treatment, its clinical application still suffers from some limitations, including insufficient delivery of photosensitizers, hypoxic tumor environment, and the development of PDT resistance. To address these limitations, a new class of mitochondria-targeting and fluorinated polymer with aggregation-induced emission characteristics was fabricated to sensitize PDT and co-deliver chemotherapeutic drugs. The amphiphilic fluoropolymer was able to efficiently carry oxygen and SN-38 (the active metabolite of irinotecan) and self-assemble into multifunctional micellar nanoparticles (SN-38-TTCF@O2 NPs). Upon internalization into tumor cells, these NPs could successfully escape lysosomes, selectively target mitochondria, efficiently produce reactive oxygen species (ROS) under light irradiation, and release drugs in response to ROS. In the HCT116 tumor xenograft model, they preferentially accumulated in tumor tissue and significantly alleviated tumor hypoxia, resulting in synergistic chemo-PDT efficacy without distinct toxicity. Furthermore, the nanoscale chemo-PDT induced immunogenic cell death, promoted the recruitment and activation of cytotoxic T lymphocytes, and ultimately augmented the anti-tumor efficacy of anti-PD-1 antibody in the murine CT26 tumor model. These results may provide novel insights into the development of efficient chemo-PDT nanomedicine to improve the outcome of immunotherapy.

Mechanically Strong, Wet Adhesive, and Self-Healing Polyurethane Ionogel Enhanced with a Semi-interpenetrating Network for Underwater Motion Detection.

The gel-based sensors have developed rapidly in recent years toward multifunctionality. However, there are still some challenges that need to be solved, such as poor mechanical properties and inaccessibility to wet or water environments. To address these issues, we have developed an ionogel with a semi-interpenetrating network structure by adopting poly(vinylidene fluoride-co-hexafluoropropylene) as the linear non-cross-linked network, a double-bonded ionic liquid and double-bonded capped polyurethane as the cross-linked network, and an ionic liquid as the conductive media. The obtained ionogel exhibits tunable mechanical properties (3.67-8.76 MPa) and excellent sensing properties (IG-20, GF = 8.2). The superb environmental stability and self-healing properties of the ionogel were also demonstrated. Meanwhile, adhesion, self-healing, and sensing performance were guaranteed for underwater due to the presence of a large number of C-F bonds. We strongly believe that this ionogel with excellent mechanical properties and underwater communication is expected for monitoring the health of the human body and information transmission in the future.

Highly transparent, mechanical, and self-adhesive zwitterionic conductive hydrogels with polyurethane as a cross-linker for wireless strain sensors.

Zwitterionic hydrogels have attracted a myriad of research interests for their excellent flexibility and biocompatibility as flexible wearable sensors. It is desired to create E-skins that integrate high mechanical strength, sensory sensitivity, and broad adhesion, possessing potential in the fields of intelligent robots and bionic prostheses. In this work, a novel macromolecular cross-linker (MPU) based on waterborne polyurethane (WPU) was designed and applied to synthesize multifunctional conductive hydrogels (PASU-Zn hydrogels). Importantly, in the presence of MPU, the hydrogels exhibited well-balanced mechanical properties (elongation at break 1193%, tensile strength 1.02 MPa, outstanding puncture resistance, and self-recovery abilities). When assembled as wireless strain sensors, PASU-Zn sensors displayed distinguished sensing characteristics to detect mechanotransduction signals of human movements in real-time. Specifically, owing to the dipole-dipole interaction and hydrogen bonding of zwitterions and MPU, the hydrogels have remarkable self-adhesion properties to various surfaces of wood, PDMS, and pigskin, allowing them to stick to skins by themselves without using any adhesive tapes when used. It is deemed that the as-designed zwitterionic hydrogels show great promise for wearable devices and bionic skins.

Highly stretchable, self-healable, and self-adhesive ionogels with efficient antibacterial performances for a highly sensitive wearable strain sensor.

Gel-based strain sensors with multi-functional outstanding properties have gained considerable attention. However, conventional gel sensors suffer from unsatisfactory mechanical properties and adhesion, and also a lack of self-healing and antibacterial ability. Herein, a multi-functional ionogel has been constructed based on Ag-Lignin nanoparticles (Ag-Lignin NPs), polyurethane (PU), and ionic liquids. The obtained ionogel exhibited excellent mechanical properties (tensile strength: 3.14 MPa, elongation at break: 1241%), and was conferred self-healing ability by introducing the disulfide bonds into the main chain (the best self-healing efficiency is 97.6%). The dynamic catechol redox system based on Ag-Lignin NPs endows the ionogel with repeatable and long-lasting adhesiveness. Besides, the obtained ionogel also presented favorable antibacterial and UV absorption properties. The sensor based on the ionogel possesses good and stable sensing performance. This study proposes a bright new strategy to fabricate multi-functional ionogel-based sensors exerting broad application prospects in the field of human movement and personalized physiological health monitoring.

Targeted delivery by pH-responsive mPEG-S-PBLG micelles significantly enhances the anti-tumor efficacy of doxorubicin with reduced cardiotoxicity.

Stimuli-responsive nanotherapeutics hold great promise in precision oncology. In this study, a facile strategy was used to develop a new class of pH-responsive micelles, which contain methoxy polyethylene glycol (mPEG) and poly(carbobenzoxy-l-glutamic acid, BLG) as amphiphilic copolymer, and ß-thiopropionate as acid-labile linkage. The mPEG-S-PBLG copolymer was synthesized through one-step ring-opening polymerization (ROP) and thiol-ene click reaction, and was able to efficiently encapsulate doxorubicin (DOX) to form micelles. The physicochemical characteristics, cellular uptake, tumor targeting, and anti-tumor efficacy of DOX-loaded micelles were investigated. DOX-loaded micelles were stable under physiological conditions and disintegrated under acidic conditions. DOX-loaded micelles can be internalized into cancer cells and release drugs in response to low pH in endosomes/lysosomes, resulting in cell death. Furthermore, the micellar formulation significantly prolonged the blood circulation, reduced the cardiac distribution, and selectively delivered more drugs to tumor tissue. Finally, compared with free DOX, DOX-loaded micelles significantly improved the anti-tumor efficacy and reduced systemic and cardiac toxicity in two different tumor xenograft models. These results suggest that mPEG-S-PBLG micelles have translational potential in the precise delivery of anti-cancer drugs.

Highly Stretchable PU Ionogels with Self-Healing Capability for a Flexible Thermoelectric Generator.

With the development of thermoelectric (TE) generator, the flexible, stretchable, self-healable, and wearable TE devices have aroused great interest. Therefore, we designed a self-healable and stretchable polyurethane (PU) ionogel, composed of polyurethane main chains with double bonds in the side, cross-linkers (BDB) and nonconjugated ionic liquids (EMIM:DCA). The PU ionogels with 30 wt % ILs have a high mechanical stretchability (300%), good tensile strength (1.61 MPa), and suitable Young's modulus (0.79 MPa). The proposed materials also exhibited an excellent ionic figure of merit (ZTi) of 0.99 ± 0.3, as well as rapid self-healability in the absence of any external stimuli. The thermoelectric capability of PU ionogels kept stable under the severe condition (50% strain) and during self-healing process, which is rarely reported in recent studies. Furthermore, a stretchable and self-healable ionic thermoelectric capacitor device is also fabricated by the PU ionogels, which can efficiently convert heat into electricity.

Fabrication of MXene/PEI functionalized sodium alginate aerogel and its excellent adsorption behavior for Cr(VI) and Congo Red from aqueous solution.

MXene/PEI modified sodium alginate aerogel (MPA) was facilely prepared by introducing polyethylenimine (PEI) and amino functionalized Ti3C2Tx into sodium alginate (SA) aerogel matrix through cross-linking reactions. Abundant active groups of PEI coupled with in situ reduction ability of MXene dramatically promoted the removal of Cr(VI), realizing the adsorption capacity of 538.97 mg/g. MPA also possessed an ultrahigh adsorption capacity (3568 mg/g) towards Congo Red (CR), ascribing to the strong electrostatic attraction and the synergetic effect of surface adsorption and intercalation adsorption. The Cr(VI) and CR adsorption mechanisms by MPA were further validated using X-ray photoelectron spectroscopy and Fourier transform infrared spectroscopy. Batch adsorption experiments were conducted to investigate pH impacts, kinetics, isotherms and thermodynamics. The results demonstrated that adsorption processes of both Cr(VI) and CR fitted felicitously with the Langmuir isotherm and the pseudo-second-order kinetic model. More importantly, having a double-network structure constructed by polymeric SA and PEI, the mechanical strength of the aerogel was significantly reinforced, which was easily recycled without secondary pollution and the capacity decreased few after five cycles. Furthermore, provided with outstanding antibacterial properties against S. aureus and E. coli, MPA can be extensively applied for the water treatment as a both highly efficient adsorbent and antimicrobial.

Bio-based, self-adhesive, and self-healing ionogel with excellent mechanical properties for flexible strain sensor.

Bio-based ionogels with versatile properties are highly desired for practical applications. Herein, we designed a novel self-healing, anti-freezing, and self-adhesive ionogel with excellent sensor capability. The ionogel was obtained by cross-linking amino groups (chitosan) and aldehyde groups (dextran oxide) to form Schiff-base bonds in the ionic liquids (EMIMOAc) with TA. Ionogels inherited the superior electrical conductivity of ionic liquids (IG2, 1.1 mS cm-1). Due to the dynamic reaction of Schiff-base bonds, the obtained IG2 possessed self-healing properties (self-healing efficiency = 89%). The presence of TA also provided the ionogel with excellent self-adhesive properties (IG2/TA, adhesive strength to hogskin = 8.05 kPa). Owing to the low freezing point and low vapor pressure of ionic liquids, ionogels were endowed with anti-freeze properties and resistance to solvent volatility. Moreover, the ionogel can act as a strain sensor, and exhibited excellent sensitivity and sensing performance. Our work provided a green and effective method in preparation of the high performance ionogel sensor, which could accommodate future practical industrial applications.

pH-Responsive hyperbranched polypeptides based on Schiff bases as drug carriers for reducing toxicity of chemotherapy.

Polymeric micelles have great potential in drug delivery systems because of their multifunctional adjustability, excellent stability, and biocompatibility. To further increase the drug loading efficiency and controlled release ability, a pH-responsive hyperbranched copolymer methoxy poly(ethylene glycol)-b-polyethyleneimine-poly(Nε-Cbz-l-lysine) (MPEG-PEI-PBLL) was synthesized successfully. MPEG-PEI-NH2 was synthesized to initiate the ring-opening polymerization of benzyloxycarbonyl substituted lysine N-carboxyanhydride (Z-lys NCA). The introduction of Schiff bases in the polymer make it possible to respond to the variation of pH values, which cleaved at pH 5.0 while stable at pH 7.4. As the polymer was amphiphilic, MPEG-PEI-PBLL could self-assemble into micelles. Owing to the introduction of PEI, which make the copolymer hyperbranched, the pH-responsive micelles could efficiently encapsulate theranostic agents, such as doxorubicin (DOX) for chemotherapy and NIRF dye DiD for in vivo near-infrared (NIR) imaging. The drug delivery system prolonged the drug circulation time in blood and allowed the drug accumulate effectively at the tumor site. Following the guidance, the DOX was applied in chemotherapy to achieve cancer therapeutic efficiency. All the results demonstrate that the polymer micelles have great potential for cancer theranostics.

Synergetic enhancement of mechanical and fire-resistance performance of waterborne polyurethane by introducing two kinds of phosphorus-nitrogen flame retardant.

In this work, a novel hydroxyl-terminated monomer containing phosphorus and nitrogen, tri(N, N-bis-(2-hydroxy-ethyl) acyloxoethyl) phosphate (TNAP), was synthesized successfully with phosphorus oxychloride, hydroxyethyl acrylate, and diethanolamine as raw materials, and then incorporated into flame-retarded waterborne polyurethanes to improve their flame retardancy, thermal behavior, and mechanical properties. Their structures were confirmed by nuclear magnetic resonance (NMR) and fourier transform infrared spectroscopy (FTIR). Besides, the thermal performance and combustion behaviors of crosslinked flame-retarded waterborne polyurethane (CFRWPU) films were evaluated through thermogravimetric analysis (TGA), thermogravimetry-FTIR, limiting oxygen index (LOI) tests, and microscale combustion calorimeter tests (MCC). Additionally, the mechanical properties were investigated by tensile stress-strain tests. These results revealed that the monomer TNAP exhibited remarkable residual char formation ability of 34.98 wt% and that TNAP-embedded FRWPU films attained an LOI value of 25.5% at a TNAP content of 4 wt%. Moreover, there was significant enhancement in tensile strength (15.81 MPa) obtained with the combined incorporation of TNAP into FRWPU. Also, scanning electron microscopy (SEM) and energy dispersive spectrometry (EDS) provided the morphologies and the element distributions of char residues of CFRWPU after LOI tests. Finally, the thermal mechanical properties of CFRWPU were assessed by dynamic mechanical analysis (DMA).

A novel biocompatible zwitterionic polyurethane with AIE effect for cell imaging in living cells.

In this work, a novel and stable zwitterionic polymer (TPE-CB PUs) was prepared to realize a cellular imaging system. TPE was conjugated into the backbone of zwitterionic polyurethane, which could be well dispersed in aqueous solution and emitted strong blue fluorescence because the TPE segment was aggregated in the core of TPE-CB PUs micelles. More importantly, the TPE-CB PUs micelles showed significant stability in a large pH window and with different storage times. In addition, the micelles exhibited low cytotoxicity in HeLa cells and mainly distributed in the cytoplasm after being incubated with cells. The outstanding properties of TPE-CB PUs combining the merits of AIE and a zwitterionic segment highlight its potential for use as a cell imaging material with remarkable capability.

[Inhibition of Combination of Icaritin and Doxorubicin on Human Osteosarcoma MG-63 Cells in vitro].

OBJECTIVE: To explore the inhibition and molecular mechanism of icaritin (ICT) combined doxorubicin (DOX) on human osteosarcoma MG-63 cells in vitro. METHODS: The control group, ICT groups (10, 20, 40, 80, and 160 µmol/L), DOX groups (1, 2, 4, 8, and 16 µg/mL), and combination groups (20 µmol/ L ICT +1 µg/mL DOX, 20 µmol/L ICT +2 µg/mL DOX, 20 µmol/L ICT +4 µg/mL DOX, 40 µmol/L ICT +1 µg/mL DOX, 40 µmol/L ICT +2 µg/mL DOX, 40 µmol/L ICT +4 µg/mL DOX, 80 µmol/L ICT +1 µg/mL DOX, 80 µmol/L ICT +2 µg/mL DOX, 80 µmol/L ICT +4 µg/mL DOX) were set up. Human osteosarcoma MG-63 cells were respectively cultured and their effects on morphological changes were observed using inverted phase contrast microscope after 24-and 48-h intervention. The cell proliferation inhibition rate of each group was de- termined using CCK-8, and IC50 calculated. The MG-63 apoptosis rate was detected using Annexin V-FITC/ PI double dye flow cytometry. Expression levels of bcl-2, caspase-3, and p21 were detected using RT-PCR. RESULTS: ICT and DOX could obviously inhibit the proliferation of MG-63 cell. Along with ICT concentration increasing from 10 µmol/L to 160 µmol/L, the cell proliferation inhibition rate also increased gradually from 9.67% ± 3.62% to 89.18% ± 9.66%. The IC50 was 46.93 µmol/L and 3.87 µg/mL respectively. ICT and DOX could cause either early or late stage apoptosis, down-regulate Bcl-2 gene expression, and up-regulate gene expressions of Caspase-3 and p21 respectively (P < 0.05). Aforesaid changes were more obviously seen in combination groups than in lCT groups and DOX groups (P < 0.05). CONCLUSION: CT combined DOX had additive or synergistic inhibition effect for the proliferation of osteosarcoma MG-63 cells, which might be related with regulating gene expressions of bcl-2, caspase-3, and p21.

[Effects of leukemia inhibitory factor combined with basic fibroblast growth factor on proliferation and differentiation of human bone marrow mesenchymal stem cells].

OBJECTIVE: To study the effects of leukemia inhibitory factor (LIF) and basic fibroblast growth factor (bFGF) on the proliferation and differentiation of human bone marrow mesenchymal stem cells (hBMSCs). METHODS: hBMSCs at passage 4 were divided into 4 groups according to different culture conditions: cells were treated with complete medium (a-MEM containing 10%FBS, group A), with complete medium containing 10 ng/mL LIF (group B), with complete medium containing 10 ng/mL bFGF (group C), and with complete medium containing 10 ng/mL LIF and 10 ng/mL bFGF (group D). The growth curves of hBMSCs at passage 4 in different groups were assayed by cell counting kit 8; cellular morphologic changes were observed under inverted phase contrast microscope; the surface markers of hBMSCs at passage 8 including CD44, CD90, CD19, and CD34 were detected by flow cytometry. RESULTS: The cell growth curves of each group were similar to the S-shape; the cell proliferation rates in 4 groups were in sequence of group D > group C > group B > group A. Obvious senescence and differentiation were observed very early in group A, cells in group B maintained good cellular morphology at the early stage, with slow proliferation and late senescence; a few cells in group C differentiated into nerve-like cells, with quick proliferation; and the cells in group D grew quickly and maintained cellular morphology of hBMSCs. The expressions of CD44 and CD90 in groups A and C at passage 8 cells were lower than those of groups B and D; the expressions of CD19 and CD34 were negative in 4 groups, exhibiting no obvious difference between groups. CONCLUSION: LIF combined with bFGF can not only maintain multiple differentiation potential ofhBMSCs, but also promote proliferation of hBMSCs.

[In vitro study on injectable alginate-strontium hydrogel for bone tissue engineering].

OBJECTIVE: To investigate the application potential of alginate-strontium (Sr) hydrogel as an injectable scaffold material in bone tissue engineering. METHODS: The alginate-Sr/-calcium (Ca) hydrogel beads were fabricated by adding 2.0 wt% alginate sodium to 0.2 mol/L SrCl2/CaCl2 solution dropwise. Microstructure, modulus of compression, swelling rate, and degradability of alginate-Sr/-Ca hydrogels were tested. Bone marrow mesenchymal stem cells (BMSCs) were isolated from femoral bones of rabbits by flushing of marrow cavity. BMSCs at passage 5 were seeded onto the alginate-Sr hydrogel (experimental group) and alginate-Ca hydrogel (control group), and the viability and proliferation of BMSCs in 2 alginate hydrogels were assessed. The osteogenic differentiation of cells embeded in 2 alginate hydrogels was evaluated by alkaline phosphate (ALP) activity, osteoblast specific gene [Osterix (OSX), collagen type I, and Runx2] expression level and calcium deposition by fluorescent quantitative RT-PCR and alizarin red staining, Von Kossa staining. The BMSCs which were embeded in alginate-Ca hydrogel and cultured with common growth medium were harvested as blank control group. RESULTS: The micromorphology of alginate-Sr hydrogel was similar to that of the alginate-Ca hydrogel, with homogeneous pore structure; the modulus of compression of alginate-Sr hydrogel and alginate-Ca hydrogel was (186.53 +/- 8.37) and (152.14 +/- 7.45) kPa respectively, showing significant difference (t=6.853, P=0.002); there was no significant difference (t=0.737, P=0.502) in swelling rate between alginate-Sr hydrogel (14.32% +/- 1.53%) and alginate-Ca hydrogel (15.25% +/- 1.64%). The degradabilities of 2 alginate hydrogels were good; the degradation rate of alginate-Sr hydrogel was significantly lower than that of alginate-Ca hydrogel on the 20th, 25th, and 30th days (P < 0.05). At 1-4 days, the morphology of cells on 2 alginate hydrogels was spherical and then the shape was spindle or stellate. When three-dimensional cultured for 21 days, the DNA content of BMSCs in experimental group [(4.38 +/- 0.24) g] was significantly higher than that in control group [(3.25 +/- 0.21) g] (t=8.108, P=0.001). On the 12th day after osteogenic differentiation, the ALP activity in experimental group was (15.28 +/- 1.26) U/L, which was significantly higher than that in control group [(12.07 +/- 1.12) U/L] (P < 0.05). Likewise, the mRNA expressions of OSX, collagen type I, and Runx2 in experimental group were significantly higher than those in control group (P < 0.05). On the 21th day after osteogenic differentiation, alizarin red staining and Von Kossa staining showed calcium deposition in 2 groups; the calcium nodules and phosphate deposition in experimental group were significantly higher than those in control group (P < 0.05). CONCLUSION: Alginate-Sr hydrogel has good physicochemical properties and can promote the proliferation and osteogenic differentiation of BMSCs, so it is an excellent injectable scaffold material for bone tissue engineering.