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Tetraselmis subcordiformis, a unicellular marine green alga, is used widely in aquaculture as an initial feeding for fish, bivalve mollusks, penaeid shrimp larvae, and rotifers because of its rich content of amino acids and fatty acids. A stable nuclear transformation system using the herbicide phosphinothricin (PPT) as a selective reagent was established previously. In this research, the recombinant expression in T. subcordiformis was investigated by particle bombardment with the rt-PA gene that encodes the recombinant human tissue-type plasminogen activator (Reteplase), which is a thrombolytic agent for acute myocardial infarction treatment. Transgenic algal strains were selected by their resistance to PPT, and expression of rt-PA was validated by PCR, Southern blotting, and Western blotting, and bioactivity of rt-PA was confirmed by the fibrin agarose plate assay for bioactivity. The results showed that rt-PA was integrated into the genome of T. subcordiformis, and the expression product was bioactive, indicating proper post-transcriptional modification of rt-PA in T. subcordiformis. This report contributes to efforts that take advantage of marine microalgae as cell factories to prepare recombinant drugs and in establishing a characteristic pathway of oral administration in aquaculture.

Circular dorsal ruffles (CDRs) are a kind of special ring-shaped membrane structure rich in F-actin, it is highly involved in the invasion-metastasis of tumor. Shear stress is one of the biophysical elements that affects the fate of tumor cells. However, how shear stress contributes to the CDRs formation is still unclear. In this study, we found that shear stress stimulated the formation of CDRs and promoted the migration of human breast MDA-MB-231 carcinoma cells. Integrin-linked kinase (ILK) mediated the recruiting of ADP-ribosylation factors (ARAP1/Arf1) to CDRs. Meanwhile, the transfection of ARAP1 or Arf1 mutant decreased the number of cells with CDRs, the CDRs areas and perimeters, thus blocked the cancer cell migration. This indicated that the ARAP1/Arf1 were necessary for the CDRs formation and cancer cell migration. Further study revealed that shear stress could stimulate the formation of intracellular macropinocytosis (MPS) thus promoted the ARAP1/Arf1 transportation to early endosome to regulate cancer cell migration after the depolymerization of CDRs. Our study elucidates that the CDRs formation is essential in shear stress-induced breast cancer cell migration, which provides a new research target for exploring the cytoskeletal mechanisms of breast cancer malignance.

Stiffening of the extracellular matrix (ECM) is considered a typical remolding of the microenvironment in multistep tumor progression. However, the molecular mechanisms by which the tumor cell responds to the ECM mechanical cues remain elusive. Here, we demonstrated that microRNA-29b (miR-29b) and its downstream signaling play critical regulatory roles that osteosarcoma cells sense the ECM stiffness to maintain the cancer stem cell-like ability. Polyacrylamide gels with a stiffness of 7, 20, and 55 kPa were used to mimic the rigidity of connective tissue, muscle tissue, and bone tissue. It was found that the stemness properties including self-renewal ability, differentiation potential, and drug resistance of osteosarcoma cells were strongly enhanced with reducing substrate stiffness, whereas spreading area, proliferation, and migration were inhibited. Moreover, miR-29 was obviously downregulated in soft substrate-cultured osteosarcoma cells, and the expression of stemness-related transcription factors (Sox2, Nanog, and Oct4) and the sphere formation ability were significantly inhibited by ectopic expression of miR-29b-5p. The soft substrate-induced miR-29 downregulation could increase Spin 1 expression and activate phosphatidylinositol 3-kinase (PI3K)/Akt and Stat3 signaling, which were suppressed by the increase in miR-29b-5p. Taken together, our results elucidated that miR-29 could be a novel mechanical sensor which manipulates osteosarcoma cell stemness. This finding uncovers the fact that the mechanical cue of the cancer niche could take part in the regulation of cancer progression through operating microRNAs and their downstream signaling.

TPN672 [7-(2-(4-(benzothiophen-4-yl) piperazin-1-yl)ethyl)quinolin-2(1H)-one maleate] is a novel antipsychotic candidate with high affinity for serotonin and dopamine receptors that is currently in clinical trial for the treatment of psychiatric disorders. In vitro binding study showed that TPN672 exhibited extremely high affinity for serotonin 1A receptor (5-HT1AR) (Ki = 0.23 nM) and 5-HT2AR (Ki = 2.58 nM) as well as moderate affinity for D3R (Ki = 11.55 nM) and D2R (Ki = 17.91 nM). In vitro functional assays demonstrated that TPN672 acted as a potent 5-HT1AR agonist, D2R/D3R partial agonist, and 5-HT2AR antagonist. TPN672 displayed robust antipsychotic efficacy in rodent models (e.g., blocking phencyclidine-induced hyperactivity), significantly better than aripiprazole, and ameliorated negative symptoms and cognitive deficits in the sociability test, dark avoidance response, Morris water maze test, and novel object recognition test. The results of electrophysiological experiments showed that TPN672 might inhibit the excitability of the glutamate system through activating 5-HT1AR in medial prefrontal cortex, thereby improving cognitive and negative symptoms. Moreover, the safety margin (the ratio of minimum catalepsy-inducing dose to minimum effective dose) of TPN672 was about 10-fold, which was superior to aripiprazole. In conclusion, TPN672 is a promising new drug candidate for the treatment of schizophrenia and has been shown to be more effective in attenuating negative symptoms and cognitive deficits while having lower risk of extrapyramidal symptoms and hyperprolactinemia. SIGNIFICANCE STATEMENT TPN672 is a promising new drug candidate for the treatment of schizophrenia and has been shown to be more effective in attenuating negative symptoms and cognitive deficits while having a lower risk of extrapyramidal symptoms and hyperprolactinemia. A phase I clinical trial is now under way to test its tolerance, pharmacokinetics, and pharmacodynamic effects in human volunteers. Accordingly, the present results will have significant impact on the development of new antischizophrenia drugs.

We report a dual-interfacial engineering approach that uses a sub-20 nm polycrystalline MOF-74 shell as a transition phase to engineer the MOF-polymer interface. The application of a shell MOF layer divides the original single interface problem into two interfaces: MOF-MOF and MOF-polymer, which can be individually addressed. The greater external surface area created by the uneven MOF-74 shell containing high-density open metal sites allows the MOF to interact with 300% polymer at the interface compared to traditional MOF, thereby ensuring good interfacial compatibility. When applied on UiO-66-NH2, its respective mixed-matrix membranes exhibit a simultaneous increase of CO2/CH4 separation selectivity and CO2 permeability with increasing MOF loading, implying a defect-free interface. When applied on MOF-801, the mixed-matrix membranes exhibit an ethylene/ethane separation selectivity up to 5.91, a drastic 76% increase compared to that of the neat polymer owing to a "gas focusing" mechanism promoted by the preferred pore orientation in the MOF-74 layer. This represents one of the most selective ethylene/ethane separation membranes reported to date.

Complex neuropsychiatric diseases such as schizophrenia require drugs that can target multiple G protein-coupled receptors (GPCRs) to modulate complex neuropsychiatric functions. Here, we report an automated system comprising a deep recurrent neural network (RNN) and a multitask deep neural network (MTDNN) to design and optimize multitargeted antipsychotic drugs. The system successfully generates novel molecule structures with desired multiple target activities, among which high-ranking compound 3 was synthesized, and demonstrated potent activities against dopamine D2, serotonin 5-HT1A and 5-HT2A receptors. Hit expansion based on the MTDNN was performed, 6 analogs of compound 3 were evaluated experimentally, among which compound 8 not only exhibited specific polypharmacology profiles but also showed antipsychotic effect in animal models with low potential for sedation and catalepsy, highlighting their suitability for further preclinical studies. The approach can be an efficient tool for designing lead compounds with multitarget profiles to achieve the desired efficacy in the treatment of complex neuropsychiatric diseases.Graphical abstract

Complex neuropsychiatric diseases such as schizophrenia require drugs that can target multiple G protein-coupled receptors (GPCRs) to modulate complex neuropsychiatric functions. Here, we report an automated system comprising a deep recurrent neural network (RNN) and a multitask deep neural network (MTDNN) to design and optimize multitarget antipsychotic drugs. The system has successfully generated novel molecule structures with desired multiple target activities, among which high-ranking compound 3 was synthesized, and demonstrated potent activities against dopamine D2, serotonin 5-HT1A and 5-HT2A receptors. Hit expansion based on the MTDNN was performed, 6 analogs of compound 3 were evaluated experimentally, among which compound 8 not only exhibited specific polypharmacology profiles but also showed antipsychotic effect in animal models with low potential for sedation and catalepsy, highlighting their suitability for further preclinical studies. The approach can be an efficient tool for designing lead compounds with multitarget profiles to achieve the desired efficacy in the treatment of complex neuropsychiatric diseases.

Mesoporous silica nanoparticles (MSNs) with unique advantages can combine multiple functionalities including imaging and therapeutic into one single platform that can provide personalized diagnosis...

We studied coordination-dependent surfactant binding on shaped MOF nanocrystals. Cetyltrimethylammonium bromide (CTAB) on the surface of ZIF-8 was used as a model system. Infrared spectroscopic analysis and molecular dynamics simulations reveal different coordination environments for Zn nodes on {100} and {110} facets, resulting in different CTAB adsorption. We found that we are able to fine-tune the ratio of {100} and {110} facets in the nanocrystals. We also observed that once the MOF nanocrystals are enclosed by pure {110} facets growth along the {100} facets is terminated because the MOF nanocrystal has no surface area for CTAB adsorption. Growth can then be reinitiated through the etching of these rhombic dodecahedral nanocrystals to form a small amount of undercoordinated sites. This work represents the first systematic study of the design principles underpinning the synthesis of shaped MOF nanocrystals.

Protoplast isolation was relevant for gene manipulation in Ulva, and universal protocols have been proposed based on evaluation for various wildly collected species. However, only clonal laboratory cultures were practical for genetic transformation, and whether applicability of such universal protocol existed for these artificial cultures has never been investigated. In this research, samples in different physiological states or developmental stages were tested in U. prolifera. The results proved that the protoplast yields were strongly dependent on the characteristics of samples. Neither Fv/Fm value nor chlorophyll content exhibited an ideal correlation with the protoplast yields. Alternatively, specific growth rate, coupled with developmental stage, could serve as an effective combined index to determine the right time for protoplast isolation. According to this instruction, here we reported the highest yields of protoplast ((31.5±1.9)×10 6 cells/g f. wt.) in U. prolifera, following comparison between protocols, and further optimizations on enzyme content, incubation period, starting biomass and pretreatment. This specified protocol for artificially cultured clonal samples could meet the need for protoplast-mediated genetic transformation in U. prolifera.

Acute lung injury (ALI) and its more severe form acute respiratory distress syndrome (ARDS) are life-threatening conditions with high morbility and mortality, underscoring the urgent need for novel treatments. Leaves of the medicinal herb Microcos paniculata have been traditionally used for treating upper airway infections, by virtue of its content of flavonoids such as apigenin C-glycosides (ACGs). C-glycosides have been shown to exert strong anti-inflammatory properties, although their mechanism of action remains unknown. Herein, hypothesizing that ACGs from M. paniculata inhibit progression of ALI, we used the experimental model of lipopolysaccharide (LPS)-induced ALI in BALB/c mice to evaluate the therapeutic potential of purified ACGs. Our results showed that M. paniculata ACGs inhibited lung inflammation in animals undergoing ALI. The protective effects of ACGs were assessed by determination of cytokine levels and in situ analysis of lung inflammation. ACGs reduced the pulmonary edema and microvascular permeability, demonstrating a dose-dependent down-regulation of LPS-induced TNF-α, IL-6 and IL-1β expression in lung tissue and bronchoalveolar lavage fluid, along with reduced apoptosis. Moreover, metabolic profiling of mice serum and subsequent Ingenuity Pathway Analysis suggested that ACGs activated protective protein networks and pathways involving inflammatory regulators and apoptosis-related factors, such as JNK, ERK1/2 and caspase-3/7, suggesting that ACGs-dependent effects were related to MAPKs and mitochondrial apoptosis pathways. These results were further supported by evaluation of protein expression, showing that ACGs blocked LPS-activated phosphorylation of p38, ERK1/2 and JNK on the MAPKs signaling, and significantly upregulated the expression of Bcl-2 whilst down-regulated Bax and cleaved caspase-3. Remarkably, ACGs inhibited the LPS-dependent TLR4 and TRPC6 upregulation observed during ALI. Our study shows for the first time that ACGs inhibit acute inflammation and apoptosis by suppressing activation of TLR4/TRPC6 signaling pathway in a murine model of ALI. Our findings provide new evidence for better understanding the anti-inflammatory effects of ACGs. In this regard, ACGs could be exploited in the development of novel therapeutics for ALI and ARDS.

An acidic extracellular pH (pHe) in the tumor microenvironment has been suggested to facilitate tumor growth and metastasis. However, the molecular mechanisms by which tumor cells sense acidic signal to induce a transition to an aggressive phenotype remain elusive. Here, we showed that an acidic pHe (pH 6.5) stimulation resulted in protrusion and epithelial-mesenchymal transition (EMT) of cancer cells, which promoted migration and matrix degeneration. Using computational molecular dynamics simulations, we reported acidic pHe-induced opening of the Integrin dimers (α5β1) headpiece which indicated the activation of integrin. Moreover, acidic pHe promoted maturation of focal adhesions, temporal activation of Rho GTPases and microfilament reorganization through integrin β1-activated FAK signaling. Furthermore, mechanical balance of cytoskeleton (actin, tubulin and vimentin) contributed to acidic pHe-triggered protrusion and morphology change. Taken together, these findings revealed that integrin β1 could be a novel pH-regulated sensitive molecule which confers protrusion and malignant phenotype of cancer cells.

Aim: To enhance synergistic therapeutic effects in breast cancer therapy. Here, we used hollow mesoporous silica nanoparticles as a biocompatible carrier to coload chemotherapy drugs Irinotecan and near-infrared IR-820 dye, which enhanced antitumor efficacy by combining chemotherapy and phototherapy. Methods: The successful synthesis of hollow mesoporous silica nanoparticles/Irinotecan/IR820 (HMII) nanocomplex was confirmed by Fourier transform infrared spectroscopy and Fluorescence spectra. The photothermal conversion efficiency and antitumor efficiency in murine breast cancer cells (EMT-6) bearing mice were further evaluated. Results: The results demonstrated that HMII enhanced the delivery of Irinotecan and IR-820 into EMT-6 cells. HMII generated a high temperature upon a near-infrared laser irradiation (808 nm), and showed higher therapeutic efficacy in EMT-6-bearing mice compared with either HMII without laser or free drug with a laser. Conclusion: HMII is a desired drug codelivery system to efficiently inhibit the growth of breast cancer.

Bacterial quorum sensing (QS) molecules are involved in the coordination of certain behaviors such as biofilm formation, virulence and antibiotic resistance. QS molecules (autoinducers) and their corresponding receptors have been recognized as important therapeutic targets for drug-resistant infections and biofilm-associated infections (BAI). This study assessed the multiple biological effects of homogentisic acid γ-lactone (HgAL), a furanone derivative. The anti-QS and anti-biofilm effects of HgAL against PAO1 strain were evaluated using CLSM, SEM, HPLC and other biochemical methods The results showed that HgAL could effectively inhibit the production of pyocyanin and extracellular matrix, as well as reduce the adherence ability and biofilm formation of Pseudomonas aeruginosa. Inhibition of virulence is attributed to the suppressive effect of HgAL on biosynthesis of 3-oxo-C12-HSL and C4-HSL (two kinds of QS signaling molecules in P. aeruginosa). Our results support HgAL as a potential agent for prevention of BAI in the healthcare settings.

Tumor cell can be significantly influenced by various chemical groups of the extracellular matrix proteins. However, the underlying molecular mechanisms involved in the interaction between cancer cells and functional groups in the extracellular matrix remain unknown. Using chemically modified surfaces with biological functional groups (CH3, NH2, OH), it was found that hydrophobic surfaces modified with CH3 and NH2 suppressed cell proliferation and induced the number of apoptotic cells. Mitochondrial dysfunction, cytochrome c release, Bax upregulation, cleaved caspase-3 and PARP, and Bcl-2 downregulation indicated that hydrophobic surfaces with CH3 and NH2 triggered the activation of intrinsic apoptotic signaling pathway. Cells on the CH3- and NH2-modified hydrophobic surfaces showed downregulated expression and activation of integrin β1, with a subsequent decrease of focal adhesion kinase (FAK) activity. The RhoA/ROCK/PTEN signaling was then activated to inhibit the phosphorylation of PI3K and AKT, which are essential for cell proliferation. However, pretreatment of MDA-MB-231 cells with SF1670, a PTEN inhibitor, abolished the hydrophobic surface-induced activation of the intrinsic pathway. Taken together, the present results indicate that CH3- and NH2-modified hydrophobic surfaces induce mitochondria-mediated apoptosis by suppressing the PTEN/PI3K/AKT pathway, but not OH surfaces. These findings are helpful to understand the interaction between extracellular matrix and cancer cells, which might provide new insights into the mechanism potential intervention strategies for tumor prognosis.

Topographical patterns are widely applied in many manufacturing areas due to the unique role in modifying performance related to physical, chemical and biological fundamentals. The patterns are usually realized by buckling or wrinkling, self-assembly or epitaxy, and lithography techniques. However, the combination of satisfactory controllability, ridge robustness, cost and dimensional precision is still difficult to achieve by any of the strategies above. A novel, simple and low-cost nanopatterning technique named "photodegradation copying method" with high technological flexibility has been initially proposed in this study. As a perfect example, a nanoridge-patterned surface has been successfully realized on a polymeric film thanks to the selective photodegradation of polymer and the shielding effect of silver nanowire (AgNW) networks. Roughness, wettability and transmittance of the polymeric film became simply and effectively controllable by adjusting the photodegradation time or the size and distribution of AgNWs. In addition, the ridge-patterned film could also be employed as a substrate in transfer printing for more flexible devices. Various topographical nanopatterns are expected to be simply realized by the photocopying method, just replacing nanowires with other masks like nanodisks, nanocubes, nanotriangles, and so on. This promising photocopying technique is believed to play an important role in the development of topographical nanopatterns, and enable more intriguing applications simply, flexibly and inexpensively.

Cell culture systems are indispensable in vitro tools for biomedical research. Although conventional two-dimensional (2D) cell cultures are still used for most biomedical and biological studies, the three dimensional (3D) cell culture technology attracts increasing attention from researchers, especially in cancer and stem cell research. Due to the different spatial structures, cells in 2D and 3D cultures exhibit different biochemical and biophysical phenotypes. Therefore, a new platform with both 2D and 3D cell cultures is needed to bridge the gap between 2D and 3D cell-based assays. Here, a simultaneous 2D and 3D cell culture array system was constructed by microprinting technology, in which cancer cells exhibited heterozygous geometry structures with both 2D monolayers and 3D spheroids. Cells grown in 3D spheroids showed higher proliferation ability and stronger cell-cell adhesion. Spheroids derived from various types of cancer cell lines exhibited distinct morphologies through a geometrical confinement stimulated biomechanical transduction. Z-projected images of cancer cell aggregates were used to analyze 3D multicellular architecture features. Notably, by using a support vector machine (SVM) classifier, we distinguished tumor cells from normal cells with an accuracy greater than 95%, according to the geometrical features of multicellular spheroids in phase contrast microscopy images. Cancer cells in multicellular spheroid arrays exhibited higher drug resistance of anticancer drug cisplatin than cells grown in 2D cultures. Finally, we developed a co-culture system composed of tumor spheroid arrays, fibroblast cells and photo-crosslinkable gelatin methacryloyl (GelMA) hydrogel to mimic tumor microenvironment which consisted of solid tumor massed, surrounding stromal cells and extracellular matrix. Together, our newly developed simultaneous 2D and 3D cell culture array has great potential in comprehensive evaluation of cellular events in both 2D and 3D, rapid production of spheroid arrays and multicellular geometry-based tumor cell detection (MGTD).

The exploration of an intelligent multifunctional imaging-guided therapeutic platform is of great significance because of its ideal delivery efficiency and controlled release. In this work, a tumor microenvironment (TME)-responsive nanocarrier (denoted as MB@MSP) is designed for on-demand, sequentially release of a short D-peptide antagonist of programmed cell death-ligand 1 (named as PDPPA-1) and a photosensitizer methylene blue (MB). Fe3O4-Au located in the core of MB@MSP is used as a magnetic resonance imaging and micro-computed tomography imaging contrast agent for noninvasive diagnosis of solid tumors and simultaneous monitoring of drug delivery. The PDPPA-1 coated on MB@MSP can be shed due to the cleavage of the peptide substrate by matrix metalloproteinase-2 (MMP-2) that is highly expressed in the tumor stroma, and disulfide bonding is further broken when it encounters high levels of glutathione (GSH) in TME, which finally leads to significant size reduction and charge-reversal. These transitions facilitate penetration and uptake of nanocarriers against tumors. Noticeably, the released PDPPA-1 can block the immune checkpoint to create an environment that favors the activation of cytotoxic T lymphocytes and augment the antitumor immune response elicited by photodynamic therapy, thus significantly improving therapeutic outcomes. Studies of the underlying mechanisms suggest that the designed MMP-2 and GSH-sensitive delivery system not only induce apoptosis of tumor cells but also modulate the immunosuppressive tumor microenvironment to eventually augment the suppression tumor metastasis effect of CD8+ cytotoxic T cells. Overall, the visualization of the therapeutic processes with comprehensive information renders MB@MSP an intriguing platform to realize the combined treatment of metastatic tumors.

Nanoscaled metal organic frameworks have emerged as a novel type of organic-inorganic hybrid coordination polymeric nanomaterials and showed great promise in biomedical area in recent decades. As a special subclass, zeolitic imidazolate frameworks (ZIFs), constructing with metal ions and imidazolate linkers, own unique advantages of high porosity, large surface area, good biocompatibility, pH sensitivity and etc. These render ZIFs as attractive and promising platforms to delivery various cargos of drugs, imaging probes and biomacromolecules for cancer diagnosis and therapy. And this review specially summaries the state-of-the-art research on ZIFs for biosensing, cancer imaging and phototheranostics within the latest 5 years. The multiply strategies of synthesis, characterization and functionalization of ZIFs-based nanosystems are firstly discussed. The vital roles of ZIFs in biosensors, including electrochemical, fluorescent and colorimetric sensors are analyzed. Then, the monomodal and/or multimodal cancer imaging techniques mediated by ZIFs are addressed. Particular emphasis is placed on the ZIFs-based cancer phototheranostics which provide a potential alternative avenue to greatly improve the therapeutic index of cancer. Finally, the future opportunities and challenges of ZIFs are tentatively proposed and discussed from the point of translational medicine.

In the present study, a series of tetrahydropyridopyrimidinone derivatives, possessing potent dopamine D2, serotonin 5-HT1A and 5-HT2A receptors properties, was synthesized and evaluated as potential antipsychotics. Among them, 3-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)-9-hydroxy-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one (10d) held the best pharmacological profile. It not only exhibited potent and balanced activities for D2, 5-HT1A, and 5-HT2A receptors, but was also endowed with low activities for α1A, 5-HT2C, H1 receptors and hERG channels, suggesting a low propensity for inducing orthostatic hypotension, weight gain and QT prolongation. In animal models, compound 10d reduced phencyclidine-induced hyperactivity with a high threshold for catalepsy induction. On the basis of its robust in vitro potency and in vivo efficacy in preclinical models of schizophrenia, coupled with a good pharmacokinetic profile, 10d was selected as a candidate for further development.

The cloud model is a typical model which transforms the qualitative concept into the quantitative description. The cloud model has been used less extensively in texture studies before. The purpose of this study was to apply the cloud model in food crispness comparison. The acoustic signals of carrots, white radishes, potatoes, Fuji apples, and crystal pears were recorded during compression. And three time-domain signal characteristics were extracted, including sound intensity, maximum short-time frame energy, and waveform index. The three signal characteristics and the cloud model were used to compare the crispness of the samples mentioned above. The crispness based on the Ex value of the cloud model, in a descending order, was carrot > potato > white radish > Fuji apple > crystal pear. To verify the results of the acoustic signals, mechanical measurement and sensory evaluation were conducted. The results of the two verification experiments confirmed the feasibility of the cloud model. The microstructures of the five samples were also analyzed. The microstructure parameters were negatively related with crispness (p

To explore the changes in the cell physiological status of pork tissues at different storage stages, electrical impedance spectroscopy (EIS) was used in this study. The measured impedance values were analyzed with equivalent circuit models consisting of several electrical components. In order to model the complex pork tissues accurately, a constant phase element (CPE) was introduced instead of Cm in the conventional Fricke model to reflect the capacitance of cell membrane. R2 values of the real part of impedance were within the range between 0.961 and 0.999, and those for the imaginary part were between 0.730 and 0.999. The results suggested that the modified model with CPE can be further developed to monitor tissues conductivity changes and to evaluate cell physiological status of heterogeneous pork tissues in storage. Control and evaluation of meat maturation state with electrical impedance spectroscopy, which is a convenient and inexpensive method, is feasible and applicable.

Xue Shen,1 Tingting Li,1 Zhongyuan Chen,1 Yue Geng,1 Xiaoxue Xie,1 Shun Li,1,2 Hong Yang,1,2 Chunhui Wu,1,2 Yiyao Liu1,2 1Department of Biophysics, School of Life Science and Technology, 2Center for Information in Biology, University of Electronic Science and Technology of China, Chengdu, Sichuan, People’sRepublic of China Abstract: Cancer diagnosis and treatment represent an urgent medical need given the rising cancer incidence over the past few decades. Cancer theranostics, namely, the combination of diagnostics and therapeutics within a single agent, are being developed using various anticancer drug-, siRNA-, or inorganic materials-loaded nanocarriers. Herein, we demonstrate a strategy of encapsulating quantum dots, superparamagnetic Fe3O4 nanocrystals, and doxorubicin (DOX) into biodegradable poly(D,L-lactic-co-glycolic acid) (PLGA) polymeric nanocomposites using the double emulsion solvent evaporation method, followed by coupling to the amine group of polyethyleneimine premodified with polyethylene glycol-folic acid (PEI-PEG-FA [PPF]) segments and adsorption of vascular endothelial growth factor (VEGF)-targeted small hairpin RNA (shRNA). VEGF is important for tumor growth, progression, and metastasis. These drug-loaded luminescent/magnetic PLGA-based hybrid nanocomposites (LDM-PLGA/PPF/VEGF shRNA) were fabricated for tumor-specific targeting, drug/gene delivery, and cancer imaging. The data showed that LDM-PLGA/PPF/VEGF shRNA nanocomposites can codeliver DOX and VEGF shRNA into tumor cells and effectively suppress VEGF expression, exhibiting remarkable synergistic antitumor effects both in vitro and in vivo. The cell viability was ~14% when treated with LDM-PLGA/PPF/VEGF shRNA nanocomposites ([DOX] =25 µg/mL), and in vivo tumor growth data showed that the tumor volume decreased by 81% compared with the saline group at 21 days postinjection. Magnetic resonance and fluorescence imaging data revealed that the luminescent/magnetic hybrid nanocomposites may also be used as an efficient nanoprobe for enhanced T2-weighted magnetic resonance and fluorescence imaging in vitro and in vivo. The present work validates the great potential of the developed multifunctional LDM-PLGA/PPF/VEGF shRNA nanocomposites as effective theranostic agents through the codelivery of drugs/genes and dual-modality imaging in cancer treatment. Keywords: doxorubicin, codelivery, dual-modality imaging, synergistic antitumor effects, VEGF shRNA

In order to ensure stable, correct and real-time high-speed transmission of indoor visible light communication (VLC), the key modulation and demodulation technologies of orthogonal frequency division multiplexing (OFDM) are studied in this paper. The time-domain synchronization, frequency synchronization and channel equalization of receiver are analyzed and optimized by utilizing short and long training preamble. Moreover, field programmable gate array (FPGA) development board (Xilinx Kintex-7) and Verilog hardware description language are used to realize the design of proposed OFDM-VLC system. Simulation and experiment both verify the feasibility of the hardware designs of this system. The proposed OFDM-based VLC system can process signal in real-time, which can be used in actual VLC application systems.

Multifunctional theranostics have offered some interesting new opportunities for cancer therapy and diagnosis in the last decade. Herein, magnetic mesoporous silica nanoparticles (M-MSNs) were designed and synthesized, then the photosensitizer chlorin e6 (Ce6) and antitumor drug doxorubicin (Dox) were adsorbed onto the M-MSNs. Biocompatible alginate/chitosan polyelectrolyte multilayers (PEM) were assembled on the M-MSNs to achieve a pH-responsive drug delivery system and adsorb P-gp shRNA for reversing the multidrug resistance. The obtained M-MSN(Dox/Ce6)/PEM/P-gp shRNA nanocomposites were characterized using TEM, SEM, X-ray diffraction, BET, FTIR and electrophoresis. The nanocomposites with average diameter of 280 nm exhibited a pH-responsive drug release profile, and more singlet oxygen generation in cancer cells after laser illumination. CCK-8 assay and calcein-AM/PI co-staining showed that the multifunctional nanocomplexes significantly increased cell apoptosis in vitro. With tumor-bearing Balb/c mice employed as the animal model, combined photodynamic therapy and chemotherapy was carried out, also achieving synergistic anti-tumor effects in vivo. The cores of bifunctional Fe3O4-Au nanoparticles in the multifunctional nanocomposites enabled dual-modal MR and CT imaging, which illustrated strong tumor uptake of these nanocomposites after intravenous injection into tumor-bearing mice. This work highlights the great potential of magnetic mesoporous silica nanocomposites as a multifunctional delivery platform, which is promising for imaging-guided cancer combination therapy with high efficacy.

To realize precise tumor therapy, a versatile oncotherapy nanoplatform integrating both diagnostic and therapeutic functions is necessary. Herein, we fabricated a hybrid micelle (HM) utilizing two amphiphilic diblock copolymers, polyethylenimine-polycaprolactone (PEI-PCL) and diethylenetriaminepentaacetic acid gadolinium(III) (Gd-DTPA)-conjugated polyethyleneglycol-polycaprolactone (Gd-PEG-PCL), to codeliver the small-molecule chemotherapy drugs doxorubicin (Dox) and microRNA-34a (miR-34a), denoted as Gd-HM-Dox/34a. Conjugating Gd-DTPA on the surface of hybrid micelles, leading the relaxation rate of Gd-DTPA increased more than 1.4 times (13.6 mM

Brown algae have convergently evolved plant-like body plans and reproductive cycles, which in plants are controlled by differential DNA methylation. This contribution provides the first single-base methylome profiles of haploid gametophytes and diploid sporophytes of a multicellular alga. Although only c. 1.4% of cytosines in Saccharina japonica were methylated mainly at CHH sites and characterized by 5-methylcytosine (5mC), there were significant differences between life-cycle stages. DNA methyltransferase 2 (DNMT2), known to efficiently catalyze tRNA methylation, is assumed to methylate the genome of S.japonica in the structural context of tRNAs as the genome does not encode any other DNA methyltransferases. Circular and long noncoding RNA genes were the most strongly methylated regulatory elements in S.japonica. Differential expression of genes was negatively correlated with DNA methylation with the highest methylation levels measured in both haploid gametophytes. Hypomethylated and highly expressed genes in diploid sporophytes included genes involved in morphogenesis and halogen metabolism. The data herein provide evidence that cytosine methylation, although occurring at a low level, is significantly contributing to the formation of different life-cycle stages, tissue differentiation and metabolism in brown algae.

Metal-organic frameworks (MOFs) is a promising class of sorbent materials for swing adsorption gas separation. However, although sorption kinetics plays a major role in column breakthrough experiments, it is rarely studied with MOF materials. This is largely because the synthesis of uniform yet separation-relevant MOFs is a challenging task. Here, we report a dual-modulation approach for the synthesis of well-defined Mg-MOF-74 hexagonal rods with an extremely uniform size distribution (polydispersity index = 1.02). Through epitaxial growth and wet chemical etching, uniform hollow Ni-MOF-74 with plate-shaped caps were obtained. CO2 adsorption kinetic study shows that hollow Ni-MOF-74 exhibits 54% faster diffusion rate compared to solid Ni-MOF-74 due to a shortened diffusion length, despite their identical CO2 uptake capacity. This has led to a 21% extension of column breakthrough time during CO2/N2 separation under identical conditions.

In egress routes of malignancy, cancer cells are constantly subjected to shear stress imposed by blood/lymph flow. Increasing evidence points toward the regulatory roles of shear stress in tumor cell adhesion and motility. Although it is known that integrin endocytic trafficking governs focal adhesion (FA) turnover and cell migration, the effect and biological consequences of low shear stress (LSS) on integrin trafficking remain unclear. Here, we identified the critical role of integrin β1 trafficking and caveolin-1 (Cav-1) mediated endocytosis in LSS-induced cell directional migration. LSS altered the distribution of integrin β1 in MDA-MB-231 cells and significantly promoted its internalization and recycling, which in turn facilitated FA turnover and directional cell migration. Furthermore, LSS induced cytoskeleton remodeling, which was required for internalization of integrin β1. LSS down-regulated the acetylation level of microtubules (MTs) via activating ROCK/HDAC6 pathway, resulting in elevation of MTs dynamics, Cav-1 motility, and Cav-1-dependent integrin β1 recycling. We also showed that high HDAC6 expression was a ROCK-dependent prognostic factor, which was correlated with poor outcomes in breast cancer patients. Taken together, these results defined a novel mechanism by which LSS enhanced integrin β1 trafficking via actin cytoskeleton remodeling and ROCK/HDAC6 mediated deacetylation of MTs, thereby promoting FAs turnover and directional cell migration.

The thermolysis routes of two isostructural metal–organic framework compounds (Zn-based ZIF-8 and Co-based ZIF-67) are investigated based on temperature-dependent and time-dependent in situ Fourier transform infrared (FTIR) spectroscopy and in situ X-ray diffraction data, as well as thermogravimetric-differential scanning calorimetry (TG-DSC) analyses and density functional theory (DFT) calculations. These data highlight thermolysis effects on different vibrations and dissociations within specific atomic moieties. The coordination differences between Zn–N and Co–N lead to the distinct thermolysis routes of ZIF-8 and ZIF-67. ZIF-8 is easily deformed during heating while decomposes at a higher temperature due to the saturated Zn–N coordination. ZIF-67, however, does not deform during heating due to the stronger Co–N bonds, but easily reacts with oxygen due to the unsaturated Co–N bonds. Our results demonstrate that in situ FTIR paired with in situ XRD is a powerful technique for MOF thermolysis investigation, and we suggest that the thermolysis mechanisms of MOFs may be unveiled by investigating a series of MOFs having different coordination types using in situ characterisation methods.

One of the hallmarks of cancer progression is strong drug resistance during clinical treatments. The tumor microenvironment is closely associated with multidrug resistance, the optimization of tumor microenvironments may have a strong therapeutic effect. In this study, we configured polyacrylamide hydrogels of varying stiffness [low (10 kPa), intermediate (38 kPa) and high (57 kPa)] to simulate tissue physical matrix stiffness across different stages of breast cancer. After treatment with doxorubicin, cell survival rates on intermediate stiffness substrate are significantly higher. We find that high expression of ILK and YAP reduces the survival rates of breast cancer patients. Drug resistance is closely associated with the inactivation of the hippo pathway protein Merlin/MST/LATS and the activation of YAP. These results not only highlight the understanding of drug resistance mechanisms but also serve as a new basis for developing breast cancer treatment delivery systems.

Phosphodiesterase type 5 (PDE5) inhibitors are first-line therapy for pulmonary arterial hypertension (PAH) and erectile dysfunction. As a continuing work to improve the terminal half-lives and oral bioavailabilities of our previously reported 4(3 H)-pyrimidones, a pharmacokinetics-driven optimization focusing on the terminal substituent is described. Two major congeneric series of 4(3 H)-pyrimidones, the aminosulfonylphenylpyrimidones and acylaminophenylpyrimidones, were designed, synthesized, and pharmacologically assessed in vitro and in vivo. Among them, compound 15 (TPN171) with subnanomolar potency for PDE5 and good selectivity over PDE6 was finally recognized as a potential drug candidate, and its pharmacokinetic profiles in rats and dogs are significantly improved compared to the starting compound (3). Moreover, TPN171 was proven to exert a longer lasting effect than sildenafil in animal models, providing a foundation for a once-daily oral administration for its clinical use. TPN171 is currently being investigated in a phase II clinical trial for the treatment of PAH.

Clinical and preclinical researches have shown that sub-anesthetic ketamine elicits sustained antidepressant effects for up to 1–2 weeks. Pharmacokinetics studies (t1/2 = 23 min) in mice showed no ketamine residue at 24 h after sub-anesthetic or anesthetic ketamine administration. Therefore, this study aims to reveal the mechanism underlying these different biological functions at 24 h after sub-anesthetic and anesthetic ketamine treatment. First, at the animal behavioral level, we found that sub-anesthetic ketamine induced antidepressant and anxiolytic effects while anesthetic ketamine induced depressive-like phenotypes and cognitive impairment. Second, we examined the correlation between behavior phenotype and protein expression, and found that the Brain-derived neurotrophic factor (BDNF) level is oppositely regulated by sub-anesthetic and anesthetic ketamine. Sub-anesthetic ketamine significantly increased the BDNF level, correlating to antidepressant effects; whereas anesthetic dose reduced BDNF expression in the hippocampus, correlating to depressive-like behaviors, anxiety-like behaviors and cognitive impairment. Third, the antidepressant effects of sub-anesthetic ketamine were prevented by pre-treatment of ANA-12, a Tropomyosin receptor kinase B (TrkB) inhibitor. Thus, we conclude that BDNF may be the key factor underlying antidepressant and anxiolytic effects of sub-anesthetic ketamine at 24 h after treatment. These results may shed light on future studies and the development of long-lasting anti-depressant drugs and therapies.

The new hybrid nanomaterials have unique nanoparticle surface modification or core characteristics, with two or more chemical, physical, and optical properties. They have shown more personalized application prospects in disease management and treatment, and can significantly improve the diagnosis and treatment of various diseases. This article reviews the synthesis methods and structural characteristics of a series of new hybrid nanomaterials recently produced, including metallic oxide-containing hybrid nanomaterials, biopolymers-containing hybrid nanomaterials and in situ biosynthesis of hybrid nanomaterials. We focus on applying various types of hybrid nanomaterials in magnetic resonance imaging, photoacoustic, fluorescence imaging, and computed tomography imaging technology. At the same time, it summarizes the therapeutic effects of theranostics, cancer immunotherapy, photomedicine, and photothermal therapy under the guidance of imaging diagnosis. Finally, we briefly analyze the challenges in biomedical applications by hybrid materials as a nano-platform for imaging diagnosis and treatment and provides suggestions for future research in this field.

Cannabidiol (CBD) is a non-psychotomimetic compound derived from Cannabis sativa. Preclinical and clinical studies have shown therapeutic potential of CBD in a variety of disorders. Despite several research efforts on CBD, its antidepressant activity has been poorly investigated and the exact mechanism of action remains unclear. Thus, this study aimed to further explore the mechanism of CBD after chronic administration (7 days). First, the dose level of CBD that is enough to produce antidepressant effects after chronic administration was explored. Second, the changes in key proteins and neurotransmitters through such methods as real-time polymerase chain reaction (RT-PCR), western blotting, and high-performance liquid chromatography-electrochemical detection (HPLC-ECD) were critically studied. Furthermore, correlation between behavioral phenotypes with protein and neurotransmitters was established and the possible mechanism was herein postulated. The results showed that only the high dose CBD 100 mg/kg chronic administration induced antidepressant-like effects in mice subjected to forced swim test. Chronic CBD 100 mg/kg administration resulted in significant increases in serotonin (5-HT) and noradrenaline (NA) levels in the hippocampus (HPC). Similarly, the chronic administration of CBD 30 mg/kg and CBD 100 mg/kg significantly decreased nuclear factor kappa B (NF-κB) expression in the HPC. Moreover, none of the treatments were observed to induce locomotor effects. Thus, we concluded that chronic administration of CBD (100 mg/kg) induced antidepressant-like effects by increasing 5-HT and NA levels in the HPC. These results shed new light on further discovery of the antidepressant effect of CBD.

In predictable delay tolerant networks (PDTNs), the network topology is known a priori or can be predicted over time such as vehicular networks based on public buses or trains and space planet network. Previous DTN research mainly focuses on routing and data access. However, data collecting are used widely in PDTNs and it is very important in practical application, how to maintain the dynamic topology of this type of PDTNs becomes crucial. In this paper, a spanning tree (ST) based topology control method for data collecting in PDTNs is proposed. The PDTN is modeled as layered space-time directed graph which includes spatial, temporal and energy cost information, which can be simplified as reduced aggregated directed graph. The topology control problem is defined as constructing a ST that the total energy cost of the ST is minimized and the time delay threshold is satisfied. We propose three heuristic algorithms based on layered space-time directed graph and reduced aggregated directed graph to solve the defined problem, and compare them in terms of energy cost and time delay. Extensive simulation experiments demonstrate that the proposed algorithms can guarantee data transmission effectively, reduce the network energy consumption significantly, and shorten the time delay of data transmission.

An appropriate codelivery system for chemotherapeutic agents and nucleic acid drugs will provide a more efficacious approach for the treatment of cancer. Combining gene therapy with chemotherapeutics in a single delivery system is more effective than individual delivery systems carrying either gene or drug. In this work, we developed folate (FA) receptor targeted magnetic-mesoporous silica nanoparticles for the codelivery of VEGF shRNA and doxorubicin (DOX) (denoted as M-MSN(DOX)/PEI-FA/VEGF shRNA). Our data showed that M-MSN(DOX)/PEI-FA could strongly condense VEGF shRNA at weight ratios of 30:1, and possesses higher stability against DNase I digestion and sodium heparin. In vitro antitumor activity assays revealed that HeLa cell growth was significantly inhibited. The intracellular accumulation of DOX by confocal microscopy and fluorescence spectrophotometry showed that M-MSN(DOX)/PEI-FA were more easily taken up than nontargeted M-MSN(DOX). Quantitative PCR and ELISA data revealed that M-MSN/PEI-FA/VEGF shRNA induced a significant decrease in VEGF expression as compared to cells treated with either the control or other complexes. The invasion and migration phenotypes of the HUVECs were significantly decrease after coculture with MSN/PEI-FA/VEGF shRNA nanocomplexes-treated HeLa cells. The approach provides a potential strategy to treat cancer by a singular nanoparticle delivery system.

Monocyte chemoattractant protein-1 (MCP-1) is a chemotactic cytokine that can bind to its receptor cysteine–cysteine chemokine receptor 2 (CCR2) and plays an important role in breast cancer cell metastasis. However, the molecular mechanisms underlying MCP-1-induced alterations in cellular functions during tumor progression are poorly understood. Here, we showed that MCP-1 stimulated the epithelial–mesenchymal transition (EMT) and induced the tumorigenesis of breast cancer cells by downregulating E-cadherin, upregulating vimentin and fibronectin, activating matrix metallopeptidase-2 (MMP-2), and promoting migration and invasion. Moreover, MCP-1 treatment reduced glycogen synthase kinase-3β (GSK-3β) activity via the MEK/ERK-mediated phosphorylation of serine-9 in MCF-7 cells. The inhibition of MEK/ERK by U0126 attenuated the MCP-1-induced phosphorylation of GSK-3β and decreased the expression of Snail, an EMT-related transcription factor, leading to the inhibition of MCF-7 cell migration and invasion. Inactivation of GSK-3β by LiCl (lithium chloride) treatment notably increased MMP-2 activity, vascular endothelial growth factor expression and EMT of MCF-7 cells. These findings revealed that MCP-1-induced EMT and migration are mediated by the ERK/GSK-3β/Snail pathway, and identified a potential novel target for therapeutic intervention in breast cancer.

Ethnopharmacological relevance Angelicae dahurica (Hoffm.) Benth. & Hook.f.ex Franch. & Sav combined with Pueraria and Gastrodia elata Bl. combined with Inula japonica Thunb. are widely used in herb-pairs of traditional chinese medicine. Previous studies have shown that Angelicae dahuricae essential oil (ADO) enhanced puerarin internalization into ABCB1-overexpressed Caco-2 cells. These findings suggest the possibility that essential oils may enhance the absorption via certain mechanisms related to ABCB1 and reverse multidrug resistance (MDR). Aim of the study ADO and essential oils from Inula japonica (IJO) may reverse ABCB1-mediated MDR, but this ability has not been investigated in detail in the well-established cancer cell lines. In this study, the underlying molecular mechanisms were further investigated to examine how IJO and ADO reverse MDR in the resistant human breast cancer cell line of MCF-7/ADR. Also this work may help uncover the conceivable compatibility mechanisms of above herb-pairs involved in ABCB1. Materials and methods The MDR human breast cancer MCF-7/ADR cells were treated with IJO, its sesquiterpene component isoalantolactone (ISO) or ADOat non- cytotoxic concentrations. The MDR ability was examined by measuring the sensitivity to doxorubicin (DOX), DOX accumulation and efflux, ABCB1 ATPase activity, ABCB1 expression, membrane fluidity, and stability and localization of lipid rafts and caveolae. Finally, the molecular modeling was performed to postulate how ISO interacts with ABCB1. Results Treating MCF-7/ADR cells with IJ oil, ISO or AD oil reversed MDR 2- to 3-fold, without affecting the sensitivity of the non-MDR parental cell line. Mechanistic studies showed that these oils down-regulated mRNA and protein expression of ABCB1, and reduced the stability of lipid rafts in the cell membrane, which has previously been shown to reduce ABCB1-mediated transport. On the other hand, IJO, ISO and ADO did not inhibit ABCB1 ATPase activity, and fluorescence polarization experiments showed that low concentrations of the oils did not appear to alter membrane fluidity, unlike some MDR-reversing agents, ISO showed a higher docking score than verapamil but lower than dofequidar and tariquidar. Conclusions Our results suggest that IJO, ISO and ADO could reverse MDR by down-regulating ABCB1 expression and reducing lipid raft stability. These findings may be useful for developing safer and effective MDR reversal agents and also help find out the compatibility mechanisms.

Blind quantum computation (BQC) can allow a client with limited quantum power to delegate his quantum computation to a powerful server and still keep his own data private. In this paper, we present a multiple-server flexible BQC protocol, where a client who only needs the ability of accessing qua ntum channels can delegate the computational task to a number of servers. Especially, the client’s quantum computation also can be achieved even when one or more delegated quantum servers break down in networks. In other words, when connections to certain quantum servers are lost, clients can adjust flexibly and delegate their quantum computation to other servers. Obviously it is trivial that the computation will be unsuccessful if all servers are interrupted.

Featuring outstanding electrical and optical properties, silver nanowires (AgNWs) have been regarded as one of the most promising candidates for ITO to manufacture transparent conductive electrodes. However, the poor long-term stability of bare AgNWs, due to sulfidation/oxidation corrosion, is an unavoidable and urgent problem in practical applications. In the present work, a large-area ultrathin and uniform graphene oxide (GO) film was freely self-assembled at the interface of pentane–water by a rapid process within only 3 minutes, and subsequently transferred onto the surface of AgNW film by a simple dip coating process, resulting in an impressive improvement in the conductive performance and stability of the AgNWs. The ultrathin GO film was formed by the evaporation driven instability effect of acetone to induce the self assembly of GO nanosheets and an assistant thermal treatment to accelerate the formation rate. The thickness of GO film could be effectively controlled by changing the amount of acetone and the self-assembly time. The sheet resistance of the GO/AgNW electrode has been decreased approximately 3–4 times, with only a 2% loss in transmittance, compared to the original AgNW electrode. A GO/AgNW electrode with a sheet resistance of 21.5 Ω sq−1 at 90% transmittance has been achieved. The stability of the AgNW electrodes at room temperature and high temperature (120 °C) environments has been improved using GO as a protective film. The uniform and large-scale GO film can be transferred onto various substrates by a simple dip coating method with an arbitrary shape, which will open a new window for the protection of various metal nanowires.

The current strategies for drug/gene and multimodal imaging probes integrated into a single nanoparticle have some limitations still. Here, multifunctional chitosan hybrid nanoparticles (denoted as FA–CS–FITC(DOX/C-dots)/VEGF shRNA) containing folic acid (FA), fluorescein isothiocyanate (FITC) and doxorubicin (DOX)/carbon quantum dots (C-dots)/VEGF shRNA were fabricated as a targeted drug/gene co-delivery nanovector for potential cancer therapy and fluorescence imaging. The self-assembled FA–CS–FITC(DOX/C-dots)/VEGF shRNA nanocomplexes exhibited a desirable and homogenous particle size (154 ± 24 nm), moderate positive charges (23.2 ± 1.8 mV) and superior stability. The nanocomplexes without noteworthy cytotoxicity are capable of delivering VEGF shRNA into human cervical cancer HeLa cells with high efficiency while effectively protecting shRNA from degradation by exogenous DNase I and nucleases. The release behavior of DOX exhibited a biphasic pattern characterized by an initial burst release followed by a slower and continuous release at both pH 7.4 and pH 4.5, and also presented a pH-triggered release profile. Confocal microscopy analysis confirmed that both FA-targeted function and FA-enhanced buffering capacity induced high transfection, specific cellular uptake and efficient intracellular delivery of FA–CS–FITC(DOX/C-dots)/VEGF shRNA nanocomplexes in folate receptor-overexpressed HeLa cells. Transfected HeLa cells exhibited significantly decreased VEGF expression, inhibited cell proliferation, and increased cell apoptosis, which led to synergistic antitumor activities. Furthermore, the nanocomplexes demonstrated excellent dual fluorescence cellular imaging at a modest concentration. This work indicates that the integrated theranostic design of FA–CS–FITC(DOX/C-dots)/VEGF shRNA nanocomplexes potentially allows for the image-guided and target-specific treatment of cancer.

Hyperbranched zinc phthalocyanines (HBZnPCs) showing dual-emissive fluorescence in N, N-dimethylformamide (DMF) solution were synthesized via a facile one-step cycloaddition of conjugated bisphthalonitrile precursors. The chemical, crystalline structures, surface morphology, and photophysical properties of synthesized HBZnPCs for different reaction times were systematically studied. It was found that HBZnPCs synthesized for 4 h exhibit the strongest dual fluorescent emission at ~440 and 690 nm in DMF, respectively, when excited at 365 nm, and micrometer scale sheet-like morphology was obtained in this case. In addition, the fluorescent emission of HBZnPCs dramatically changed in different solvents: the red emission was amplified in solvent of strong polarity, while blue emission dominated in non-co-ordinated solvent. More interestingly, we found for the first time that the fluorescence of initially “dark” H-aggregates of HBZnPCs in DMF/H2O mixed solvent was gradually recovered through self-assembling driven by the poor solvent, leading to a strong emission around 460 nm, which contributed to the formation of stable J-type superstructures.

Multidrug resistance (MDR) is a major impediment to the success of cancer chemotherapy. One of the effective approaches to overcome MDR is to use nanoparticle-mediated the gene silence of chemotherapeutic export proteins by RNA interference to increase drug accumulation in drug resistant cancer cells. In this work, a new co-delivery system, DOX-PLGA/PEI/P-gp shRNA nanobubbles (NBs) around 327 nm, to overcome doxorubicin (DOX) resistance in MCF-7 human breast cancer was designed and developed. Positively charged polyethylenimine (PEI) were modified onto the surface of DOX-PLGA NBs through DCC/NHS crosslinking, and could efficiently condense P-gp shRNA into DOX-PLGA/PEI NBs at vector/shRNA weight ratios of 70:1 and above. An in vitro release profile demonstrated an efficient DOX release (more than 80%) from DOX-PLGA/PEI NBs at pH 4.4, suggesting a pH-responsive drug release for the multifunctionalized NBs. Cellular experimental results further showed that DOX-PLGA/PEI/P-gp shRNA NBs could facilitate cellular uptake of DOX into cells and increase the cell proliferation suppression effect of DOX against MCF-7/ADR cells (a DOX-resistant and P-glycoprotein (P-gp) over-expression cancer cell line). The IC50 of DOX-PLGA NBs against MCF-7/ADR cells was 2-fold lower than that of free DOX. The increased cellular uptake and nuclear accumulation of DOX delivered by DOX-PLGA/PEI/P-gp shRNA NBs in MCF-7/ADR cells was confirmed by fluorescence microscopy and fluorescence spectrophotometry, and might be owning to the down-regulation of P-gp and reduced the efflux of DOX. The cellular uptake mechanism of DOX-PLGA/PEI/P-gp shRNA NBs indicated that the macropinocytosis was one of the pathways for the uptake of NBs by MCF-7/ADR cells, which was also an energy-dependent process. Furthermore, the in vitro cellular ultrasound imaging suggested that the employment of the DOX-PLGA/PEI/P-gp shRNA NBs could efficiently enhance ultrasound imaging of cancer cells. These results demonstrated that the developed DOX-PLGA/PEI/P-gp shRNA NBs is a potential, safe and efficient theranotic agent for cancer therapy and diagnostics.