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Imatinib mesylate (IM) is highly effective in the treatment of gastrointestinal stromal tumors (GISTs). However, the most of GISTs patients develop secondary drug resistance after 1-3 years of IM treatment. The aim of this study was to explore the IM-resistance mechanism via the multi-scope combined with plasma concentration of IM, genetic polymorphisms and plasma sensitive metabolites.This study included a total of 40 GISTs patients who had been regularly treated and not treated with IM. The plasma samples were divided into three experiments, containing therapeutic drug monitoring (TDM), OCT1 genetic polymorphisms and non-targeted metabolomics. According to the data of above three experiments, the IM-resistant cell line, GIST-T1/IMR cells, was constructed for verification the IM-resistance mechanism.The results of non-targeted metabolomics analysis suggested that the sphingophospholipid metabolic pathway including the SPK1/S1P axis was inferred in IM-insensitive patients with GISTs. A GIST cell line (GIST-T1) was immediately induced as an IM resistance cell model (GIST-T1/IMR) and we found that blocking the signal pathway of SPK1/S1P in the GIST-T1/IMR could sensitize treatment of IM and reverse the IM-resistance.Our findings suggest that IM secondary resistance is associated with the elevation of S1P, and blockage the signaling pathway of SPK1/S1P warrants evaluation as a potential therapeutic strategy in IM-resistant GISTs. The design of this study from blood management, group information collection, IM plasma concentration with different elements, identification of sphingolipid metabolism and lastly verification the function of SPK1/S1P in the IM-resistance GISTs cells.

The importance of the "gut-liver axis" in the pathogenesis of liver diseases has been revealed recently; which promotes the process of developing preventive and therapeutic strategies. However, considering that there are still many challenges in the medical treatment of liver diseases, potential preventive dietary intervention may be a good alternative choice. Plant-based foods have received much attention due to their reported health-promoting effects in targeting multiple pathways involved in the pathogenesis of liver diseases as well as the relative safety for general use. Based on the PubMed and Web of Science databases, this review emphatically summarizes the plant-based foods and their chemical constituents with reported effects to impact the LPS/TLR4 signaling pathway of gut-liver axis of various liver diseases, reflecting their health benefits in preventing/alleviating liver diseases. Moreover, some plant-based foods with potential gut-liver effects are specifically analyzed from the reported studies and conclusions. This review intends to provide readers an overview of the current progress in the field of this research topic. We expect to see more hepatoprotective measures for alleviating the current prevalence of liver diseases.

Ginsenosides, the main components isolated from Panax ginseng, can play a therapeutic role by inducing tumor cell apoptosis and reducing proliferation, invasion, metastasis; by enhancing immune regulation; and by reversing tumor cell multidrug resistance. However, clinical applications have been limited because of ginsenosides’ physical and chemical properties such as low solubility and poor stability, as well as their short half-life, easy elimination, degradation, and other pharmacokinetic properties in vivo. In recent years, developing a ginsenoside delivery system for bifunctional drugs or carriers has attracted much attention from researchers. To create a precise treatment strategy for cancer, a variety of nano delivery systems and preparation technologies based on ginsenosides have been conducted (e.g., polymer nanoparticles [NPs], liposomes, micelles, microemulsions, protein NPs, metals and inorganic NPs, biomimetic NPs). It is desirable to design a targeted delivery system to achieve antitumor efficacy that can not only cross various barriers but also can enhance immune regulation, eventually converting to a clinical application. Therefore, this review focused on the latest research about delivery systems encapsulated or modified with ginsenosides, and unification of medicines and excipients based on ginsenosides for improving drug bioavailability and targeting ability. In addition, challenges and new treatment methods were discussed to support the development of these new tumor therapeutic agents for use in clinical treatment.

Colorectal cancer (CRC), among the most aggressive and prevailing neoplasms, is primarily treated with chemotherapy. Voacamine (VOA), a novel bisindole natural product, possesses a variety of conspicuous pharmacological activities. Within the current research, we evaluated in vitro and in vivo the anticancer efficacy of VOA against CRC and its potential mechanisms. Our results illustrated that VOA concentrationdependently suppressed the proliferation and migration of CT26 and HCT116 cells as correspondingly indicated by IC

Imatinib mesylate (IM) is highly efficacious in the treatment of gastrointestinal stromal tumors (GISTs). Therapeutic drug monitoring (TDM) and pharmacogenetic screening are affirmed for better management of IM therapy. The goal of this study was to explore the most sensitive metabolites and the role of organic cation transporter 1 (OCT1) on single nuclear polymorphisms (SNP) of IM treatment, which could supply a greater mechanistic understanding of therapeutic effect or resistance of IM. A total of 40 human serum samples from patients with GISTs were collected for TDM. Basing on the results of TDM, the untargeted metabolomic analysis was to determine characteristics of the serum. Principal component analysis (PCA), orthogonal partial least-squares discrimination analysis (OPLS-DA), and heat map were used for multivariate analysis. In addition, KEGG database were used to identify the pathways of metabolites. Differential metabolites were identified based on a heat map with a t-test threshold (p < 0.05), fold-change (FC) threshold (FC > 1.5 or FC < 2/3) and variable importance (VIP) in the projection (VIP>1). The potential differential metabolites were included D-sphingosine, 1-sphingosine phosphate, phytosphingosine and phosphoethanolamine, which were belonged to the metabolism pathway of sphingolipid. Because of the function of OCT1 transporters was related with drug in the liver, the OCT1 1386C>A (rs 622342) was statistically significant (P

Two-dimensional (2D) nanosheet (NS)-based photothermal agents (PTAs), such as transition-metal dichalcogenides, have shown immense potential for their use in cancer photothermal therapy (PTT). However, the nano-bio interaction study regarding these NS-based PTAs is still in its infancy. In this study, we used WS2-PEG NS-based PTA as an example to provide comprehensive insights into the experimental understanding of their fate in cancer cells. The data revealed that three different endocytosis pathways (macropinocytosis, clathrin-dependent, and caveolae-dependent endocytosis), autophagy-mediated lysosome accumulation, and exocytosis-induced excretion contribute to the integrated pathways of WS2-PEG NSs within cells. These pathways are consistent with our previous reports on MoS2-PEG NS-based drug delivery platform, indicating that the composition difference of 2D NSs with PEGylation may have little influence on their intercellular fate. Moreover, by blocking the revealed exocytosis pathway-mediated secretion of WS2 NSs in tumor cells, an effective approach is proposed to attain enhanced photothermal therapeutic outcomes with low doses of WS2 NSs and under a low power of a near-infrared (NIR) laser. We expect that the exocytosis inhibition strategy may be a universal one for 2D NSs to achieve combination cancer therapy. This study may also provide more experimental basis for the future development of 2D NS’s application in biomedicine (e.g. PTT).

Gestational trophoblastic neoplasia (GTN), the most aggressive form of which is choriocarcinoma, can result from over-proliferation of trophoblasts. Treating choriocarcinoma requires high doses of systemic chemotherapeutic agents, which result in nonspecific drug distribution and severe toxicity. To overcome these disadvantages and enhance chemotherapeutic efficacy, we synthesized redox- and pH-sensitive, self-assembling, ascorbic acid-derived (PEG-ss-aAPP) micelles to deliver the drug methotrexate (MTX). Methods: We developed and tested self-assembling PEG-ss-aAPP micelles, which release their drug cargo in response to an intracellular reducing environment and the acidity of the early lysosome or tumoral microenvironment. Uptake into JEG3 choriocarcinoma cancer cells was examined using confocal microscopy and transmission electron microscopy. We examined the ability of MTX-loaded PEG-ss-aAPP micelles to inhibit metastasis in an orthotopic mouse model of human choriocarcinoma. Results: Drug-loaded micelles had encapsulation efficiency above 95%. Particles were spherical based on transmission electron microscopy, with diameters of approximately 229.0 nm based on dynamic light scattering. The drug carrier responded sensitively to redox and pH changes, releasing its cargo in specific environments. PEG-ss-aAPP/MTX micelles efficiently escaped from lysosome/endosomes, and they were effective at producing reactive oxygen species, strongly inducing apoptosis and inhibiting invasion and migration. These effects correlated with the ability of PEG-ss-aAPP/MTX micelles to protect IκBα from degradation, which in turn inhibited translocation of NF-κB p65 to the nucleus. In an orthotopic mouse model of human choriocarcinoma, PEG-ss-aAPP/MTX micelles strongly inhibited primary tumor growth and significantly suppressed metastasis without obvious side effects. Conclusions: Our results highlight the potential of PEG-ss-aAPP micelles for targeted delivery of chemotherapeutic agents against choriocarcinoma.

Reducing post-surgical pain can promote recovery of mobility, improve patient satisfaction, and reduce the risk of chronic pain syndrome. When managing post-surgical pain, single-injection local anesthesia is more convenient and involves lower risk to the patient than multi-injection regimes, but the effects are not long-lasting. Here we developed a system that can prolong local anesthesia after a single injection. In this system, ropivacaine (Ro) is encapsulated into liposomes, which are then loaded into Poloxamer 407-based thermosensitive hydrogels. The Ro-loaded liposome-in-gel system (Ro-Lip-Gel) is in a sol state before injection, and immediately after subcutaneous injection, it forms a gel in situ. We show through in vitro release and in vivo pharmacokinetics studies that this gel acts as a drug release depot. In rats, the initial burst release of Ro was smaller from Ro-Lip-Gel than from Ro solution or Ro-Gel, and Ro-Lip-Gel caused nerve blockade lasting four times longer than Ro solution. Ro-Lip-Gel degraded in vivo and showed good biocompatibility. Our results suggest that a liposome-in-gel system can show small initial burst release, long-term nerve blockade and good biocompatibility in vitro and in vivo. Therefore, such a system may be useful for sustained local anesthesia without systemic toxicity.

Background Cancer stem cells (CSCs) are highly proliferative and tumorigenic, which contributes to chemotherapy resistance and tumor occurrence. CSCs specific therapy may achieve excellent therapeutic effects, especially to the drug-resistant tumors. Results In this study, we developed a kind of targeting nanoparticle system based on cationic albumin functionalized with hyaluronic acid (HA) to target the CD44 overexpressed CSCs. All-trans-retinoic acid (ATRA) was encapsulated in the nanoparticles with ultrahigh encapsulation efficiency (EE%) of 93% and loading content of 8.37%. TEM analysis showed the nanoparticles were spherical, uniform-sized and surrounded by a coating layer consists of HA. Four weeks of continuously measurements of size, PDI and EE% revealed the high stability of nanoparticles. Thanks to HA conjugation on the surface, the resultant nanoparticles (HA-eNPs) demonstrated high affinity and specific binding to CD44-enriched B16F10 cells. In vivo imaging revealed that HA-eNPs can targeted accumulate in tumor-bearing lung of mouse. The cytotoxicity tests illustrated that ATRA-laden HA-eNPs possessed better killing ability to B16F10 cells than free drug or normal nanoparticles in the same dose, indicating its good targeting property. Moreover, HA-eNPs/ATRA treatment decreased side population of B16F10 cells significantly in vitro. Finally, tumor growth was significantly inhibited by HA-eNPs/ATRA in lung metastasis tumor mice. Conclusions These results demonstrate that the HA functionalized albumin nanoparticles is an efficient system for targeted delivery of antitumor drugs to eliminate the CSCs. Electronic supplementary material The online version of this article (10.1186/s12951-018-0424-4) contains supplementary material, which is available to authorized users.

Methicillin-resistant Staphylococcus aureus (MRSA) is emerging as a serious pathogenic bacterium in the clinical setting, and antibiotic resistance is spreading faster than the introduction of new agents to kill such bacteria. In our study, Fusarium sp. 152, a marine fungus obtained from the South China Sea, was fermented to screen new anti-MRSA compounds including equisetin (EQ) with a MIC value of 1 µg/mL. Then, EQ was loaded into nanoparticle-based polyvinylpyrrolidone (PVP) electrospinning to facilitate its practical use. After electrospinning, the EQ nanofibers (EQ/NPs nanofiber) were 374.9 nm in diameter, and they showed a good flexibility and foldability. Additionally, the EQ/NPs nanofibers showed a better antibacterial effect both in vitro and in vivo than cefoxitin. Simultaneously, the infectious wounds treated with EQ/NPs nanofiber healed better and faster than those treated with EQ and cefoxitin. These findings strongly demonstrate that PVP-based electrospinning dressings are a candidate delivery carrier for the new anti-MRSA compound EQ for topical therapy.

Dendrobium officinableKimura et Migo is a famous traditional herb medicine and is wildly used in folk as a tonic herb. Its endophytic fungi play prominent part in the function ofD.officinableKimura et Migo. In this study we first report the co-production of trichosetin (1), beauvericin (2), beauvericin A (3), enniatin B (4), enniatin H (5), enniatin I (6), enniatin MK1688 (7), fusaric acid (8) and dehydrofusaric acid (9) by the endophytic fungusFusariumsp. TP-G1 deriving from the root ofD.officinablekimura et Migo. These isolates’ reported bioactivities and the tested biological activities in this paper consisted with the functions ofD.officinableKimura et Migo. We found the MICs value of compounds1−7againstStaphylococcus aureusand MRSA showed nearly no difference, while compounds8−9were first found to have the antimicrobial activities againstAcinetobacter baumanniiwith a MIC value of 64 μg/mL and 128 μg/mL respectively. Compounds2,4,5and6were first found to show moderate anti-tumor activities against BL16F10; and compounds4and5were first found to show moderate anti-tumor activities against MCF-7. Furthermore, we report first here the isoleucine (Ile) replacement in beauvericin and enniatin will influence their antibacterial and brine shrimp lethality activities.

The ether extract ofArtemisia integrifoliawas separated by chromatography and afforded a new iridoid, arteintegin A (6), together with five known compounds, namely chamazulene (1) , acetylenes (E)-2, (E)-3, (Z)-4, eugenol (5). The structure elucidation of the new compound was carried out by 1D ( 1H NMR and 13C NMR) and 2D-NMR (COSY, HSQC and NOESY) spectral analysis .

The anti-infection ability and skin regeneration are important aspects on the progress of wound healing, which needs an ideal wound dressing that not only resists bacteria but also promotes skin regeneration. In this study, zinc oxide/silver/polyvinylpyrrolidone/polycaprolactone (ZnO/Ag/PVP/PCL) nanofibres were prepared through electrospinning. Firstly, zinc oxide nanoparticles (ZnONPs) and silver nanoparticle (AgNPs) were synthesized respectively. Secondly, the two nanoparticles were mixed with polyvinylpyrrolidone (PVP) and polycaprolactone (PCL) to obtain the nanofibres. The results of scanning electron microscopy (SEM) showed that ZnONPs and AgNPs were 40.07 ± 9.70 nm and 37.46 ± 12.02 nm, respectively. After electrospinning, the nanofibres were 368.22 ± 123.96 nm in diameter. Infrared spectroscopy revealed that ZnONPs/AgNPs bimetallic nanomaterials were physically embedded in the nanofibres. The antibacterial effects against Staphylococcus aureus and Escherichia coli of ZnO/Ag/PVP/PCL nanofibres were significantly better than these of the single metal material-loaded nanofibres. More importantly, the combination of ZnO and Ag reduced the cytotoxicity of ZnO/Ag/PVP/PCL bimetallic nanofibres toward fibroblasts. These findings demonstrated that ZnO/Ag/PVP/PCL bimetallic nanofibres should be of greater interest than the single metal nanomaterial-loaded nanofibres in inhibiting growth of bacteria.

A co-loaded drug delivery system based on ascorbyl palmitate that can transport various functional drugs to their targets within a tumor represents an attractive strategy for increasing the efficiency of anticancer treatment. In this study, we developed a dual drug delivery system to encapsulate ascorbyl palmitate (AP) and paclitaxel (PTX) for synergistic cancer therapy. AP, which is a vitamin C derivative, and PTX were incorporated into solid lipid nanoparticles (AP/PTX-SLNs), which were used to treat murine B16F10 melanoma that had metastasized to the lungs of mice. These nanoparticles were spherical with an average size of 223 nm as measured by transmission electron microscope and dynamic light scattering. In vitro cytotoxicity assays indicated that the AP/PTX-SLNs with an AP/PTX mass ratio of 2/1 provided the optimal synergistic anticancer efficacy. In vivo, AP/PTX-SLNs were revealed to be much more effective in suppressing tumor growth in B16F10-bearing mice and in eliminating cancer cells in the lungs than single drug (AP or PTX)-loaded SLNs via a synergistic effect through reducing the Bcl-2/Bax ratio. Furthermore, no marked side effects were observed during the treatment with the AP/PTX-SLNs, indicating that the co-delivery system with ascorbyl palmitate holds promising clinical potential in cancer therapy.

Wound healing is a complex pathophysiological process that occurs frequently in everyday pathology and remains a challenge during the treatment of trauma. Previously, we prepared silver nanoparticle/chitosan oligosaccharide/poly(vinyl alcohol) (PVA/COS-AgNP) nanofibers via an electrospinning technique. These nanofibers promoted the proliferation of human skin fibroblasts (HSFs) and the expression of transforming growth factor TGF-β1 in the early stage of wound repair, although the specific mechanisms remain unclear. Therefore, considering that TGF-β1 has emerged as a major modulator of wound healing, the objective of this study was to further understand whether the molecular mechanisms responsible for PVA/COS-AgNP nanofiber-mediated wound healing include the TGF-β1/Smad signal transduction pathway. In this study, we used human skin fibroblasts (HSFs) to investigate the molecular and cellular mechanisms underlying PVA/COSAgNP nanofiber-mediated wound healing. Cell adhesion and proliferation experiments, immunofluorescence staining, hydroxyproline content measurements, flow cytometry, quantitative real-time PCR (qRT-PCR), and western blotting (WB) were used to analyze the wound healing mechanisms of human skin fibroblasts treated with various concentrations of PVA/COS-AgNP nanofibers and the combined application of silver nanofibers and SB431542 (an inhibitor of the TGF-β1 receptor kinase). Our study showed that PVA/COS-AgNP nanofibers markedly promoted fibroblast proliferation, collagen synthesis, and cell adherence. We also found that treating fibroblasts with PVA/COS-AgNP nanofibers stimulated cell cycle progression from G1 into the S and G2 phases, reducing the proportion of cells in the G0/G1 phase and inducing S and G2/M arrest. Importantly, the cell factors associated with the TGF-β1/Smad signal transduction pathway, such as TGF-β1, TGFβRI, TGFβRII, pSmad2, pSmad3, collagen I, collagen III, and fibronectin were also up-regulated. Moreover, this enhancing effect was markedly inhibited by the TGFβRI receptor inhibitor, SB431542. Therefore, the PVA/COS-AgNP nanofibers used to accelerate wound healing do so by activating the TGF-β1/Smad signal transduction pathway.

Loss of function in tumor suppressor genes is commonly associated with the onset/progression of cancer and treatment resistance. The p53 tumor suppressor gene, a master regulator of diverse cellular pathways, is frequently altered in various cancers, for example, in ~36% of hepatocellular carcinomas (HCCs) and ~68% of non-small cell lung cancers (NSCLCs). Current methods for restoration of p53 expression, including small molecules and DNA therapies, have yielded progressive success, but each has formidable drawbacks. Here, a redox-responsive nanoparticle (NP) platform is engineered for effective delivery of p53-encoding synthetic messenger RNA (mRNA). We demonstrate that the synthetic p53-mRNA NPs markedly delay the growth of p53-null HCC and NSCLC cells by inducing cell cycle arrest and apoptosis. We also reveal that p53 restoration markedly improves the sensitivity of these tumor cells to everolimus, a mammalian target of rapamycin (mTOR) inhibitor that failed to show clinical benefits in advanced HCC and NSCLC. Moreover, cotargeting of tumor-suppressing p53 and tumorigenic mTOR signaling pathways results in marked antitumor effects in vitro and in multiple animal models of HCC and NSCLC. Our findings indicate that restoration of tumor suppressors by the synthetic mRNA NP delivery strategy could be combined together with other therapies for potent combinatorial cancer treatment.

Phytochemical study of Valeriana jatamansi Jones afforded 45 compounds, including twenty-three iridoids (1–23), five sesquiterpenes (24–28), three steroids (29–31) and fourteen lignins (32–45). The structures of these compounds were assigned by detailed interpretation of spectroscopic data (1D and 2D NMR, HRESIMS) and comparisons with the published data. This is the first report of isolation of compounds (1–6, 10, 21, 25, 41, 43, 44, 45) from Valerianaceae , compounds (13, 27, 39) within the genus Valeriana and compound 30 from V. jatamans. The chemotaxonomic data can support the genus Valeriana being accepted as a member of transitional taxa between the family Valerianaceae and Caprifoliaceae .

Conventional enhanced permeation and retention (EPR) mediates the effects of many drugs, including the accumulation of nanocarriers at tumor sites, but its efficiency remains low. In this study, this limitation was overcome by developing a dual-targeting delivery system based on hyaluronan (HA, a major ligand of CD44) and tetraiodothyroacetic acid (tetrac, a specific ligand of αvβ3), which was exploited to carry docetaxel (DTX) for the synergistic active targeting to tumors. First, a tetrac-HA (TeHA) conjugate was synthesized and grafted onto the surfaces of solid lipid nanoparticles (SLNs) (TeHA-SLNs/DTX), with a high encapsulation efficiency of >91.6%. The resulting SLNs exhibited an approximately toroid morphology revealed using TEM. The cellular uptake and cytotoxicity of various formulations on CD44/αvβ3-enriched B16F10 cells were then assessed, and both results confirmed the selective uptake and high cytotoxicity of the TeHA-SLNs/DTX in a TeHA-dependent manner. In vivo imaging and vessel distribution tests revealed the efficiency of synergistic active targeting was higher than that of EPR-mediated passive targeting by the TeHA-SLNs to αvβ3-expressing tumor blood vessels and CD44-expressing tumor cells via selective targeting. Finally, in both xenograft tumor mice and in situ lung metastasis tumor mice, tumor growth was significantly inhibited by TeHA-SLNs/DTX. Therefore, TeHA-SLNs are an efficient system for the dual-targeted delivery of drugs to treat cancer in vivo.

Chen-wen Li,1,* Qing Wang,2,* Jing Li,3 Min Hu,1 San-jun Shi,1 Zi-wei Li,1 Guo-lin Wu,1 Huan-huan Cui,1 Yuan-yuan Li,1 Qian Zhang,1 Xiu-heng Yu,2 Lai-chun Lu1 1Department of Pharmacy, Institute of Surgery Research, Daping Hospital, Third Military Medical University, 2College of Pharmacy, Chongqing Medical University, Chongqing, 3Department of Pharmacy, the Affiliated Hospital of Qingdao University, Qingdao, People’s Republic of China *These authors contributed equally to this work Abstract: Wound healing occupies a remarkable place in everyday pathology and remains a challenging clinical problem. In our previous study, we prepared a silver nanoparticle/chitosan oligosaccharide/poly(vinyl alcohol) (PVA/COS-AgNPs) nanofiber via electrospinning and revealed that it could promote wound healing; however, the healing mechanism remained unknown. Therefore, we aimed to clarify the mechanism underlying the accelerated healing effect of the PVA/COS-AgNPs nanofiber. The TGFβ1/Smad signaling pathway is actively involved in wound healing. Considering the key role of this signaling pathway in wound healing, our preliminary study showed that the TGFβ1 level was significantly increased during the early stage of wound healing. Thus, in this study, hematoxylin–eosin, Masson’s trichrome, immunofluorescent staining, hydroxyproline content, quantitative real-time polymerase chain reaction, and Western blot analyses were used to analyze the wound healing in a rat model treated with gauze, the PVA/COS-AgNPs nanofiber, and the nanofiber plus SB431542 (an inhibitor of TGFβ1 receptor kinase). The results showed that the PVA/COS-AgNPs nanofiber promoted wound healing and upregulated the expression levels of cytokines associated with the TGFβ1/Smad signaling pathway such as TGFβ1, TGFβRI, TGFβRII, collagen I, collagen III, pSmad2, and pSmad3. Inhibiting this pathway with SB431542 resulted in prevention of the PVA/COS-AgNPs nanofiber-associated salutary effects on the early stage of wound healing and relative cytokines expression. In conclusion, the wound healing effect of the PVA/COS-AgNPs nanofiber involves activation of the TGFβ1/Smad signaling pathway. Keywords: wound healing, electrospinning, nanofiber, silver nanoparticles, TGFβ1, Smad proteins

Tissue adhesives are commonly used in surgeries and regenerative engineering for the repair and regeneration of topical and internal wounds on tissues and organs such as skin, heart, blood vessels, and bone. However, achieving rapid crosslinking, strong wet adhesion and cohesion strengths, and minimal cytotoxicity remains a critical roadblock for clinical translation. Herein, in contrast to harsh and cytotoxic oxidants, magnesium oxide (MgO) particles were found to facilitate rapid crosslinking for injectable citrate-based mussel-inspired tissue bioadhesives synthesized by reacting citric acid, PEG-PPG-PEG diol and dopamine (iC-EPE). Our results confirmed the role of MgO particles as both crosslinkers and composite fillers to concurrently enhance bioadhesive cohesion and adhesion. iC-EPE crosslinked by MgO with/without sodium periodate (PI) exhibit enhanced mechanical strengths (1.0 Mpa tensile strength ≤ 4.5 MPa) compared to that of iC-EPE crosslinked only by PI (~0.75 MPa), high adhesion strength (up to 125 kPa, 8 fold that of fibrin glue (~15 kPa)), tunable degradability (full degradation from1 week to 1 month), excellent in vitro and in vivo biocompatibility, encouraging anti-bacterial performance, and favorable wound closure efficacy. Thus, MgO crosslinked bioadhesives possess great potential for a wide range of applications in surgery and regenerative engineering.

Loss of function in tumor suppressor genes is commonly associated with the onset/progression of cancer and treatment resistance. The p53 tumor suppressor gene, a master regulator of diverse cellular pathways, is frequently altered in various cancers, for example, in ~36% of hepatocellular carcinomas (HCCs) and ~68% of non–small cell lung cancers (NSCLCs). Current methods for restoration of p53 expression, including small molecules and DNA therapies, have yielded progressive success, but each has formidable drawbacks. Here, a redox-responsive nanoparticle (NP) platform is engineered for effective delivery of p53-encoding synthetic messenger RNA (mRNA). We demonstrate that the synthetic p53-mRNA NPs markedly delay the growth of p53-null HCC and NSCLC cells by inducing cell cycle arrest and apoptosis. We also reveal that p53 restoration markedly improves the sensitivity of these tumor cells to everolimus, a mammalian target of rapamycin (mTOR) inhibitor that failed to show clinical benefits in advanced HCC and NSCLC. Moreover, cotargeting of tumor-suppressing p53 and tumorigenic mTOR signaling pathways results in marked antitumor effects in vitro and in multiple animal models of HCC and NSCLC. Our findings indicate that restoration of tumor suppressors by the synthetic mRNA NP delivery strategy could be combined together with other therapies for potent combinatorial cancer treatment.

Additional file 1. Fig. S1. MALDI-TOFâ MS spectrum of eBSA. Fig. S2. A working curve for quantification of HA content in HA-eNPs using Alcian blue assay. Fig. S3 Difference on expression of CD44 between B16F10 and MCF-7 cells. Fig. S4 In vitro antitumor effects of NP formulations on the MCF-7 cells. Fig. S5. Time-dependent intensity of fluorescence distribution of eNPs in mouse. Fig. S6. HA-eNPs/ATRA reduced the tumorigenicity of CD44-enriched B16F10 cells.

Successful anticancer chemotherapy requires targeting tumors efficiently and further potential to eliminate cancer stem cell (CSC) subpopulations. Since CD44 is present on many types of CSCs, and it binds specially to hyaluronic acid (HA), we tested whether coating solid lipid nanoparticles with hyaluronan (HA-SLNs)would allow targeted delivery of paclitaxel (PTX) to CD44-overexpressing B16F10 melanoma cells. First, we developed a model system based on melanoma stem-like cells for experiments in vitro and in mouse xenografts, and we showed that cells expressing high levels of CD44 (CD44(+)) displayed a strong CSC phenotype while cells expressing low levels of CD44 (CD44(-)) did not. This phenotype included sphere and colony formation, higher proportion of side population cells, expression of CSC-related markers (ALDH, CD133, Oct-4) and tumorigenicity in vivo. Next we showed that administering PTX-loaded HA-SLNs led to efficient intracellular delivery of PTX and induced substantial apoptosis in CD44(+) cells in vitro. In the B16F10-CD44(+) lung metastasis model, PTX-loaded HA-SLNs targeted the tumor-bearing lung tissues well and subsequently exhibited significant antitumor effects with a relative low dose of PTX, which provided significant survival benefit without evidence of adverse events. These findings suggest that the HA-SLNs targeting system shows promise for enhancing cancer therapy.

An injectable, phospholipid-based phase transition gel (PPTG) has been developed for prolonging the release of ropivacaine (RO) for local anesthesia. PPTG was prepared by mixing phospholipids, medium-chain triglyceride and ethanol. Prior to injection, the PPTG is in a sol state with low viscosity. After subcutaneous injection, the PPTG rapidly forms a gel in situ, which acts as a drug release depot as verified by in vitro release profiles and in vivo pharmacokinetics. Administering RO-PPTG to rats led to a significantly smaller initial burst release than administering RO solution or RO base suspension. Nerve blockade in guinea pigs lasted 3-fold longer after injection of RO-PPTG than after injection of RO solution. RO-PPTG showed good biocompatibility and excellent degradability in vivo . These results suggest that this PPTG-based depot system may be useful for sustained release of local anesthetics to prolong analgesia without causing systemic toxicity. Statement of Significance The sustained release of local anesthetics at the surgical site after a single injection is the optimal method to control post-surgical pain. In situ forming implant is an attractive alternative for the sustained release of local anesthetics. However, its practical use is highly limited by certain drawbacks including high viscosity, involved toxic organic solvents and fast drug release. To date, phospholipids-based phase transition gel (PPTG) is emerging for clinical development because of the non-toxicity, biocompatibility and ready availability of phospholipids in body. Thus, we present a novel strategy for sustained release of local anesthetics to control post-surgical pain based on PPTG, which showed a prolonged duration of nerve blockade and excellent biocompatibility.

Cancer stem cells (CSCs) with stem-cell properties are regarded as tumor initiating cells. Sharing stem-cell properties, circulating tumor cells (CTCs) are responsible for the development of metastasis, which significant affects CTC analysis in clinical practice. Due to their extremely low occurrence in blood, however, it is challenging to enumerate and analyze CTCs. Nanotechnology is able to address the problems of insufficient capture efficiency and low purity of CTCs owing to the unique structural and functional properties of nanomaterials, showing strong promise for CTC isolation and detection. In this review, we discuss the role of stem-like CTCs in metastases, provide insight into recent progress in CTC isolation and detection approaches using various nanoplatforms, and highlight the role of nanotechnology in the advancement of CTC research.

This study reports on the performance of sodium alginate (SA)/poly(vinyl alcohol) (PVA)/moxifloxacin hydrochloride (MH) nanofibrous membranes (NFM) capable of providing antibacterial agent delivery for wound-dressing applications. The aim of this work was to prepare antibacterial NFM with good permeability properties by employing PVA and SA as carriers. A group of 12% PVA/2% SA solutions blended in various ratios (8:2, 7:3, 6:4, 5:5 and 4:6, v/v) and containing 0.5, 1, 2 or 4 wt% MH were studied for electrospinning into nanoscale fibermats. The optimum ratio found to form smooth fibers with uniform fibrous features was 6:4. The drug release behavior of the electrospun, the antibacterial effects on Pseudomonas aeruginosa and Staphylococcus aureus and the animal wound dressing capabilities were also investigated. As much as 80% of the MH was released from the electrospun after 10 h of incubation at 37 °C. In addition, the NFM with 0.5 MH exhibited less activity, whereas those with higher concentrations of MH exhibited greater antibacterial effect. Furthermore, the MH-loaded electrospun accelerated the rate of wound dressing compared to other groups. The results of the in vitro and in vivo experiments suggest that MH/PVA/SA nanofibers might be an interesting bioactive wound dressing for clinical applications.

Metabolic diseases occur when normal metabolic processes are disrupted in the human body, which can be congenital or acquired. The incidence of metabolic diseases worldwide has reached epidemic proportions. So far, various methods including systemic drug therapy and surgery are exploited to prevent and treat metabolic diseases. However, current pharmacotherapeutic options for treatment of these metabolic disorders remain limited and ineffective, especially reducing patient compliance to treatment. Therefore, it is desirable to exploit effective drug delivery approaches to effectively treat metabolic diseases and reduce side effects. This brief review summarizes novel delivery strategies including local, targeted, and oral drug delivery strategies, as well as intelligent stimulus-responsive drug delivery strategy, for the treatment of metabolic disorders including diabetes, obesity, and atherosclerosis.

It has been well-established that chemo-immunotherapy using cytotoxic drugs and appropriate cytokines offers a promising approach for the treatment of neoplastic diseases. In view of this, to improve melanoma treatment effect, our study developed a new codelivery system (AL/Ad5/PTX) that paclitaxel (PTX) and adenovirus encoding for murine interleukin-12 (Ad5-mIL-12) were incorporated into anionic liposomes (AL). First, AL/Ad5/PTX complexes were prepared by incorporating Ad5 into anionic PTX liposomes using calcium-induced phase change. Second, the size distribution and zeta potential of AL/Ad5/PTX were investigated. Third, the results of in vitro transduction assays showed that PTX introduced into AL/Ad-luc or AL/Ad5-mIL-12 highly enhanced gene transduction efficiency in B16 cells than naked Ad5 or AL/Ad complexes while it had no comparability in A549 cells. Finally, a melanoma-bearing mouse model was established to assess the antitumor effect. Tumor growth inhibition and prolonged survival time, accompanied by increased mIL-12 or interferon-γ (IFN-γ) expression levels in serum or tumor sites, were observed in mice treated with AL/Ad5-mIL-12/PTX, as compared with those treated with either AL/Ad5-mIL-12 or AL/PTX. In conclusion, these results suggested that codelivery of Ad5-mIL-12 and PTX incorporated into AL could be a relatively efficient strategy for the treatment of melanoma.

The cancer stem cell (CSC) theory is gaining increasing attention from researchers and has become an important focus of cancer research. According to the theory, a minority population of cancer cells is capable of self-renewal and generation of differentiated progeny, termed cancer stem cells (CSCs). Understanding the properties and characteristics of CSCs is key to future study on cancer research, such as the isolation and identification of CSCs, the cancer diagnosis, and the cancer therapy. Standard oncology treatments, such as chemotherapy, radiotherapy and surgical resection, can only shrink the bulk tumor and the tumor tends to relapse. Thus, therapeutic strategies that focus on targeting CSCs and their microenvironmental niche address the ineffectiveness of traditional cancer therapies to eradicate the CSCs that otherwise result in therapy resistance. The combined use of traditional therapies with targeted CSC-specific agents may target the whole cancer and offer a promising strategy for lasting treatment and even cure.

To improve gene transducibility mediated by adenovirus (Ad) in cancer cells and further enhance anti-tumor effects by co-delivery.Calcium-induced phase change method was used to prepare the complex of anionic liposomes and adenovirus (AL/Ad5). Gene expression was qualitatively detected by X-gal staining and quantitatively detected by ELISA. Taking adenovirus-mediated stromal cell-derived factor-1α (Ad5-SDF1α) as therapeutic gene and carmustine (BCNU) as chemotherapeutic agent, a co-delivering system of AL/Ad5-SDF1α/BCNU was prepared and administered to tumor-bearing mice by intratumor injection.Enhanced LacZ gene transduction was obtained in B16 and Lewis lung carcinoma cells in vitro and in vivo. Complexes of AL/Ad5-SDF1α improved SDF1α gene expression and led to accumulation of dendritic cells among the murine B16 melanoma cells in vivo. This co-delivery system of AL/Ad5-SDF1α/BCNU could significantly suppress tumor growth and prolong survival of tumor-bearing mice.Through the co-delivering system, AL/Ad5-SDF1α could synergize with BCNU to improve the antitumor effect. It may be a promising strategy for solid tumor therapy.

Single atom non-metal two-dimensional (2D) nanomaterials have shown considerable potential in cancer nanomedicines, owing to their intriguing properties and biocompatibility. Herein, ultrathin boron nanosheets (B NSs) were prepared through a novel top-down approach by coupling thermal oxidation etching and liquid exfoliation technologies, with controlled nanoscale thickness. Based on the PEGylated B NSs, a new photonic drug delivery platform was developed, which exhibited multiple promising features for cancer therapy and imaging, including (i) efficient NIR light to heat conversion with a high photothermal conversion efficiency of 42.5%, (ii) high drug-loading capacity and triggered drug release by NIR light and moderate acidic pH, (iii) strong accumulation at tumor sites, (iv) multimodal imaging properties (photoacoustic, photothermal and fluorescent imaging), and (v) complete tumor ablation and excellent biocompatibility. To the best of our knowledge, this is the first report on the top-down fabrication of ultrathin 2D B NSs by the combined thermal oxidation etching and liquid exfoliation, as well as their application as a multi-modal imaging-guided drug delivery platform. We also expect the newly prepared B NSs to provide a robust and useful 2D nanoplatform for various biomedical applications.

Despite remarkable progress in the research of both viral and nonviral gene delivery vectors, the drawbacks in each delivery system have limited their clinical applications. Therefore, one of the concepts for developing novel vectors is to overcome the limitations of individual vectors by combining them. In the current study, adenoviral vectors were formulated with anionic liposomes to protect them from neutralizing antibodies and to improve their transduction efficiency in Coxsackievirus-adenovirus receptor (CAR) deficient cells. A calcium-induced phase change method was applied to encapsulate adenovirus 5 (Ad5) into anionic liposomes to formulate the complexes of Ad5 and anionic liposomes (Ad5-AL). Meanwhile, the complexes of Ad5 and cationic liposomes (Ad5-CL) were also prepared as controls. LacZ gene expression in CAR overexpressing cells (A549) and CAR deficient cells (CHO and MDCK) was measured by either qualitative or quantitative detection. Confocal laser scanning microscopy was performed to determine intracellular location of Ad5 after their infection. Human sera with a high titer of antiadenovirus antibody were used to assess the neutralizing antibody protection ability of the complexed vectors. Accompanying the enhanced gene expression, a high ability to introduce Ad5 into cytoplasm and nucleus mediated by Ad5-AL was also observed in CAR deficient cells. Additionally, antibody neutralizing assay indicated that neutralizing serum inhibited naked Ad5 and Ad5-CL at rather higher dilution than Ad5-AL, which demonstrated Ad5-AL was more capable of protecting Ad5 from neutralizing than Ad5-CL. In conclusion, anionic liposomes prepared by the calcium-induced phase change method could significantly enhance the transduction ability of Ad5 in CAR deficient cells.