Huang-Lian-Jie-Du decoction drug-containing serum inhibits IL-1ß secretion from D-glucose and PA induced BV2 cells via autophagy/NLRP3 signaling.

ETHNOPHARMACOLOGICAL RELEVANCE: Huang-Lian-Jie-Du decoction (HLJDD), a famous traditional Chinese medicine prescription with heat-clearing and detoxifying effects, has been widely used to treat diabetes, dementia, stroke, and other diseases. However, the detailed mechanisms of HLJDD against type 2 diabetes associated cognitive dysfunction (DACD) through inhibiting interleukin-1ß (IL-1ß) mediated neuroinflammation remain to be further elucidated. AIM OF THE STUDY: The aim of this study was to investigate the effect and potential mechanism of HLJDD on IL-1ß secretion in a DACD model of BV2 cells induced by D-glucose and palmitic acid (PA). MATERIALS AND METHOD: sUltra-performance liquid chromatography-quadrupole/electrostatic field orbital well high-resolution mass spectrometry technology was used to analyze the compounds in HLJDD drug-containing serum. The cytotoxicity was detected by cell counting kit-8. Enzyme-linked immunosorbent assay was used to measure the secretion of IL-1ß in BV2 cells. Reactive oxygen species, glutathione, superoxide dismutase, and malondialdehyde kits were used to detect the intracellular oxidative stress levels. The autophagy level was determined by autophagy staining kit and transmission electron microscope. The expression levels of autophagy-related 7 (Atg7), P62, LC3, nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3(NLRP3), Caspase1, and IL-1ß were detected by real-time PCR, immunofluorescence, and western blotting. The Atg7siRNA was transfected into BV2 cells to produce autophagy inhibitory effect. Then the effect of HLJDD drug-containing serum on IL-1ß secretion in D-glucose and PA induced BV2 cells and the potential mechanism of autophagy-NLRP3 inflammasome activation were further observed. RESULTS: Eighty-eight compounds were preliminarily identified in HLJDD drug-containing serum, among which geniposide, baicalin, palmatine, berberine, wogonoside, wogonin, and geniposidic acid were identified as the main prototype components of HLJDD into the blood. In this study, the DACD model of BV2 cells induced by high concentrations of glucose and PA was successfully constructed. HLJDD drug-containing serum significantly reduced the secretion of IL-1ß and the activity of NLRP3 inflammasome with improving the oxidative stress level. Interestingly, the enhanced autophagy level was also found. After transfection of Atg7siRNA into BV2 cells, the effect of HLJDD drug-containing serum on autophagy promotion was reversed, but the inhibitory effects on IL-1ß secretion, NLRP3 inflammasome activation, and oxidative stress were reduced. CONCLUSIONS: These results indicated that the inhibition of HLJDD drug-containing serum on the IL-1ß secretion in D-glucose and PA induced BV2 cells was related to autophagy promotion, the decreased NLRP3 inflammasome activation, and the improved oxidative stress. Moreover, the improvement of HLJDD drug-containing serum on IL-1ß secretion, NLRP3 inflammasome activation, and oxidative stress were all closely associated with Atg7 mediated autophagy promotion. Geniposide, baicalin, palmatine, berberine, wogonoside, wogonin, and geniposidic acid may be the potential active ingredients of HLJDD drug-containing serum.

Synthesis and biological activity assay of novel camptothecin-peptidic conjugates based on PEPT1.

Camptothecin (CPT) and its derivatives are potent candidates for cancer treatment. However, the clinical applications are largely restricted by non-selectivity and severe toxicities. The peptide transporter 1 (PEPT1), which is highly expressed in human intestines, has been found to be overexpressed in several cancer cells. This discovery suggests that PEPT1 has the potential to serve as a therapeutic target for both improving bioavailability and cancer-targeting treatment. Therefore, a prodrug approach for CPT targeting at PEPT1 highly expressed cancer cells was adopted in the present study. Eighteen CPT prodrugs, its peptidic conjugates, were synthesized and the structures were confirmed by NMR and HRMS. The protein expression profiles of PEPT1 in different cell lines were performed using immunofluorescence assay and western blotting analysis. The cytotoxicity of CPT prodrugs and their uptake via competition with Gly-Sar, a typical substrate of PEPT1, were evaluated in both PEPT1-overexpressed and under expressed cells. The results demonstrated that most CPT prodrugs significantly impaired Gly-Sar uptake, suggesting a higher affinity of CPT-peptidic conjugates for PEPT1 and PEPT1 overexpression cells. In addition, these prodrugs demonstrated a higher capability for inhibiting cell growth in PEPT1 highly-expressed cancer cells compared to PEPT1 under expressed cells. These results indicated that this peptidic prodrug strategy might offer great potential for improved tumor selectivity and chemotherapeutic efficacy of CPT.

Network module analysis and molecular docking-based study on the mechanism of astragali radix against non-small cell lung cancer.

BACKGROUND: Most lung cancer patients worldwide (stage IV non-small cell lung cancer, NSCLC) have a poor survival: 25%-30% patients die < 3 months. Yet, of those surviving > 3 months, 10%-15% patients survive (very) long. Astragali radix (AR) is an effective traditional Chinese medicine widely used for non-small cell lung cancer (NSCLC). However, the pharmacological mechanisms of AR on NSCLC remain to be elucidated. METHODS: Ultra Performance Liquid Chromatography system coupled with Q-Orbitrap HRMS (UPLC-Q-Orbitrap HRMS) was performed for the qualitative analysis of AR components. Then, network module analysis and molecular docking-based approach was conducted to explore underlying mechanisms of AR on NSCLC. The target genes of AR were obtained from four databases including TCMSP (Traditional Chinese Medicine Systems Pharmacology) database, ETCM (The Encyclopedia of TCM) database, HERB (A high-throughput experiment- and reference-guided database of TCM) database and BATMAN-TCM (a Bioinformatics Analysis Tool for Molecular mechanism of TCM) database. NSCLC related genes were screened by GEO (Gene Expression Omnibus) database. The STRING database was used for protein interaction network construction (PIN) of AR-NSCLC shared target genes. The critical PIN were further constructed based on the topological properties of network nodes. Afterwards the hub genes and network modules were analyzed, and enrichment analysis were employed by the R package clusterProfiler. The Autodock Vina was utilized for molecular docking, and the Gromacs was utilized for molecular dynamics simulations Furthermore, the survival analysis was performed based on TCGA (The Cancer Genome Atlas) database. RESULTS: Seventy-seven AR components absorbed in blood were obtained. The critical network was constructed with 1447 nodes and 28,890 edges. Based on topological analysis, 6 hub target genes and 7 functional modules were gained. were obtained including TP53, SRC, UBC, CTNNB1, EP300, and RELA. After module analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis showed that AR may exert therapeutic effects on NSCLC by regulating JAK-STAT signaling pathway, PI3K-AKT signaling pathway, ErbB signaling pathway, as well as NFkB signaling pathway. After the intersection calculation of the hub targets and the proteins participated in the above pathways, TP53, SRC, EP300, and RELA were obtained. These proteins had good docking affinity with astragaloside IV. Furthermore, RELA was associated with poor prognosis of NSCLC patients. CONCLUSIONS: This study could provide chemical component information references for further researches. The potential pharmacological mechanisms of AR on NSCLC were elucidated, promoting the clinical application of AR in treating NSCLC. RELA was selected as a promising candidate biomarker affecting the prognosis of NSCLC patients.

Synergistic degradation of Azure B and sulfanilamide antibiotics by the white-rot fungus Trametes versicolor with an activated ligninolytic enzyme system.

The treatment of complex polluted wastewater has become an increasingly critical concern for the various types of hazardous organic compounds, including synthetic dyes and pharmaceuticals. Due to their efficient and eco-friendly advantages, the white-rot fungi (WRF) have been applied to degrade environmental pollutants. This study aimed to investigate the removal ability of WRF (i.e., Trametes versicolor WH21) in the co-contamination system composed of Azure B dye and sulfacetamide (SCT). Our study discovered that the decolorization of Azure B (300 mg/L) by strain WH21 was significantly improved (from 30.5% to 86.5%) by the addition of SCT (30 mg/L), while the degradation of SCT was also increased from 76.4% to 96.2% in the co-contamination system. Transcriptomic and biochemical analyses indicated that the ligninolytic enzyme system was activated by the enhanced enzymatic activities of MnPs and laccases, generating higher concentration of extracellular H2O2 and organic acids in strain WH21 in response to SCT stress. Purified MnP and laccase of strain WH21 were revealed with remarkable degradation effect on both Azure B and SCT. These findings significantly expanded the existing knowledge on the biological treatment of organic pollutants, indicating the strong promise of WRF in the treatment of complex polluted wastewater.

Uncovering the Fate and Risks of Intravenously Injected Prussian Blue Nanoparticles in mice by an Integrated Methodology of Toxicology, Pharmacokinetics, Proteomics, and Metabolomics.

BACKGROUND: Prussian blue (PB) nanoparticles (NPs) have been intensively investigated for medical applications, but an in-depth toxicological investigation of PB NPs has not been implemented. In the present study, a comprehensive investigation of the fate and risks of PB NPs after intravenous administration was carried out by using a mouse model and an integrated methodology of pharmacokinetics, toxicology, proteomics, and metabolomics. RESULTS: General toxicological studies demonstrated that intravenous administration of PB NPs at 5 or 10 mg/kg could not induce obvious toxicity in mice, while mice treated with a relatively high dose of PB NPs at 20 mg/kg exhibited loss of appetite and weight decrease in the first two days postinjection. Pharmacokinetic studies revealed that intravenously administered PB NPs (20 mg/kg) underwent fast clearance from blood, highly accumulated in the liver and lungs of mice, and finally cleared from tissues. By further integrated proteomics and metabolomics analysis, we found that protein expression and metabolite levels changed significantly in the liver and lungs of mice due to the high accumulation of PB NPs, leading to slight inflammatory responses and intracellular oxidative stress. CONCLUSIONS: Collectively, our integrated experimental data imply that the high accumulation of PB NPs may cause potential risks to the liver and lungs of mice, which will provide detailed references and guidance for further clinical application of PB NPs in the future.

Huang-Lian-Jie-Du decoction attenuates cognitive dysfunction of rats with type 2 diabetes by regulating autophagy and NLRP3 inflammasome activation.

ETHNOPHARMACOLOGICAL RELEVANCE: Huang-Lian-Jie-Du decoction (HLJDD) is a traditional Chinese formula that is efficacious in treating diabetes mellitus, Alzheimer's disease, and diabetic encephalopathy; the underlying mechanisms of HLJDD in diabetes-associated cognitive dysfunction remain unclear. AIM OF THE STUDY: This study investigated the neuroprotective effects of HLJDD on cognitive function, and the possible underlying mechanisms in type 2 diabetes mellitus (T2DM) in a rat model of cognitive impairment. MATERIALS AND METHODS: Twelve active ingredients in HLJDD were detected using high-performance liquid chromatography analysis. An animal model of cognitive dysfunction in T2DM was induced via a high-sugar and high-fat diet combined with a low dose of streptozotocin. Sprague-Dawley rats were randomly divided into six groups: control, T2DM, metformin (0.34 g/kg/day), and HLJDD groups (3, 1.5, and 0.75 g/kg/day). All treatments were intragastrically administrated for nine continuous weeks after the development of T2DM. Body weight, food and water intake, fasting blood glucose, insulin sensitivity, and blood lipid levels were measured. Spatial learning and memory of the rats were assessed using the Morris water maze test. Hematoxylin and eosin and Nissl staining were performed to evaluate neuronal morphology and vitality. Glutathione, malondialdehyde, and superoxide dismutase levels were measured to determine the level of oxidative stress in the hippocampus. Transmission electron microscopy was performed to observe the synaptic morphology and structure of hippocampal neurons. IL-1ß levels in the hippocampus and cerebrospinal fluid were determined. The protein expression of NLRP3, cleaved caspase-1, mature IL-1ß, ATG7, P62, LC3, and brain-derived neurotrophic factor (BDNF) was determined using western blotting and immunofluorescence analysis. RESULTS: HLJDD attenuated cognitive dysfunction in rats with T2DM as shown by the decreased escape latency, increased times crossing the platform and time spent in the target quadrant in the Morris water maze test (P < 0.05), improvement in hippocampal histopathological changes, and an elevated level of cell vitality. HLJDD treatment also reduced blood glucose and lipid levels, ameliorated oxidative stress, and downregulated IL-1ß expression in the hippocampus and cerebrospinal fluid (P < 0.05). Moreover, HLJDD enhanced BDNF, ATG7, and LC3 protein expression and significantly inhibited the expression of P62, NLRP3, cleaved caspase-1, and mature IL-1ß in the hippocampal CA1 region (P < 0.05). Immunofluorescence results further confirmed that the fluorescence intensity of NLRP3 and P62 in the hippocampus decreased after HLJDD intervention (P < 0.05). CONCLUSIONS: HLJDD ameliorated cognitive dysfunction in T2DM rats. The neuroprotective effect is exerted via the modulation of glucose and lipid metabolism, upregulation of autophagy, and inhibition of NLRP3 inflammasome signaling pathway.

A tumor-penetrable drug nanococktail made from human histones for interventional nucleus-targeted chemophotothermal therapy of drug-resistant tumors.

Nanoparticle-based chemophotothermal therapy (CPT) is a promising treatment for multidrug resistant tumors. In this study, a drug nanococktail of DIR825@histone was developed by employing doxorubicin (DOX), NIR dye IR825 and human histones for interventional nucleus-targeted CPT of multidrug resistant tumors with an interventional laser. After localized intervention, DIR825@histone penetrated tumor tissues by transcytosis, efficiently entered tumor cells and targeted the cell nuclei. DIR825@histone also exhibited good photothermal performance and thermal-triggered drug release. Efficient multidrug resistant tumor inhibition was achieved by enhanced CPT sensitization and MDR reversion via nuclear targeting. Moreover, an interventional laser assisted DIR825@histone in inhibiting multidrug resistant tumors by promoting the sufficient delivery of laser energy inside the tumor while reducing skin injury. Therefore, DIR825@histone together with this interventional nucleus-targeted CPT strategy holds great promise for treating multidrug resistant tumors.

Different Data Mining Approaches Based Medical Text Data.

The amount of medical text data is increasing dramatically. Medical text data record the progress of medicine and imply a large amount of medical knowledge. As a natural language, they are characterized by semistructured, high-dimensional, high data volume semantics and cannot participate in arithmetic operations. Therefore, how to extract useful knowledge or information from the total available data is very important task. Using various techniques of data mining can extract valuable knowledge or information from data. In the current study, we reviewed different approaches to apply for medical text data mining. The advantages and shortcomings for each technique compared to different processes of medical text data were analyzed. We also explored the applications of algorithms for providing insights to the users and enabling them to use the resources for the specific challenges in medical text data. Further, the main challenges in medical text data mining were discussed. Findings of this paper are benefit for helping the researchers to choose the reasonable techniques for mining medical text data and presenting the main challenges to them in medical text data mining.

Traditional Chinese Medicine Aconiti Radix Cocta Improves Rheumatoid Arthritis via Suppressing COX-1 and COX-2.

According to Traditional Chinese Medicine (TCM), Aconiti Radix Cocta (AC) is clinically employed to expel wind, remove dampness, and relieve pain. We evaluated the antirheumatoid arthritis (RA) activities and underlying mechanisms of AC. The chemical constituents of AC were analyzed by high-performance liquid chromatography (HPLC) using three reference compounds (benzoylaconitine, benzoylmesaconine, and benzoylhypacoitine). The anti-RA effects of AC were evaluated in adjuvant-induced arthritis (AIA) rats by hind paw volume and histopathological analysis. The effects of AC on inflammatory cytokines (IL-1ß and IL-17A) were determined by enzyme-linked immunosorbent assay. The regulation of cyclooxygenases (COX-1 and/or COX-2) was determined by Western blot and real-time quantitative reverse transcription polymerase chain reaction analyses. AC significantly reduced paw swelling, attenuated the inflammation and bone destruction in joint tissues, and reduced IL-1ß and IL-17A in the serum. Moreover, AC downregulated the expression of COX-1 and COX-2 in the synovial tissues. We also identified that AC possesses significant anti-RA activities on AIA, which may be ascribed to the regulation of inflammatory cytokines IL-1ß and IL-17, as well as to the inhibition of arachidonic acid signaling pathways. Our findings provide theoretical support for AC as an effective nature-derived therapeutic agent for RA treatment.

Engineering temperature-sensitive plateletsomes as a tailored chemotherapy platform in combination with HIFU ablation for cancer treatment.

Chemotherapy is widely used in combination with high-intensity focused ultrasound (HIFU) ablation for cancer therapy; however, the spatial and temporal integration of chemotherapy and HIFU ablation remains a challenge. Here, temperature-sensitive plateletsomes (TSPs) composed of platelet (PLT) membrane, 1-stearoyl-2-hydroxy-sn-glycero-3-phosphocholine and 1,2-dipalmitoyl-sn-glycero-3-phosphocholine were developed to adequately integrate chemotherapy with HIFU tumor ablation in vivo. Methods: The thermosensitive permeability of TSPs was evaluated under both water bath heating and HIFU hyperthermia. The targeting performance, pharmacokinetic behavior and therapeutic potential of TSPs in combination with HIFU ablation were evaluated using HeLa cells and a HeLa cell tumor-bearing nude mouse model in comparison with temperature-sensitive liposomes (TSLs). Results: TSPs showed high drug loading efficiency and temperature-sensitive permeability. When applied in vivo, TSPs showed a circulation lifetime comparable to that of TSLs and exhibited PLT-specific cancer cell affinity and a vascular damage response. Upon HIFU hyperthermia, TSPs displayed ultrafast drug release and enhanced tumor uptake, providing high drug availability in the tumor site to cooperate with HIFU ablation. After HIFU ablation, TSPs rapidly targeted the postoperative tumor site by adhesion to the damaged tumor vasculature, leading to targeted and localized postoperative chemotherapy. Conclusion: Due to effective integration at both intraoperative and postoperative stages, TSPs could be a promising chemotherapy nanoplatform in combination with HIFU ablation for cancer therapy.

Synthesis, antitumor activity and pharmacokinetic study of 10-propionyloxy camptothecin in rats.

In the present study, a 10-position modified of camptothecin, 10-propionyloxy camptothecin (PCPT) was esterified from 10-hydroxcamptothecin (HCPT), which could metabolize to HCPT in vivo. PCPT displayed a relatively stronger antitumor activity in vitro and in vivo. Thereafter a simple, sensitive and rapid HPLC method coupled with a fluorescence detector was developed and validated for the assay of PCPT and its active metabolite HCPT in rat plasma. The method was validated for accuracy, precision, linearity, selectivity and recovery. The validated method was successfully applied to the pharmacokinetic study of PCPT in rats after intravenous administration. The results showed that PCPT could be mainly converted to HCPT in plasma with the AUC0-∞ value of 3.69 ± 4.44 and 311.16 ± 188.81 ng h/mL for PCPT and HCPT, respectively.

Platelet-camouflaged nanococktail: Simultaneous inhibition of drug-resistant tumor growth and metastasis via a cancer cells and tumor vasculature dual-targeting strategy.

Multidrug resistance (MDR) poses a great challenge to cancer therapy. It is difficult to inhibit the growth of MDR cancer due to its chemoresistance. Furthermore, MDR cancers are more likely to metastasize, causing a high mortality among cancer patients. In this study, a nanomedicine RGD-NPVs@MNPs/DOX was developed by encapsulating melanin nanoparticles (MNPs) and doxorubicin (DOX) inside RGD peptide (c(RGDyC))-modified nanoscale platelet vesicles (RGD-NPVs) to efficiently inhibit the growth and metastasis of drug-resistant tumors via a cancer cells and tumor vasculature dual-targeting strategy. Methods: The in vitro immune evasion potential and the targeting performance of RGD-NPVs@MNPs/DOX were examined using RAW264.7, HUVECs, MDA-MB-231 and MDA-MB-231/ADR cells lines. We also evaluated the pharmacokinetic behavior and the in vivo therapeutic performance of RGD-NPVs@MNPs/DOX using a MDA-MB-231/ADR tumor-bearing nude mouse model. Results: By taking advantage of the self-recognizing property of the platelet membrane and the conjugated RGD peptides, RGD-NPVs@MNPs/DOX was found to evade immune clearance and target the αvß3 integrin on tumor vasculature and resistant breast tumor cells. Under irradiation with a NIR laser, RGD-NPVs@MNPs/DOX produced a multipronged effect, including reversal of cancer MDR, efficient killing of resistant cells by chemo-photothermal therapy, elimination of tumor vasculature for blocking metastasis, and long-lasting inhibition of the expressions of VEGF, MMP2 and MMP9 within the tumor. Conclusion: This versatile nanomedicine of RGD-NPVs@MNPs/DOX integrating unique biomimetic properties, excellent targeting performance, and comprehensive therapeutic strategies in one formulation might bring opportunities to MDR cancer therapy.

Pharmacokinetics and tissue distribution study of 10-methoxycamptothecin in rats following intragastric administration.

Natural bioactive derivatives of camptothecin (CPT), 10-methoxycamptothecin (MCPT) and 10-hydroxycamptothecin (HCPT) have been confirmed to possess high antitumor activities. MCPT could be metabolized to HCPT in vivo. The HPLC method for the quantification of MCPT and HCPT was established and validated, and the pharmacokinetics and the tissue distribution of MCPT in rats after i.v. administration have been well carried out in our previous studies. To improve the further understanding of the in vivo behavior of MCPT, a rapid and sensitive UPLC-MS/MS method was developed and validated for the quantification of MCPT and HCPT in plasma and tissue samples, and the pharmacokinetics and tissue distribution as well as the bioavailability of MCPT after i.g. were also illustrated. The results showed that MCPT could be highly converted to its active metabolite HCPT in plasma with the AUC0-∞ value of (185.28±61.73) ngh/mL and (717.25±165.67) ngh/mL for MCPT and HCPT, respectively. Meanwhile, MCPT and HCPT were rapidly absorbed and diffused into all the tested tissues (heart, liver, spleen, lung, kidney and brain) after i.g. administration. Similar with the results after i.v. administration of MCPT, MCPT concentration in lung tissue was also extremely higher than in other tested tissues, which implied that MCPT might have a great potential for the treatment of lung cancer.

CuInS2/ZnS Quantum Dots Conjugating Gd(III) Chelates for Near-Infrared Fluorescence and Magnetic Resonance Bimodal Imaging.

A bimodal contrast nanoagent was developed by chelating gadolinium ions to 2-[bis[2-[carboxymethyl-[2-oxo-2-(2-sulfanylethyl-amino)ethyl]amino]ethyl]amino]acetic acid (DTDTPA)-modified CuInS2/ZnS quantum dots (QDs). The longitudinal relaxivity (r1) of the resulted QDs@DTDTPA-Gd nanoparticles (NPs) was calculated to be 9.91 mM-1 s-1, which was 2.5 times as high as that of clinically approved Gd-DTPA (3.9 mM-1 s-1). In addition, the in vivo imaging experiments showed that QDs@DTDTPA-Gd NPs could enhance both near-infrared fluorescence and T1-weighted magnetic resonance (MR) imaging of tumor tissue through passive targeting accumulation. Moreover, the high colloidal and fluorescence stabilities and good biocompatibility indicate that QDs@DTDTPA-Gd NPs have a great potential for use as an efficient nanoagent to integrate the extremely high sensitivity of fluorescence imaging to the high resolution of MR imaging. Integration of bimodal detectability in the same agent of QDs@DTDTPA-Gd NPs can avoid extra stress on the blood clearance mechanisms as the administration of multiple dose of agents.

Hyaluronic Acid Conjugated Magnetic Prussian Blue@Quantum Dot Nanoparticles for Cancer Theranostics.

A multifunctional nanotheranostic agent was developed by conjugating both hyaluronic acid and bovine serum albumin coated CuInS2-ZnS quantum dots onto the surface of magnetic Prussian blue nanoparticles. The obtained nanoagent could serve as an efficient contrast agent to simultaneously enhance near infrared (NIR) fluorescence and magnetic resonance (MR) imaging greatly. The coexistence of magnetic core and CD44 ligand hyaluronic acid was found to largely improve the specific uptake of the nanoagent by CD44 overexpressed HeLa cells upon applying an external magnetic field. Both NIR fluorescence and MR imaging in vivo proved high accumulation of the nanoagent at tumor site due to its excellent CD44 receptor/magnetic dual targeting capability. After intravenous injection of the nanoagent and treatment of external magnetic field, the tumor in nude mice was efficiently ablated upon NIR laser irradiation and the tumor growth inhibition was more than 89.95%. Such nanotheranostic agent is of crucial importance for accurately identifying the size and location of the tumor before therapy, monitoring the photothermal treatment procedure in real-time during therapy, assessing the effectiveness after therapy.

Chitosan Functionalized CuS Nanoparticles Boots Gene Transfection via Photothermal Effect.

BACKGROUND: The lack of smart and controllable gene vectors with high safety and efficiency is still a main obstruction for clinical applications of gene therapy. Recently, the external physical stimuli, such as near infrared light induced temperature elevation, have been applied to enhance the gene transfection efficiency and specificity. The aim of this paper is to fabricate chitosan functionalized CuS nanoparticles (CuS@CS NPs) with small size and higher biocompatibility for enhanced gene delivery by photothermal effect. METHODS: CuS@CS NPs were successfully prepared by simple hydrothermal method. The biocompatibility was detected by MTT method and hymolytic analysis. pEGFP-C1was used as gene model, and its expression efficiency was detected by fluorescence microscopy and flow cytometry to investigate the effect of photothermal effect on the transfection efficiency. RESULTS: The CuS@CS NPs around 15 nm were successfully engineered. The modification of CuS nanoparticles with chitosan conduced to higher physiological stability and biocompatibility. The utilization of CuS@CS NPs in combination with external near infrared (NIR) laser irradiation could enhance gene transfection efficiency due to photothermal effect. The gene transfection efficiency of CuS@CS NPs found to increase from 5.05±0.54% (0 min) to 23.47±1.27% (10 min), significantly higher than the free polyethylenimine (18.15±1.03%). CONCLUSION: CuS@CS NPs showed great capability to control gene delivery by an external NIR laser irradiation and enhance the gene transfection efficiency and specificity because of convenient preparation, stabilized optical properties, excellent photothermal effect and good biocompatibility. It encourages further exploration of the CuS@CS NPs as a photocontrollable nanovector for combined photothermal and gene therapy, as well as image guided therapy.

Infra Red Dye and Endostar Loaded Poly Lactic Acid Nano Particles as a Novel Theranostic Nanomedicine for Breast Cancer.

Endostar, a novel recombinant human endostatin, has been proven to inhibit tumor angiogenesis and is utilized as an anticancer drug. While free drugs can display limited efficacy, nanoscaled anticancer drugs have been fabricated and proven to possess superior therapeutic effects. Poly(lactic acid) (PLA) is a FDA-approved biomaterial displaying excellent biocompatibility and low toxicity. In this study, Endostar-loaded PLA nanoparticles (EPNPs) were first prepared, and a near-infrared (NIR) dye, IRDye 800CW, was conjugated to the surface for detecting nanoparticle biodistribution through fluorescence molecular imaging (FMI) using an orthotopic breast tumor mouse model. The antitumor efficacy of EPNPs was examined using bioluminescence imaging (BLI) and immunohistology. To further improve the antitumor effects, we combined EPNPs with zoledronic acid monohydrate (ZA), which is known to decrease the tumor-associated macrophages (TAM) and inhibit tumor progression. We found that EPNPs decreased human umbilical vein endothelial cell (HUVEC) viability by inhibiting tumor growth gene expression more significantly than free Endostar in vitro. In vivo, EPNPs displayed better tumor growth inhibitory effects compared with free Endostar, and the combination of EPNPs with ZA exhibited more significant antitumor effects. As confirmed by CD31 and CD11b immunohistochemistry, the combination of EPNPs and ZA showed synergistic effects in reducing tumor angiogenesis and TAM accumulation in tumor regions. Taken together, this study presents a novel and effective form of nanoscaled Endostar for the treatment of breast cancer that displays synergistic antitumor effects in combination with ZA.

Hyaluronic Acid Modified Hollow Prussian Blue Nanoparticles Loading 10-hydroxycamptothecin for Targeting Thermochemotherapy of Cancer.

This paper reported the fabrication of a multifunctional nanoplatform by modifying hollow Prussian blue nanoparticles with hyaluronic acid grafting polyethylene glycol, followed by loading 10-hydroxycamptothecin for tumor-targeted thermochemotherapy. It was found that the surface modification of hollow Prussian blue nanoparticles with hyaluronic acid grafting polyethylene endowed a great colloidal stability, long blood circulation time and the capability for targeting Hela cells over-expressing the CD44 receptor. The obtained nanoagent exhibited efficient photothermal effect and a light triggered and stepwise release behavior of 10-hydroxycamptothecin due to the strong optical absorption in the near-infrared region. The investigations on the body weight change, histological injury and blood biochemical indexes showed that such nanoagent had excellent biocompatibility for medical application. Both in vitro and in vivo experiments proved that the combination of chemotherapy and photothermal therapy through the agent of hyaluronic acid modified Prussian blue nanoparticles loading 10-hydroxycamptothecin could significantly improve the therapeutic efficacy compared with either therapy alone because of a good synergetic effect.

[Advances of Function of Prussian Blue Nano-materials in Cancer Diagnosis and Therapy].

Prussian blue(PB),a kind of ferrous ferricyanide composed of Fe2+and Fe3+,has been approved by Food and Drug Administration(FDA,USA)as an oral drug for the treatment of thallium and cesium poisoning.The biosafety of PB has been proved by long-term clinical trials.In recent years,PB nano-materials have attracted intensive research interests for medical application,especially for tumor imaging and treatment of cancer.Compared to other nano-materials,PB has potential advantage in medical application due to the high biosafety.This paper reviews the new advances in the functions of cancer diagnosis and therapy of PB nano-materials.

(177)Lu-Labeled Cerasomes Encapsulating Indocyanine Green for Cancer Theranostics.

This Article reported the fabrication of a robust theranostic cerasome encapsulating indocyanine green (ICG) by incorporating 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[carboxy(polyethylene glycol)2000]-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid monoamide (DSPE-PEG2000-DOTA), followed by chelating radioisotope of (177)Lu. Its applications in optical and nuclear imaging of tumor uptake and biodistribution, as well as photothermal killing of cancer cells, were investigated. It was found that the obtained cerasome could act efficiently as fluorescence contrast agent as well as nuclear imaging tracer. Encapsulating ICG into cerasome could protect ICG from degradation, aggregation, and fast elimination from body, resulting in remarkable improvement in near-infrared fluorescence imaging, photothermal stability, and in vivo pharmacokinetic profile. Both fluorescence and nuclear imaging showed that such agent could selectively accumulate in tumor site after intravenous injection of the cerasome agent into Lewis lung carcinoma tumor bearing mice, resulting in efficient photothermal ablation of tumor through a one-time NIR laser irradiation at the best time window. The ability to track the uptake of cerasomes on a whole body basis could provide researchers with an excellent tool for developing cerasome-based drug delivery agents, especially the strategy of labeling cerasomes with theranostic radionuclide (177)Lu, enabling the ability of the (177)Lu-labeled cerasomes for radionuclide cancer therapy and even the combined therapy.