Joint pollution and source apportionment of PM2.5 among three different urban environments in Sichuan Basin, China.

The PM2.5 were sampled in three different urban environments: (city of) Chengdu, Leshan, and Dazhou, which are located in Sichuan Basin. 8 types of water-soluble ion and 25 types of metal element were measured in each PM2.5 sample across the seasons of 2017. The study results suggest that the joint PM2.5 pollution among the three cities mainly occurred in autumn and winter, and the air quality of Chengdu and Leshan was largely affected by Dazhou. Overall, the mass concentrations of PM2.5 of these three cities exhibited no statistically significant differences. However, Leshan had the highest level of ionic pollution, and the dominant form of inorganic compound in ambient PM2.5 was NH4NO3, and a competitive relationship between form of NH4NO3 and (NH4)2SO4 (NH4HSO4) was found as well. High homology between SO42- and NO3- has been observed in all the three cities, and the ratio between [SO42-] and [NO3-] indicated that the stationary source contributed the most to ambient PM2.5 in Dazhou. The mass concentrations of the total metal elements from the three cities exhibited similar levels, nevertheless, Dazhou had the highest mass fraction of total metal elements in PM2.5. The enrichment factor of each element indicated that the natural source was highly contributory to the crustal elements in PM2.5 of all the three cities, whereas Cr, Cu, Se, Mo, Cd, Tl and Bi were primarily originated from anthropogenic source. In addition, the source apportionment of PM2.5 suggest that Dazhou had the different factors and factor-contributions comparing with Chengdu and Leshan.

N-Doped graphene-supported PdCu nanoalloy as efficient catalyst for reducing Cr(vi) by formic acid.

Reducing Cr(vi) to Cr(iii) with formic acid is desirable for environmental protection, but the sluggish kinetics limits its practical application, which currently motivates the intensive study of efficient catalysts for this redox reaction. Here bimetallic PdCu nanoalloy (∼5 nm in size) supported by N-doped graphene was synthesized through a one-pot hydrothermal process. The catalytic activity of PdCu nanoalloy highly depends on the Pd/Cu atomic ratio and N-doped graphene support. The obtained Pd6Cu4/NG shows superior catalysis towards the Cr(vi) reduction by formic acid with a high kinetic constant (kn = 23.2 min-1 mg-1) and a low activation energy (Ea = 34.9 kJ mol-1). Active H atoms were found to be the exact reductant for the Cr(vi) reduction, quite different from the reported H2-reduction route. The enhanced catalysis originates from the electronic and geometric modification of active Pd after formation of PdCu alloy. Electron transfer from Cu to Pd enhances the electron density of Pd atoms, which favors the adsorption of the bridging formate intermediate and subsequent generation of active H atoms over PdCu/NG. The catalyst can be recycled five times without obvious loss of activity. Our work provides an example to explore the alloying effect on the catalytic behavior of PdCu alloy, which may shed light on developing other advanced nanoalloys for Cr(vi) reduction.

Combined Tumor- and Neovascular-"Dual Targeting" Gene/Chemo-Therapy Suppresses Tumor Growth and Angiogenesis.

A rational combination is critical to achieve efficiently synergistic therapeutic efficacy for tumor treatment. Hence, we designed novel antitumor combinations (T-NPs) by integrating the tumor vascular and tumor cells dual-targeting ligand with antiangiogenesis/antitumor agents. The truncated bFGF peptide (tbFGF), which could effectively bind to FGFR1 overexpressed on tumor neovasculature endothelial cells and tumor cells, was selected to modify PLGA nanoparticles (D/P-NPs) simultaneously loaded with PEDF gene and paclitaxel in this study. The obtained T-NPs with better pharmaceutical properties had elevated cytotoxicity and enhanced expression of PEDF and α-tubulin on FGFR1-overexpressing cells. The uptake of T-NPs increased in C26 cells, probably mediated by tbFGF via specific recognization of the overexpressed FGFR1. T-NPs dramatically disrupted the tube formation of primary human umbilical vein endothelial cells (HUVECs) and displayed improved antiangiogenic activity in the transgenic zebrafish model and the alginate-encapsulated tumor cell model. More importantly, T-NPs achieved a markedly higher antitumor efficacy in the C26 tumor-bearing mice model. The antitumor effect involved the inhibition of tumor cell proliferation and angiogenesis, induction of apoptosis, and down-regulation of FGFR1. The enhanced antitumor activity of T-NPs probably resulted from the raised distribution in tumor tissues. In addition, T-NPs had no obvious toxicity as evaluated by weight monitoring, serological/biochemical analyses, and H&E staining. These results revealed that T-NPs, an active targeting gene/chemo-therapy, indeed had superior antitumor efficacy and negligible side effect, suggesting that this novel combination is a potential tumor therapy and a new treatment strategy and that the tbFGF modified nanoparticles could be applied to a wide range of tumor-genetic therapies and/or tumor-chemical therapies.

Pigment epithelial-derived factor gene loaded novel COOH-PEG-PLGA-COOH nanoparticles promoted tumor suppression by systemic administration.

Anti-angiogenesis has been proposed as an effective therapeutic strategy for cancer treatment. Pigment epithelium-derived factor (PEDF) is one of the most powerful endogenous anti-angiogenic reagents discovered to date and PEDF gene therapy has been recognized as a promising treatment option for various tumors. There is an urgent need to develop a safe and valid vector for its systemic delivery. Herein, a novel gene delivery system based on the newly synthesized copolymer COOH-PEG-PLGA-COOH (CPPC) was developed in this study, which was probably capable of overcoming the disadvantages of viral vectors and cationic lipids/polymers-based nonviral carriers. PEDF gene loaded CPPC nanoparticles (D-NPs) were fabricated by a modified double-emulsion water-in-oil-in-water (W/O/W) solvent evaporation method. D-NPs with uniform spherical shape had relatively high drug loading (~1.6%), probably because the introduced carboxyl group in poly (D,L-lactide-co-glycolide) terminal enhanced the interaction of copolymer with the PEDF gene complexes. An excellent in vitro antitumor effect was found in both C26 and A549 cells treated by D-NPs, in which PEDF levels were dramatically elevated due to the successful transfection of PEDF gene. D-NPs also showed a strong inhibitory effect on proliferation of human umbilical vein endothelial cells in vitro and inhibited the tumor-induced angiogenesis in vivo by an alginate-encapsulated tumor cell assay. Further in vivo antitumor investigation, carried out in a C26 subcutaneous tumor model by intravenous injection, demonstrated that D-NPs could achieve a significant antitumor activity with sharply reduced microvessel density and significantly promoted tumor cell apoptosis. Additionally, the in vitro hemolysis analysis and in vivo serological and biochemical analysis revealed that D-NPs had no obvious toxicity. All the data indicated that the novel CPPC nanoparticles were ideal vectors for the systemic delivery of PEDF gene and might be widely used as systemic gene vectors.

Polymeric Nanomedicine for Combined Gene/Chemotherapy Elicits Enhanced Tumor Suppression.

Combination treatment through simultaneous delivery of DNA and anticancer drugs with nanoparticles has been demonstrated to be an elegant and efficient approach for cancer therapy. Herein, we employed a combination therapy for eliminating both the tumor cells and intratumoral neovascular network based on the nanoplatform we designed. Pigment epithelium-derived factor (PEDF) gene, a powerful antiangiogenic agent, and the clinically widely used chemotherapy agent paclitaxel (PTX) were simultaneously encapsulated in the same nanoparticle by a modified double-emulsion solvent evaporation method. The dual-drug-loaded nanoparticles (D/P-NPs) exhibited a uniform spherical morphology and released PTX and PEDF gene in a sustained manner. D/P-NPs showed an enhanced antitumor effect on C26 and A549 cells and a stronger inhibitory activity on proliferation of HUVECs. Moreover, D/P-NPs could dramatically elevate the PEDF expression levels in both C26 and A549 cells in comparison with PEDF gene loaded nanoparticles and significantly promote the cellular uptake of PTX. Additionally, microtubules were stabilized and G2/M phase arrest along with a higher subG1 cell population was induced by D/P-NPs in contrast to PTX or PTX loaded nanoparticles. Besides, D/P-NPs showed sustained release of PTX and PEDF gene in tumors as well as long-term gene expression. A significantly improved anticancer effect was also demonstrated in a C26 subcutaneous tumor model using this combinational therapy. D/P-NPs could sharply reduce the microvessel density and significantly promoted tumor cell apoptosis in vivo. More importantly, the in vivo distribution, serological and biochemical analysis, and H&E staining revealed that D/P-NPs had no obvious toxicity. Our study suggested that this novel polymeric nanomedicine had great potential for improving the therapeutic efficacy of combined gene/chemotherapy of cancer.

Pharmacokinetic studies of a novel multikinase inhibitor for treating cancer by HPLC-UV.

Small-molecule inhibitors are promising antitumor drugs. We have designed and synthesized a novel multi-targeted inhibitor, 2-methylcarbamoyl-4-{4-[3-(trifluoro-methyl)benzamido]phenoxy}pyridinium (SKLB610), that potently inhibits human tumor growth. In the study, the pharmacokinetic profile of SKLB610 was investigated. A simple, rapid and sensitive high-performance liquid chromatography-ultraviolet detection method was developed for the determination of SKLB610 in rat plasma. Samples were extracted with methanol and SKLB610 was separated on a C18 column using a mobile phase system consisting of 55% acetonitrile and 45% water, with ultraviolet detection at 270 nm. Sorafenib was used as the internal standard. The retention times of SKLB610 and the internal standard were 5.6 and 8.1 min, respectively. The quantification limit was 67 ng/mL. The calibration curves were linear over a concentration range of 0.1-50 µg/mL. The inter-day and intra-day accuracy and precision were within ± 10%. The recovery and stability of the assay were evaluated from spiked rat plasma. The method was successfully applied to a pharmacokinetic study of SKLB610 in rats. The pharmacokinetic profile of SKLB610 indicated that the oral formulations should be further optimized to improve bioavailability and intravenous formulation of SKLB610 should be developed.

Micelles based on methoxy poly(ethylene glycol)-cholesterol conjugate for controlled and targeted drug delivery of a poorly water soluble drug.

In this study, quercetin (QC) with cancer chemoprevention effect and anticancer potential was loaded into polymeric micelles of methoxy poly(ethylene glycol)-cholesterol conjugate (mPEG-Chol) in order to increase its water solubility. MPEG-Chol with lower critical micelle concentration (CMC) value (4.0 x 10(-7) M - 13 x 10(-7) M) was firstly synthesized involving two steps of chemical modification on cholesterol by esterification, and then QC was incorporated into mPEG-Chol micelles by self-assembly method. After the process parameters were optimized, QC-loaded micelles had higher drug loading (3.66%) and entrapment efficiency (93.51%) and nano-sized diameter (116 nm). DSC analysis demonstrated that QC had been incorporated non-covalently into the micelles and existed as an amorphous state or a solid solution in the polymeric matrix. The freeze-dried formulation with addition of 1% (w/v) mannitol as cryoprotectant was successfully developed for the long-term storage of QC-loaded micelles. Compared to free QC, QC-loaded micelles could release QC more slowly. Moreover, the release of QC from micelles was slightly faster in PBS at pH 5 than that in PBS at pH 7.4, which implied that QC-loaded micelles might be pH-sensitive and thereby selectively deliver QC to tumor tissue with unwanted side effects. Therefore, mPEG-Chol was a promising micellar vector for the controlled and targeted drug delivery of QC to tumor and QC-loaded micelles were also worth being further investigated as a potential formulation for cancer chemoprevention and treatment.

Antitumor effects of PLGA nanoparticles encapsulating the human PNAS-4 gene combined with cisplatin in ovarian cancer.

Human PNAS-4 (hPNAS-4), as a pro-apoptotic gene, can inhibit tumor growth when overexpressed in some malignant cells. Poly (lactic-co-glycolic acid) (PLGA) was used as a gene transfer vector due to the advantage of sustained release, nontoxicity and biodegradability. In this study, we aimed to investigate the effect of PLGA nanoparticles encapsulating hPNAS-4 combined with cisplatin (DDP) on ovarian carcinoma. Expression of hPNAS-4 was determined by RT-PCR. Mice bearing intraperitoneal ovarian carcinomas were treated with PBS, pVAX-PLGA nanoparticles (P-P), pVAX-hPNAS-4-PLGA nanoparticles (PhP-P), DDP and PhP-P plus DDP, respectively. Intraperitoneal tumors were weighed to assess the antitumor efficacy. The percentage of proliferative cells and apoptotic cells was evaluated by Ki-67 staining and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling. The anti-angiogenic effects were detected by CD31 staining and the alginate-encapsulate assay. Overexpression of hPNAS-4 was detected by RT-PCR in the PhP-P and PhP-P plus DDP groups. PhP-P exerted significant antitumor activity through induction of apoptosis, inhibition of cell proliferation and suppression of angiogenesis, compared with treatment with P-P or PBS alone. The combination of PhP-P with DDP showed enhanced antitumor activity compared with therapy of PhP-P or DDP alone. PLGA encapsulating hPNAS-4 combined with DDP may have promising applications in the therapy of ovarian cancer.

Efficient inhibition of ovarian cancer by short hairpin RNA targeting claudin-3.

Ovarian cancer is one of the most lethal gynecologic neoplasms. Even though various new chemotherapeutics have been developed for the treatment of ovarian cancer, drug resistance and undesired serious side effects remain unavoidable obstacles for chemotherapeutic approaches. New strategies to overcome the therapeutic dilemma are needed. Claudin-3 (CLDN3) is a recently discovered gene generally overexpressed in human ovarian cancers but not in normal ovarian tissue. Its high expression has been identified to associate with the invasion, proliferation and survival of cancer cells, making it a promising target for gene therapy of ovarian cancer. However, in gene therapy, traditional gene carriers such as virus or cationic liposomes suffer from distressing shortcomings of potential carcinogenicity, obvious cytotoxicity and immunogenicity. Nanoparticles (NPs) based on PLGA are a novel gene delivery system with good biodegradability, excellent biocompatibility and low toxcity for in vivo gene delivery compared with traditional gene carriers. We constructed a plasmid expressing shRNA targeted CLDN3 (pshCLDN3) encapsulated with PLGA-NPs, and administered it by i.p. injection to nude mice bearing intraperitoneal SKOV3 ovarian cancer, to investigate the antitumor potential of knocking down CLDN3. After 12 times of administration, the tumors of each group were compared. The underlying antitumor mechanisms were revealed by immunostaining of CD31, Ki-67 and TUNEL assay, to exhibit possible alterations in microvessel density, cell proliferation and cell apoptosis. Our study demonstrated that i.p. administration of pshCLDN3 effectively suppressed the expression of CLDN3 and, thus, inhibited the growth of ovarian tumors, significantly reducing tumor weight by 67.4% compared with blank controls (p<0.05). Immunostaining of CD31, Ki-67 and TUNEL assay demonstrated decreased angiogenesis (p<0.05), reduced proliferation (p<0.05) and increased apoptosis (p<0.05) in the pshCLDN3 treated group compared with controls. No obvious toxicity of PLGA-NPs was observed either in vitro or in vivo. Our results indicated that knockdown of CLDN3 by pshCLDN3 encapsulated in PLGA NPs may provide a promising approach for the treatment of ovarian cancer.

The pigment epithelial-derived factor gene loaded in PLGA nanoparticles for therapy of colon carcinoma.

Colon carcinoma is one of the common malignant tumors and has high morbidity and mortality in the world. Pigment epithelial-derived factor (PEDF) has been found to be the most potent natural inhibitor of angiogenesis and PEDF gene has been extensively used for the therapy of tumors, which suggests a potential approach to the therapy of colon carcinoma. However, the transfer of PEDF gene largely depends on the effective gene delivery systems. Poly (lactic-co-glycolic acid) nanoparticles (PLGANPs) have been extensively used for gene therapy due to its low-toxicity, biocompatibility and biodegradability, due to its potential to be an excellent carrier of the PEDF gene. We investigated the effect of PEDF gene loaded in PLGA nanoparticles (PEDF-PLGANPs) on the mouse colon carcinoma cells (CT26s) in vitro and in vivo. Blank PLGANPs (bPLGANPs) showed lower cytotoxicity than PEI to the CT26s. In vitro, PEDF-PLGANPs directly induced CT26 apoptosis and inhibit human umbilical vein endothelial cell (HUVEC) proliferation. In vivo, PEDF-PLGANPs inhibited CT26 tumors growth by inducing CT26 apoptosis, decreasing MVD and inhibiting angiogenesis. Our present study demonstrates the inhibitory effect of PEDF-PLGANPs on the growth of CT26s in vitro and in vivo for the first time. PLGANP-mediated PEDF gene could provide an innovative strategy for the therapy of colon carcinoma.

Pharmacokinetics and disposition of various drug loaded biodegradable poly(lactide-co-glycolide) (PLGA) nanoparticles.

Poly(lactic-co-glycolic acid) (PLGA) nanoparticles (PLGANPs) have been widely investigated for sustained and targeted delivery of various drugs including small molecular drugs (hydrophobic/ hydrophilic drugs) and macromolecule drugs (such as proteins, peptides, genes, vaccines, antigens, human growth factors, etc.). The in vivo pharmacokinetics and disposition profile of these encapsulated drugs and PLGANPs themselves is a key factor that determines their therapeutic index and potential for clinical use. Therefore, this review attempts to outline the in vivo behaviors of diverse drugs loaded PLGANPs administrated via different routes such as oral route, intravenous injection, nasal path, etc. Also, the associated analytical techniques used to investigate the in vivo disposition of PLGANPs loaded with drugs are focused on.