Unraveling how Fe-Mn modified biochar mitigates sulfamonomethoxine in soil water: The activated biodegradation and hydroxyl radicals formation.

This study indicated that the application of a novel Fe-Mn modified rice straw biochar (Fe/Mn-RS) as soil amendment facilitated the removal of sulfamonomethoxine (SMM) in soil water microcosms, primarily via activating degradation mechanism rather than adsorption. The similar enhancement on SMM removal did not occur using rice straw biochar (RS). Comparison of Fe/Mn-RS with RS showed that Fe/Mn-RS gains new physic-chemical properties such as abundant oxygenated C-centered persistent free radicals (PFRs). In the Fe/Mn-RS microcosms, the degradation contributed 79.5-83.8% of the total SMM removal, which was 1.28-1.70 times higher than that in the RS microcosms. Incubation experiments using sterilized and non-sterilized microcosms further revealed that Fe/Mn-RS triggered both the biodegradation and abiotic degradation of SMM. For abiotic degradation of SMM, the abundant •OH generation, induced by Fe/Mn-RS, was demonstrated to be the major contributor, according to EPR spectroscopy and free radical quenching experiments. Fenton-like bio-reaction occurred in this process where Fe (Ⅲ), Mn (Ⅲ) and Mn (Ⅳ) gained electrons, resulting in oxidative hydroxylation of SMM. This work provides new insights into the impacts of biochar on the fates of antibiotics in soil water and a potential solution for preventing antibiotic residues in agricultural soil becoming a non-point source pollutant.

Biodegradation of sulfametoxydiazine by Alcaligenes aquatillis FA: Performance, degradation pathways, and mechanisms.

This study reports the isolation and characterization of a novel bacterial strain Alcaligenes aquatillis FA with the ability to degrade sulfametoxydiazine (SMD), a commonly used sulfonamide antibiotic (SA) in livestock and poultry production. The biodegradation kinetics, pathways, and genomic background of SMD by FA were investigated. The results showed that strain FA had high specificity to degrade SMD, and was unable to effectively degrade its isomer, sulfamonomethoxine. The SMD biodegradation followed a first-order kinetic model with a rate constant of 27.39 mg·L-1·day-1 and a half-life of 5.98 days. The biodegradation pathways and detoxification processes of SMD were proposed based on the identification of its biodegradation byproducts and the biotoxicity assessment using both the ecological structure-activity relationship (ECOSAR) model and biological indicator. The involvement of novel degrading enzymes, such as dimethyllsulfone monooxygenase, 4-carboxymuconolactone decarboxylase, and 1,4-benzoquinone reductase, was inferred in the SMD biodegradation process. The presence of sul2 and dfrA genes in strain FA, which were constitutively expressed in its cells, suggests that multiple mechanisms were employed by the strain to resist SMD. This study provides new insights into the biodegradation of sulfonamide antibiotics (SAs) as it is the first to describe an SMD-degrading bacterium and its genetic information.

IDTI Dyes for Fluoride Anion Chemosensors.

Fluoride anions play a key role in human health and chemical engineering, such as in organic synthesis and biological processes. The development of high-sensitivity naked-eye detection sensors for fluoride anions in organic solutions is crucial and challenging. In this study, (3Z,3'Z)-3,3'-[4,4,9,9-tetrakis(4-hexylphenyl)-4,9-dihydro-s-indaceno(1,2-b:5,6-b')dithiophene]-2,7-diylbis(methan-1-yl-1-ylidene) bis(6-bromo-indolin-2-one) (IDTI) was designed and used as a fluoride chemosensor for the first time. IDTI is a highly sensitive fluoride sensor with a detection limit of as low as 1 × 10-7 M. In addition, upon the reaction of IDTI with fluoride anions in a tetrahydrofuran (THF) solution, color changes from red to yellow under ambient light and from purple to green under UV light were detectable by the naked eye. These studies indicate that IDTI is a promising fluoride chemosensor.

High Loading of Hydrophobic and Hydrophilic Agents via Small Immunostimulatory Carrier for Enhanced Tumor Penetration and Combinational Therapy.

Development of small-sized nanoformulations for effective tumor penetration, particularly for those tumors with dense stroma is a major challenge in cancer nanomedicine. It is even more challenging to achieve effective co-loading of both hydrophobic and hydrophilic anticancer agents through a small-sized nanocarrier. In this work, we designed a novel redox-responsive gemcitabine (GEM)-conjugated polymer POEG-co-PVDGEM (PGEM) as a small-sized nanocarrier to co-deliver hydrophilic GEM and hydrophobic paclitaxel (PTX). Methods: The in vitro physicochemical and biological properties of PTX/PGEM NPs were characterized. The efficiency of the PGEM carrier in selective codelivery of GEM and PTX in two murine tumor models as well as a patient derived xenograft model (PDX) was also evaluated. In addition, we investigated the changes in tumor immune microenvironment after treatment with PTX/PGEM nanoparticles. Results: We discovered that GEM conjugation could significantly decrease the nanoparticle size from 160 nm to 13 nm. Moreover, different from most reported GEM-conjugated polymers, PGEM polymer could serve as a prodrug carrier to load a wide variety of hydrophobic agents with high drug loading capacity and excellent stability. More importantly, our strategy could be extended to various nucleotides-based drugs such as azacytidine, decitabine and cytarabine, suggesting a new platform for co-delivery of various first line hydrophilic and hydrophobic anticancer agents. Imaging showed that our small-sized carrier was much more effective in tumor accumulation and penetration compared to the relatively large-sized drug carrier. The PGEM prodrug-based carrier not only well retained the pharmacological activity of GEM, but also boosted T-cell immune response. Furthermore, delivery of PTX via PGEM led to significantly improved antitumor activity in several murine cancer models and a PDX model of colon cancer. Conclusion: This work not only provided a small-sized carrier platform that was able to load multiple hydrophilic and hydrophobic drugs with high loading capacity, but also provided an effective regimen for enhanced tumor penetration and improved anti-tumor immunity.

Bioinspired nanoplatelets for chemo-photothermal therapy of breast cancer metastasis inhibition.

Breast cancer is associated with high mortality due to tumor metastasis. The anti-metastasis efficacy of photochemotherapy is strictly limited by poor targeting capability with respect to circulating tumor cells (CTCs) in blood and lymph. Herein, we decorate the platelet membrane (PM) on a surface of nanoparticles (NPs), referred to as nanoplatelets. A chemotherapeutic drug, doxorubicin (DOX), and an FDA-approved photothermal agent, indocyanine green (ICG), are co-encapsulated into the biomimetic nanoplatelets. Nanoplatelets possess immune surveillance-escaping capability and specifically capture and clear CTCs in both blood and lymphatic circulations via high-affinity interactions between the P-Selectin of PM and CD44 receptors of tumor cells. PM-coated NPs show greater cellular uptake in MDA-MB-231 breast cancer cells and further elicit higher cytotoxicity to tumor cells relative to uncoated NPs. In vivo, we disclose that the multifunctional nanoplatelets not only completely ablate the primary tumor but also inhibit breast cancer metastasis with high efficiency in the three established xenograft or orthotopic breast tumor-bearing mice models. We conclude that such biomimetic nanoplatelets represent a promising strategy of coating a surface of nanoparticles with platelet membrane to actively capture and destroy CTCs in blood and lymph in breast cancer anti-metastasis therapy.

Dipeptide-modified nanoparticles to facilitate oral docetaxel delivery: new insights into PepT1-mediated targeting strategy.

Oligopeptide transporter 1 (PepT1) has been a striking prodrug-designing target. However, the underlying mechanism of PepT1 as a target to facilitate the oral absorption of nanoparticles (NPs) remains unclear. Herein, we modify Poly (lactic-co-glycolic acid) (PLGA) NPs with the conjugates of dipeptides (L-valine-valine, L-valine-phenylalanine) and polyoxyethylene (PEG Mw: 1000, 2000) stearate to facilitate oral delivery of docetaxel (DTX) to investigate the oral absorption mechanism and regulatory effects on PepT1 of the dipeptide-modified NPs. The cellular uptake of the dipeptide-modified NPs is more efficient than that of the unmodified NPs in the stably transfected hPepT1- Hela cells and Caco-2 cells, suggesting the involvement of PepT1 in the endocytosis of NPs. The internalization of the dipeptide-modified NPs is proved to be a proton-dependent process. Moreover, the L-valine-valine modified NPs with shorter PEG chain exhibit distinct advantages in terms of intestinal permeability and oral absorption, resulting in significantly improved oral bioavailability of DTX. In summary, PepT1 could serve as a desirable target for oral nanoparticulate drug delivery and the dipeptide-modified NPs represent a promising nanoplatform to facilitate oral delivery of hydrophobic drugs with low bioavailability.

Cotransporting Ion is a Trigger for Cellular Endocytosis of Transporter-Targeting Nanoparticles: A Case Study of High-Efficiency SLC22A5 (OCTN2)-Mediated Carnitine-Conjugated Nanoparticles for Oral Delivery of Therapeutic Drugs.

OCTN2 (SLC22A5) is a Na+ -coupled absorption transporter for l-carnitine in small intestine. This study tests the potential of this transporter for oral delivery of therapeutic drugs encapsulated in l-carnitine-conjugated poly(lactic-co-glycolic acid) (PLGA) nanoparticles (LC-PLGA NPs) and discloses the molecular mechanism for cellular endocytosis of transporter-targeting nanoparticles. Conjugation of l-carnitine to a surface of PLGA-NPs enhances the cellular uptake and intestinal absorption of encapsulated drug. In both cases, the uptake process is dependent on cotransporting ion Na+ . Computational OCTN2 docking analysis shows that the presence of Na+ is important for the formation of the energetically stable intermediate complex of transporter-Na+ -LC-PLGA NPs, which is also the first step in cellular endocytosis of nanoparticles. The transporter-mediated intestinal absorption of LC-PLGA NPs occurs via endocytosis/transcytosis rather than via the traditional transmembrane transport. The portal blood versus the lymphatic route is evaluated by the plasma appearance of the drug in the control and lymph duct-ligated rats. Absorption via the lymphatic system is the predominant route in the oral delivery of the NPs. In summary, LC-PLGA NPs can effectively target OCTN2 on the enterocytes for enhancing oral delivery of drugs and the critical role of cotransporting ions should be noticed in designing transporter-targeting nanoparticles.

Development of novel self-assembled ES-PLGA hybrid nanoparticles for improving oral absorption of doxorubicin hydrochloride by P-gp inhibition: In vitro and in vivo evaluation.

To increase the encapsulation efficiency and oral absorption of doxorubicin hydrochloride (DOX), a novel drug delivery system of enoxaparin sodium-PLGA hybrid nanoparticles (EPNs) was successfully designed. By introducing the negative polymer of enoxaparin sodium (ES) to form an electrostatic complex with the cationic drug, DOX, the encapsulation efficiency (93.78%) of DOX was significantly improved. The X-ray diffraction (XRD) results revealed that the DOX-ES complex was in an amorphous form. An in vitro release (pH6.8 PBS) study showed the excellent sustained-release characteristics of DOX-loaded EPNs (DOX-EPNs). In addition, in situ intestinal perfusion and intestinal biodistribution experiments demonstrated the improved membrane permeability and intestinal wall bioadhesion of DOX-EPNs, and caveolin- and clathrin-mediated endocytosis pathways were the main mechanisms responsible. The cytotoxicity of DOX was significantly increased by EPNs in Caco-2 cells, compared with DOX-Sol. Confocal laser scanning microscope (CLSM) images confirmed that the amount of DOX-EPNs internalized by Caco-2 cells was higher than that of DOX-Sol showing that P-glycoprotein-mediated drug efflux was reduced by the introduction of EPNs. The qualitative detection of transcytosis demonstrated the ability of the nanoparticles (NPs) to cross Caco-2 cell monolayers. An in vivo toxicity experiment demonstrated that DOX-EPNs reduced cardiac and renal toxic effects and were biocompatible. An in vivo pharmacokinetics study showed that the AUC(0-t) and t1/2 of DOX-EPNs were increased to 3.63-fold and 2.47-fold in comparison with DOX solution (DOX-Sol), respectively. All these results indicated that the novel EPNs were an excellent platform to improve the encapsulation efficiency of an aqueous solution of this antitumor drug and its oral bioavailability.

Absolute oral bioavailability of fenofibric acid and choline fenofibrate in rats determined by ultra-performance liquid chromatography tandem mass spectrometry.

Choline fenofibrate is the choline salt of fenofibric acid, which releases free fenofibric acid in the gastrointestinal tract. To estimate the absolute oral bioavailability of fenofibric acid and choline fenofibrate, a novel and sensitive UPLC-MS/MS method with liquid-liquid extraction procedure was developed for the determination of fenofibric acid in rat plasma. The separation was achieved on a Phenomenex Kinetex C18 column (50 × 2.1 mm, 2.6 µm) containing 2 mm ammonium acetate-methanol with a gradient elution program. Validations of this method including specificity, sensitivity (limit of quantification, 5 ng/mL), linearity (0.005-10 µg/mL), accuracy (within ±4.3%), precision (intra- and inter-day coefficient of variation <11.3%), recovery (94.9-105.2% for fenofibric acid), matrix effect, stability and dilution, were all within acceptable limits. This method successfully supported the determination of fenofibric acid and choline fenofibrate. The absolute oral bioavailability was 93.4% for choline fenofibrate and 40.0% for fenofibric acid. These results suggested that choline fenofibrate and fenofibric acid had a better in vivo pharmacokinetic behavior than that of fenofibrate. The two new orally administrated pharmaceuticals, fenofibric acid and choline fenofibrate, can be developed as alternatives to fenofibrate.

Self-Assembled Redox Dual-Responsive Prodrug-Nanosystem Formed by Single Thioether-Bridged Paclitaxel-Fatty Acid Conjugate for Cancer Chemotherapy.

Chemotherapeutic efficacy can be greatly improved by developing nanoparticulate drug delivery systems (nano-DDS) with high drug loading capacity and smart stimulus-triggered drug release in tumor cells. Herein, we report a novel redox dual-responsive prodrug-nanosystem self-assembled by hydrophobic small-molecule conjugates of paclitaxel (PTX) and oleic acid (OA). Thioether linked conjugates (PTX-S-OA) and dithioether inserted conjugates (PTX-2S-OA) are designed to respond to the redox-heterogeneity in tumor. Dithioether has been reported to show redox dual-responsiveness, but we find that PTX-S-OA exhibits superior redox sensitivity over PTX-2S-OA, achieving more rapid and selective release of free PTX from the prodrug nanoassemblies triggered by redox stimuli. PEGylated PTX-S-OA nanoassemblies, with impressively high drug loading (57.4%), exhibit potent antitumor activity in a human epidermoid carcinoma xenograft. This novel prodrug-nanosystem addresses concerns related to the low drug loading and inefficient drug release from hydrophobic prodrugs of PTX, and provides possibilities for the development of redox dual-sensitive conjugates or polymers for efficient anticancer drug delivery.

Core-matched encapsulation of an oleate prodrug into nanostructured lipid carriers with high drug loading capability to facilitate the oral delivery of docetaxel.

Nanostructured lipid carriers (NLC) have been considered as promising vehicles for oral delivery of taxanes, such as docetaxel (DTX). However, the low drug loading capability (∼5%, w/w) has greatly limited their clinical application. In response to this challenge, a novel lipophilic oleate prodrug of DTX (DTX-OA) was synthesized and efficiently encapsulated in NLC using core-match technology, in which liquid lipid (OA) was used as core matrix to enhance compatibility with DTX-OA. DTX-OA-NLC showed uniform particle size of about 100nm with markedly high drug loading capability (∼23% of DTX, w/w) compared with DTX-NLC (∼5%, w/w). Besides, DTX-OA-NLC showed better colloidal stability and slower drug release property compared with DTX-NLC. The prepared NLC could be accumulated more easily in MDCK cells than drug solution, and clathrin-mediated endocytosis was the main endocytosis pathway. In situ single-pass intestinal perfusion (SPIP) and intestinal biodistribution studies demonstrated the improved membrane permeability and intestinal wall bioadhesion of NLCs. The bioavailability of DTX-OA-NLC showed 4.04-fold and 2.06-fold higher than DTX solution and DTX-NLC, respectively. These results suggest that the core-matched prodrug-NLC is a promising platform to facilitate the oral delivery of DTX.

Assessment of the Cadmium Exposure in the Blood, Diet, and Water of the Pumi People in Yunnan, China.

Cadmium (Cd) is considered as one of the most toxic and carcinogenic heavy metals. Accumulation of Cd in the human body can cause multiorgan dysfunction. Long-term irrational mining activities have led to serious Cd pollution in soil, water, and even agricultural products. Therefore, evaluating the Cd exposure levels of people living in mining areas is of great importance. In the current study, we chose the Pumi people who lived in Jinding and Tongdian towns of Lanping county in Yunnan province, China, to do the on-site nutritional epidemiology investigation and laboratory detection. We analyzed the content of the Cd in peripheral blood and mixed dietary, as well as water samples in the Pumi residents of the two towns. Results showed that the blood Cd levels of people in Jinding town, which is nearer the mining district, were statistically significantly higher than those in Tongdian town. The P 50 of blood Cd level of the two towns was 0.64 ng/mL. In addition, the P 50 of the mixed diet of the two towns was 8.32 µg/kg. There was a weak correlation between blood Cd levels and Cd exposure in the mixed diet, PTDI, and PTWI of the Pumi people. In addition, higher concentrations of Cd were observed in the water of Jinding town, indicating people in Jinding town risking more Cd exposure. These results indicated that diet and water are critical factors of Cd exposure for the residents and the nearer people living to mining district risking the more Cd exposure.

Enteric polymer based on pH-responsive aliphatic polycarbonate functionalized with vitamin E to facilitate oral delivery of tacrolimus.

To improve the bioavailability of orally administered drugs, we synthesized a pH-sensitive polymer (poly(ethylene glycol)-poly(2-methyl-2-carboxyl-propylene carbonate)-vitamin E, mPEG-PCC-VE) attempting to integrate the advantages of enteric coating and P-glycoprotein (P-gp) inhibition. The aliphatic polycarbonate chain was functionalized with carboxyl groups and vitamin E via postpolymerization modification. Optimized by comparison and central composite design, mPEG113-PCC32-VE4 exhibited low critical micelle concentration of 1.7 × 10(-6) mg/mL and high drug loading ability for tacrolimus (21.2% ± 2.7%, w/w). The pH-responsive profile was demonstrated by pH-dependent swelling and in vitro drug release. Less than 4.0% tacrolimus was released under simulated gastric fluid after 2.5 h, whereas an immediate release was observed under simulated intestinal fluid. The mPEG113-PCC32-VE4 micelles significantly increased the absorption of P-gp substrate tacrolimus in the whole intestine. The oral bioavailability of tacrolimus micelles was 6-fold higher than that of tacrolimus solution in rats. This enteric polymer therefore has the potential to become a useful nanoscale carrier for oral delivery of drugs.

Improved oral absorption of doxorubicin by amphiphilic copolymer of lysine-linked ditocopherol polyethylene glycol 2000 succinate: in vitro characterization and in vivo evaluation.

In the previous study, we have synthesized an amphiphilic copolymer of nanostructure-forming material and P-glycoprotein (P-gp) inhibitor, lysine-linked ditocopherol polyethylene glycol 2000 succinate (PLV2K). The cytotoxicty in vitro and anticancer efficacy in vivo after intravenous administration of DOX-loaded PLV2K micelles (PLV2K-DOX) was found more effective than DOX solution (DOX-Sol). However, its performance and mechanism on oral absorption of doxorubicin are not well understood yet. PLV2K-DOX are spherical micelles with a narrow size distribution of 20.53 ± 2.44 nm. With an in situ intestinal perfusion model, the intestinal absorption potential of PLV2K-DOX was evaluated in comparison with DOX-Sol. PLV2K-DOX was specifically absorbed in duodenum and ileum sites of rats after oral administration. The intestinal absorption rate (Ka) of PLV2K-DOX is 3.19-, 1.61-, and 1.80-fold higher than that of DOX-Sol in duodenum, jejunum, and ileum, respectively. In Caco-2 uptake studies, PLV2K-DOX micelles significantly improve the internalized amount of DOX by P-gp inhibition of free PLV2K copolymer and endocytosis of DOX-loaded nanoparticles. Moreover, PLV2K-DOX micelles improve the membrane permeability of DOX by multiple transcytosis mechanisms, including caveolin-, clathrin-dependent, and caveolin-/clathrin-independent transcytosis in Caco-2 transport studies. However, the transepithelia electrical resistance (TEER) of Caco-2 cellular monolayer is not changed, suggesting no involvement of paracellular transport of PLV2K-DOX. In vivo pharmacokinetics in rats following oral administration demonstrated that PLV2K-DOX demonstrates higher AUC (5.6-fold) and longer t1/2 (1.2-fold) than DOX-Sol. The findings suggest the new PLV2K micelles might provide an effective nanoplatform for oral delivery of anticancer drugs with poor membrane permeability and low oral bioavailability.

Stealth CD44-targeted hyaluronic acid supramolecular nanoassemblies for doxorubicin delivery: probing the effect of uncovalent pegylation degree on cellular uptake and blood long circulation.

Stealth active targeting nanoparticles (NPs) usually include two types of ligand sites: ligand anchored on distal ends of the polyethylene glycol (PEG) and ligand buried under pegylated layer. The latter typical case is hyaluronic acid (HA)-based NPs; however, there is little information available for the latter NPs about effect of the optimal density of surface PEG coating on the blood circulation time, cellular uptake and in vivo anticancer activity. Thus, in this study, in order to optimize the anticancer effects of HA-based NPs, we focus on how uncovalent pegylation degree modulates blood circulation time and cellular uptake of HA-based NPs. We firstly designed a new double-hydrophilic copolymer by conjugating HP-ß-cyclodextrin with HA, and this carrier was further pegylated with adamantyl-peg (ADA-PEG) to form inclusion complex HA-HPCD/ADA-PEG, termed as HCPs. The supramolecular nanoassemblies were fabricated by host-guest and polar interactions between HCPs and doxorubicin (Dox), with vitamin E succinate (VES) being a nanobridge. Despite the active recognition between HA and CD44 receptor, the cellular uptake and targeting efficiency of HA-NPs decreased with the increasing peg density, demonstrating HA was partly buried by high density peg coating. However, the high density of peg coating was beneficial to long circulation time, tumor biodistribution and anticancer activity in vivo. NPs with 5% peg coating had the optimal cellular targeting efficiency in vitro and anticancer effects in vivo. The findings suggest that balancing long circulation property and cellular uptake is important to achieve the optimal antitumor efficacy for pegylated HA-based NPs, and that PEG coating densities cannot be extended beyond a certain density for shielding effect without compromising the efficacy of hyaluronic acid targeted delivery.

Emerging integrated nanohybrid drug delivery systems to facilitate the intravenous-to-oral switch in cancer chemotherapy.

Nanohybrid drug delivery systems have presented lots of characteristic advantages as an efficient strategy to facilitate oral drug delivery. Nonetheless, oral administration of chemotherapy agents by nanoparticulate delivery technology still faces great challenges owing to the multiple biobarriers ranging from poorly physicochemical properties of drugs, to complex gastrointestinal disposition and to presystemic metabolism. This review briefly analyzes a series of biobarriers hindering oral absorption and describes the multiple aspects for facilitating the intravenous-to-oral switch in cancer therapy. Moreover, the developed nanoparticulate drug delivery strategies to overcome the above obstacles are provided, including metabolic enzyme inhibition, enteric-coated nanocarriers, bioadhesive and mucus-penetrating strategies, P-gp inhibition and active targeting. On these foundations, the emerging trends of integrated hybrid nanosystems in response to the present low-efficiency drug delivery of any single approach are summarized, such as mixed polymeric micelles and nanocomposite particulate systems. Finally, the recent advances of high-efficiency hybrid nanoparticles in oral chemotherapy are highlighted, with special attention on integrated approach to design drug delivery nanosystems.