Regional differences in the impact paths of climate on aboveground biomass in alpine grasslands across the Qinghai-Tibet Plateau.

Alpine grasslands on the Qinghai-Tibet Plateau (QTP) play an essential role in water conservation, biodiversity protection and climate feedback, with aboveground biomass (AGB) serving as a crucial indicator of grassland health and functionality. While previous studies have independently explored the phenological differences, cumulative effects, and spatial variability of climatic impacts on biomass/productivity in alpine grasslands, the cascading effects regarding climate and phenology on AGB still present knowledge gaps. Here, using peak AGB measurements, remote sensing and gridded climate data in the QTP alpine grasslands during 2002-2018, we systematically analyzed the impact paths of climatic variables (i.e., cumulative precipitation, CP; growing degree-days, GDD) and phenology-mediated paths (start and peak date of the growing season, SOS and POS) on AGB and their regional differences. During the preseason (pre60) or the growing season (sos-pos), climate primarily directly impacted variations in AGB across different climatic regions, although a phenology-mediated path by which climate indirectly affected AGB existed (i.e., GDDsos-pos â†’ POS â†’ AGB). Three general patterns were revealed: In the plateau temperate arid regions, an increase in CPpre60 significantly promoted AGB (path coefficients w = 0.61-0.71), whereas an increase in GDDpre60 inhibited AGB (w = -0.42 ~ -0.49); In the plateau sub-cold regions, increases in both CPsos-pos and GDDsos-pos significantly promoted AGB, respectively (w = 0.46-0.81 and w = 0.37-0.70); Similarly, in the plateau temperate arid or semi-arid regions, increases in CPsos-pos also significantly promoted the AGB (w = 0.56-0.73). This study highlights that the water and heat accumulation mainly exert direct impacts on alpine grassland AGB across various climatic regions and phenological stages, providing insights into the mechanism driving AGB by climate and phenology during spring and summer.

Grazing affects ecosystem traits by regulating plateau pika activities at the landscape scale.

The mechanism underlying the effects of livestock grazing on grassland ecosystem traits has been greatly discussed. However, as a common small burrowing mammal on the Tibetan Plateau grasslands, the plateau pika's (Ochotona curzoniae) influence on alpine grassland ecosystem traits has rarely been investigated, especially beyond the plot scale. In this study, we flew an unmanned aerial vehicle (UAV) over a grassland landscape under grazing and nongrazing treatments. Mounted visible spectral remote sensing, in combination with field surveys, was utilized to explore how livestock and pika grazing modify grassland ecosystem traits at the landscape scale on the Tibetan Plateau (TP). Using object-oriented classification and partial least squares regression, we retrieved the pika burrow distribution and grassland ecosystem traits. Then, the relationships among livestock grazing, pika burrowing and ecosystem traits were evaluated. The results indicated that livestock grazing reduces the alpine meadow community height by 0.13 cm and the species number by 0.25 while increasing the vegetation coverage by 9.69 % and the aboveground biomass (AGB) by 10.07 g/m2. A lower statue grassland community with greater coverage caused by livestock grazing promotes pika burrowing. Pika burrow density increases 100/ha per 1.70 % increase in vegetation coverage, a 1.87 g/m2 increase in AGB or a 0.08 m decrease in community height. Under livestock grazing, both community structure and nutrients are more strongly associated with pika burrow density. The structural equation model demonstrated that livestock grazing regulates pika burrow density by moderating structural value and subsequently affecting nutritional value. Pika burrowing activity explains 40 % of the total variation in nutritional value. Our findings revealed an intrinsic linkage between mammal activities and alpine grassland ecosystems, which can provide guidelines for grassland management through pika population control by adjusting grazing intensity on the TP.

The Graphene Quantum Dots Gated Nanoplatform for Photothermal-Enhanced Synergetic Tumor Therapy.

Currently, the obvious side effects of anti-tumor drugs, premature drug release, and low tumor penetration of nanoparticles have largely reduced the therapeutic effects of chemotherapy. A drug delivery vehicle (MCN-SS-GQDs) was designed innovatively. For this, the mesoporous carbon nanoparticles (MCN) with the capabilities of superior photothermal conversion efficiency and high loading efficiency were used as the skeleton structure, and graphene quantum dots (GQDs) were gated on the mesopores via disulfide bonds. The doxorubicin (DOX) was used to evaluate the pH-, GSH-, and NIR-responsive release performances of DOX/MCN-SS-GQDs. The disulfide bonds of MCN-SS-GQDs can be ruptured under high glutathione concentration in the tumor microenvironment, inducing the responsive release of DOX and the detachment of GQDs. The local temperature of a tumor increases significantly through the photothermal conversion of double carbon materials (MCN and GQDs) under near-infrared light irradiation. Local hyperthermia can promote tumor cell apoptosis, accelerate the release of drugs, and increase the sensitivity of tumor cells to chemotherapy, thus increasing treatment effect. At the same time, the detached GQDs can take advantage of their extremely small size (5-10 nm) to penetrate deeply into tumor tissues, solving the problem of low permeability of traditional nanoparticles. By utilizing the photothermal properties of GQDs, synergistic photothermal conversion between GQDs and MCN was realized for the purpose of synergistic photothermal treatment of superficial and deep tumor tissues.

Triphenylphosphonium-linked derivative of hecogenin with enhanced antiproliferative activity: Design, synthesis, and biological evaluation.

Hecogenin (HCG), a steroidal sapogenin, possesses good antitumor properties. However, the application of HCG for cancer treatment has been hindered primarily by its moderate potency. In this study, we incorporated triphenylphosphonium cation (TPP+) at the C-3 and C-12 positions through different lengths of alkyl chains to target mitochondria and enhance the efficacy and selectivity of the parent compound. Cytotoxicity screening revealed that most of the target compounds exhibited potent antiproliferative activity against five human cancer cell lines (MKN45, A549, HCT-116, MCF-7, and HepG2). Structure-activity relationship studies indicated that the TPP+ group significantly enhanced the antiproliferative potency of HCG. Among these compounds, 3c demonstrated remarkable potency against MKN45 cells with an IC50 value of 0.48 µM, significantly more effective than its parent compound HCG (IC50 > 100 µM). Further investigations into the mechanism of action revealed that 3c induced apoptosis of MKN45 cells through the mitochondrial pathway. In a zebrafish xenograft model, 3c inhibited the proliferation of MKN45 cells. Overall, these results suggest that 3c, with potent antiproliferative activity, may serve as a valuable scaffold for developing new antitumor agents.

Preparation of Lamivudinyl palmitate nanoemulsome for liver-targeting delivery.

The water solubility and side effects of lamivudine limit its application for the treatment of viral hepatitis type B and human immunodeficiency virus. In order to increase the solubility of LA and improve the in vivo membrane permeability of the drug, LA was modified with hexadecane acid to prepare the prodrug lamivudine palmitic acid (LAP) and loaded into nanoemulsome (NES). LAP-NES was prepared by the thin film dispersion method. The LAP-NES showed the sustained release performance up to 72h in pH 7.4 PBS. Moreover, the pharmacokinetics of LAP-NES after tail vein injection in rats and the biodistribution characteristics were evaluated. The tmax of LAP-NES was 2.5h. The t1/2, clearance rate and average retention time of LAP-NES obviously prolonged compared with free LAP. The tissue biodistribution behavior of NES in vivo showed the good targeting in the liver and spleen, with the maximum at 4h and then the fluorescence slowly decreased until 72h. LAP-NES could significantly delay the release of LA in vivo, effectively prolong the elimination time and had obvious liver-targeting ability. In summary, LAP-NES shows great potential for liver-targeting delivery to increase the therapeutic effect and decrease the side effects of LA.

Regional inequalities of future climate change impact on rice (Oryza sativa L.) yield in China.

The implications of climate change for rice yield have significant repercussions for food security, particularly in China, where rice cultivation is diverse, involving various cropping intensities, management practices, and climate conditions across numerous regions. The regional discrepancies in the impact of climate change on rice yield in China, however, are yet to be fully understood. Using the ORYZA(v3) model and future climate data from 2025 to 2084, gathered from ten climate models and three climate change scenarios (RCP2.6, RCP4.5, and RCP8.5), we conducted an investigation into these regional discrepancies. Our findings suggest a projected average decline in rice yield ranging from 3.7 % to 16.4 % under both rainfed and fully irrigated conditions across different scenarios. Central, eastern, and northwestern China could face the most significant climate change impacts on both rainfed and irrigated rice, with yield reductions reaching 41.5 %. In contrast, low levels of climate change under the RCP2.6 scenario may benefit northeastern (2.4 %) and southern (1.0 %) regions for rainfed and irrigated rice, respectively. Fertilization effects from elevated CO2 could counterbalance climate change's negative impact, resulting in yield increases in all Chinese rice-growing regions, excluding the northwest. The primary factor influencing rice yield changes in all regions under the RCP4.5 and RCP8.5 scenarios was temperature. However, precipitation, solar radiation, and relative humidity had notable and sometimes dominant effects, especially under the RCP2.6 scenario. These results highlight the divergent, even contradictory, rice yield responses to climate change across China, underlining the need to account for regional differences in large-scale impact studies. The study's findings can inform future policy decisions regarding ensuring regional and national food security in China.

Combination immunotherapy of PEG-modified preladenant thermosensitive liposomes and PD-1 inhibitor effectively enhances the anti-tumor immune response and therapeutic effects.

Immunotherapy is a promising cancer treatment strategy. In contrast, programmed cell death 1 (PD-1)/programmed cell death ligand 1 (PD-L1) inhibitors are associated with low response rates and are only useful in a small group of cancer patients. A combination of treatments may be effective for overcoming this clinical issue. Preladenant is an adenosine (ADO) receptor inhibitor that can block the ADO pathway and improve the tumor microenvironment (TME), thereby enhancing the immunotherapeutic effect of PD-1 inhibitors. However, its poor water solubility and low targeting limit its clinical applications. We designed a PEG-modified thermosensitive-liposome (pTSL) loaded with ADO small molecule inhibitor preladenant (P-pTSL) to overcome these problems and enhance the effect of PD-1 inhibitor on breast cancer immunotherapy. The prepared P-pTSL was round and uniformly distributed with a particle size of (138.9 ± 1.22) nm, PDI: 0.134 ± 0.031, and zeta potential (-10.1 ± 1.63) mV; preladenant was released slowly at 37 °C but released fast at 42 °C from P-pTSL, which was 76.52 ± 0.44%. P-pTSL has good long-term and serum stability and excellent tumor-targeting ability in mice. Moreover, the combination with PD-1 inhibitor significantly enhanced the anti-tumor effect, and the improvement of related factors in serum and lymph was more obvious under the condition of 42 °C thermotherapy in vitro.

Polysialic acid-functionalized liposomes for efficient honokiol delivery to inhibit breast cancer growth and metastasis.

To improve the anti-metastasis effects of honokiol (HNK) on breast cancer, we designed cationic liposomes (Lip) in which HNK was encapsulated into Lip, and its surface was modified with negatively charged polysialic acid (PSA-Lip-HNK) for efficient treatment of breast cancer. PSA-Lip-HNK possessed a homogeneous spherical shape and high encapsulation efficiency. In vitro 4T1 cell experiments indicated that PSA-Lip-HNK increased cellular uptake and cytotoxicity via the endocytosis pathway mediated by PSA and selectin receptors. Furthermore, the significant antitumor metastasis impact of PSA-Lip-HNK was confirmed by wound healing and cell migration and invasion. Enhanced in vivo tumor accumulation of the PSA-Lip-HNK was observed in 4T1 tumor-bearing mice by living fluorescence imaging. For in vivo antitumor experiments using 4T1 tumor-bearing mice, PSA-Lip-HNK exhibited a higher tumor growth and metastasis inhibition compared with unmodified liposomes. Therefore, we believe that PSA-Lip-HNK well combined biocompatible PSA nano-delivery and chemotherapy, providing a promising drug delivery approach for metastatic breast cancer therapy.

Customized multi-stimuli nanovehicles with dissociable 'bomblets' for photothermal-enhanced synergetic tumor therapy.

Recently, the therapeutic effect of chemotherapy has been obviously impaired due to premature drug release, low tumor penetration, and multidrug resistance of nanoplatforms. In this paper, a novel multiple-sensitive drug delivery system (MC-ss-CDs) was developed by gating long-wavelength emitting carbon dots (CDs) on the openings of mesoporous carbon nanoparticles (MC) through disulfide bonds. The MC with excellent photothermal transition efficiency and high drug storage capacity for doxorubicin (DOX) was used as the delivery carrier. The CDs had multiple functions, including intelligent switching to hinder unwanted release, photothermal therapy (PTT) agents to improve the heat generation effect of MCs and bioimaging trackers to monitor drug delivery. The disulfide bonds, as the linkers between MC carriers and CDs, are stable under normal physical conditions and relatively labile under high GSH concentrations in the cytoplasm of tumor cells. After arriving at the tumor microenvironment, DOX/MC-ss-CDs can rapidly break into DOX/MC and CDs under high GSH concentrations. DOX/MC could realize efficient integration of PTT and chemotherapy on the surface of the tumor by stimuli-responsive DOX release and synergetic heating of MC and CDs. The small-sized CDs with excellent penetrating ability could effectively enter the deep tumor and realize NIR-triggered photothermal ablation. The DOX/MC-ss-CDs showed a chemophotothermal effect with a combination index of 0.38 in vitro and in vivo. Therefore, the DOX/MC-ss-CDs could be employed as a trackable nanovehicle for synergistic chemotherapy and PTT at different depths.

Biomimetic Antidote Nanoparticles: a Novel Strategy for Chronic Heavy Metal Poisoning.

Chronic lead poisoning has become a major factor in global public health. Chelation therapy is usually used to manage lead poisoning. Dimercaptosuccinic acid (DMSA) is a widely used heavy metal chelation agent. However, DMSA has the characteristics of poor water solubility, low oral bioavailability, and short half-life, which limit its clinical application. Herein, a long-cycle slow-release nanodrug delivery system was constructed. We successfully coated the red blood cell membrane (RBCM) onto the surface of dimercaptosuccinic acid polylactic acid glycolic acid copolymer (PLGA) nanoparticles (RBCM-DMSA-NPs), which have a long cycle and detoxification capabilities. The NPs were characterized and observed by particle size meters and transmission electron microscopy. The results showed that the particle size of RBCM-DMSA-NPs was approximately 146.66 ± 2.41 nm, and the zeta potential was - 15.34 ± 1.60 mV. The homogeneous spherical shape and clear core-shell structure of the bionic nanoparticles were observed by transmission electron microscopy. In the animal tests, the area under the administration time curve of RBCM-DMSA-NPs was 156.52 ± 2.63 (mg/L·h), which was 5.21-fold and 2.36-fold that of free DMSA and DMSA-NPs, respectively. Furthermore, the median survival of the RBCM-DMSA-NP treatment group (47 days) was 3.61-fold, 1.32-fold, and 1.16-fold for the lead poisoning group, free DMSA, and DMSA-NP groups, respectively. The RBCM-DMSA-NP treatment significantly extended the cycle time of the drug in the body and improved the survival rate of mice with chronic lead poisoning. Histological analyses showed that RBCM-DMSA-NPs did not cause significant systemic toxicity. These results indicated that RBCM-DMSA-NPs could be a potential candidate for long-term chronic lead exposure treatment.

Structural elucidation of two novel degradants of lurasidone and their formation mechanisms under free radical-mediated oxidative and photolytic conditions via liquid chromatography-photodiode array/ultraviolet-tandem mass spectrometry and one-dimensional/two-dimensional nuclear magnetic resonance spectroscopy.

Lurasidone is an antipsychotic drug clinically used for the treatment of schizophrenia and bipolar disorder. During a mechanism-based forced degradation study of lurasidone, two novel degradation products were observed under free radical-mediated oxidative (via AIBN) and solution photolytic conditions. The structures of the two novel degradants were identified through an approach combining HPLC, LC-MSn (n = 1, 2), preparative HPLC purification and NMR spectroscopy. The degradant formed under the free radical-mediated condition is an oxidative degradant with half of the piperazine ring cleaved to form two formamides; a mechanism is proposed for the formation of the novel N,N'-diformyl degradant, which should be readily applicable to other drugs that contain a piperazine moiety that is widely present in drug molecules. The degradant observed under the solution photolytic condition is identified as the photo-induced isomer of lurasidone with the benzisothiazole ring altered into a benzothiazole ring.

Species differences in the green-up date of typical vegetation in Inner Mongolia and climate-driven mechanism based on process-based phenology models.

Different species within the same community may exhibit distinct phenological responses to climate change, so it is necessary to study species differences in the green-up date among abundant species within a wide area, and a suitable phenology model should be introduced to explain the associated climate-driven mechanism. Although various models have been developed, very few studies have aimed to compare their efficiency and robustness, and the relative contributions of climate driving factors have not been sufficiently examined. We analyzed phenology data for 12 species across 17 stations in Inner Mongolia and found that essential spatiotemporal and interspecies differences existed in the green-up date. Five process-based models were established for each species and their performance was comprehensively evaluated. The two-phase models (sequential model, parallel model, unified model and unified model combined with precipitation driving) generally performed better than the one-phase model (thermal time model), and the model considering precipitation performed the best, which indicates that it is necessary to introduce the chilling effect and precipitation driving effect to improve the model accuracy in arid environments. We proposed a method to estimate the contribution rates of various climate driving factors, and significant differences in the relative demand for the various climate driving factors among different species were clearly revealed. The results indicated that for natural vegetation in Inner Mongolia, the need for the chilling and temperature driving is relatively high, and the precipitation driving is very important for herbaceous vegetation, which leads to considerable spatial and interspecies differences in green-up date. We demonstrated the feasibility of quantitatively evaluating the contributions of different climate driving factors with a process-based model, and the contradiction in phenological changes among different studies may eventually be clarified.

Investigation of an artificial solution degradant of linagliptin: An undesired linagliptin urea derivative generates in sample preparation of linagliptin tablet treated by sonication in acetonitrile containing diluent.

During the related substances testing method development for linagliptin tablet, an unknown peak was observed in HPLC chromatograms with a level exceeding the identification threshold. By using a strategy that combines LC-PDA/UV-MSn with mechanism-based stress studies, the unknown peak was rapidly identified as linagliptin urea, a solution degradant that is caused by the reaction between the API and hydrocyanic acid with sonication treatment to accelerate dissolution of the drug substance in sample preparation of linagliptin tablets, and hydrocyanic acid is a known impurity in HPLC grade acetonitrile and acetonitrile is used as part of diluent. The mechanism of the solution degradation chemistry was verified by stressing linagliptin API with trimethylsilyl cyanide (TMSCN, which can give off HCN slowly in the presence of water) treated with sonication in the sample preparation. Further investigation found that when the sonication treatment was replaced by vortex vibration in the process of the sample preparation, the RRT 1.28 species was decreased to below the level of the detection limit (0.02%). The structure of this impurity was further confirmed through the synthesis of the impurity and subsequent structure characterization by 1D and 2D NMR. Due to the presence of trace amount of HCN in HPLC grade acetonitrile, these types of solution degradation would likely occur in analysis of pharmaceutical finished products containing APIs with primary and secondary amine moieties drug product during sample preparations, particularly when sonication treatment is used to accelerate dissolution of drug substance from the finished drug product. In the GMP quality control laboratories, such events may trigger undesirable out-of-specification (OOS) events. Hence, the results of this paper can help to prevent these events from happening in the first place or resolve these OOS events in GMP laboratories.

Study of the isomeric Maillard degradants, glycosylamine and Amadori rearrangement products, and their differentiation via MS2 fingerprinting from collision-induced decomposition of protonated ions.

RATIONALE: The focus of this work was to study glycosylamine and Amadori rearrangement products (ARPs), the two major degradants in the Maillard reactions of pharmaceutical interest, and utilize their MS2 fingerprints by liquid chromatography/high-resolution tandem mass spectrometry (LC/HRMS2 ) to quickly distinguish the two isomeric degradants. These two types of degradants are frequently encountered in the compatibility and stability studies of drug products containing primary or secondary amine active pharmaceutical ingredients (APIs), which are formulated with excipients consisting of reducing sugar functionalities. METHODS: Vortioxetine was employed as the primary model compound to react with lactose to obtain the glycosylamine and ARP degradants of the Maillard reaction, and their MS2 spectra (MS2 fingerprints) were obtained by LC/MS2 . Subsequently, the two degradants were isolated via preparative HPLC and their structures were confirmed by one- and two-dimensional (1D and 2D) nuclear magnetic resonance (NMR) determination. RESULTS: The MS2 fingerprints of the two degradants display significantly different profiles, despite the fact that many common fragments are observed. Specifically, protonated glycosylamine shows a prominent characteristic fragment of [Mvort + C2 H3 O]+ at m/z 341 (Mvort is the vortioxetine core), while protonated ARP shows a prominent characteristic fragment of [Mvort + CH]+ at m/z 311. Further study of the Maillard reactions between several other structurally diverse primary/secondary amines and lactose produced similar patterns. CONCLUSIONS: The study suggests that the characteristic MS2 fragment peaks and their ratios may be used to differentiate the glycosylamine and ARP degradants, the two isomeric degradants of the Maillard reaction, which are commonly encountered in finished dosage forms of pharmaceutical products containing primary and secondary amine APIs.

Novel biomimetic nanostructured lipid carriers for cancer therapy: preparation, characterization, and in vitro/in vivo evaluation.

Nanostructured lipid carriers (NLC) have become a research hotspot, wherein cancer-targeting effects are enhanced and side effects of chemotherapy are overcome. Usually, accelerated blood clearance (ABC) occurs after repeated injections, without changing the immunologic profile, despite PEGylation which prolongs the circulation function. To overcome these problems, we designed a red blood cell-membrane-coated NLC (RBCm-NLC), which was round-like, with a particle size of 60.33 ± 3.04 nm and a core-shell structure. Its stability was good, the drug paclitaxel (PTX) release from RBCm-PTX-NLC was less than 30% at pH7.4 and pH6.5, and the integrity of RBC membrane surface protein was maintained before and after preparation. Additionally, in vitro assays showed that, with the RBCm coating, the cellular uptake of the NLC by cancer cells was significantly enhanced. RBCm-NLC can avoid recognition by macrophage cells and prolong circulation time in vivo. In S180 tumor-bearing mice, the DiR-labeled RBCm-NLC group showed a stronger fluorescence signal and longer retention in tumor tissues, indicating a prompt tumor-targeting effect and extended blood circulation. Importantly, RBCm-PTX-NLC enhanced the antitumor effect and extended the survival period significantly in vivo. In summary, biomimetic NLC offered a novel strategy for drug delivery in cancer therapy.

A Gas Sensor With Fe2O3 Nanospheres Based on Trimethylamine Detection for the Rapid Assessment of Spoilage Degree in Fish.

A spherical iron oxide precursor was prepared using a solvothermal method, and then treated thermally at 400°C to obtain α-Fe2O3 nanoparticles. The structures and morphology of the as-obtained products were characterized using X-ray diffraction (XRD), transmission electron microscopy (TEM), and scanning electron microscopy (SEM). The results showed that the diameter of the α-Fe2O3 nanoparticles was approximately 500 nm. In addition, we formed the α-Fe2O3 nanoparticles into a thick film as a gas sensor and performed a gas sensing test. When the working temperature was set at 250°C, the α-Fe2O3 nanoparticle displayed very good selectivity and high sensitivity for trimethylamine (TMA). The minimum detection was as low as 1 ppm, and the response value for 100 ppm TMA gas was 27.8. Taken together, our findings illustrated that the α-Fe2O3 nanoparticles could be used as a gas-sensitive material to test the freshness of fish.

Structure Elucidation and Mechanistic Study of a New Dimeric Degradant in Ropinirole Hydrochloride Extended-Release Tablets.

PURPOSE: The goal of the study was to elucidate the structure of a new degradant (1,3'-Dimer), generated in the stability testing of ropinirole extended-release tablets, and the formation mechanism of 1,3'-Dimer and its isomer (3,3'-Dimer). METHODS: The strategy of combining LC-PDA/UV-MSn (n = 1, 2) and NMR in conjunction with mechanism-based forced degradation study was employed to identify the structure of the unknown degradant and the formation mechanism of this dimeric degradant as well as its isomer, 3,3'-Dimer. The forced degradation was conducted by treating ropinirole API with formaldehyde under alkaline catalysis. A compatibility study between ropinirole and lactose was also performed. RESULTS: The degradant was isolated from the forced degradation sample and characterized by LC-PDA/UV-MSn as well as NMR measurement. The impurity was identified as a new dimeric degradant of ropinirole connected by a methylene bridge via the 1- and 3'-position of each ropinirole unit (i.e., 1,3'-Dimer of ropinirole), which is an isomer of a known dimeric degradant of ropinirole, namely 3,3'-Dimer. CONCLUSIONS: The newly occurred unknown degradant in ropinirole extended-release tablets was elucidated as the methylene-bridged 1,3'-Dimer of ropinirole. Based on the mechanistic study, 1,3'-Dimer and its isomer (3,3'-Dimer) were both formed by the reaction of ropinirole with residual formaldehyde present or formed in lactose, a main excipient of the formulation.

Chitosan-capped enzyme-responsive hollow mesoporous silica nanoplatforms for colon-specific drug delivery.

An enzyme-responsive colon-specific delivery system was developed based on hollow mesoporous silica spheres (HMSS) to which biodegradable chitosan (CS) was attached via cleavable azo bonds (HMSS-N=N-CS). Doxorubicin (DOX) was encapsulated in a noncrystalline state in the hollow cavity and mesopores of HMSS with the high loading amount of 35.2%. In vitro drug release proved that HMSS-N=N-CS/DOX performed enzyme-responsive drug release. The grafted CS could increase the biocompatibility and stability and reduce the protein adsorption on HMSS. Gastrointestinal mucosa irritation and cell cytotoxicity results indicated the good biocompatibility of HMSS and HMSS-N=N-CS. Cellular uptake results indicated that the uptake of DOX was obviously increased after HMSS-N=N-CS/DOX was preincubated with a colonic enzyme mixture. HMSS-N=N-CS/DOX incubated with colon enzymes showed increased cytotoxicity, and its IC50 value was three times lower than that of HMSS-N=N-CS/DOX group without colon enzymes. The present work lays the foundation for subsequent research on mesoporous carriers for oral colon-specific drug delivery.

Formation of formaldehyde as an artifact peak in head space GC analysis resulting from decomposition of sample diluent DMSO: A GC-MS investigation with deuterated DMSO.

During our method development for residual formaldehyde detection in a drug substance, unusually high levels of formaldehyde were detected when using a mixed solvent of EtOH/DMSO (4:1, v/v) as sample diluent in headspace GC analysis (HS-GC). Initial investigation found that formaldehyde is used in the preparation for one of the starting materials of the drug substance. Nevertheless, there is neither other source of formaldehyde in the manufacturing process of the drug substance, nor would formaldehyde be generated during the process. In the ensuing root cause investigation, it was found that once the solvent DMSO is replaced by other solvent [e.g., N,N-dimethylformamide (DMF)], while keeping other method parameters unchanged in the HS-GC analysis, the level of formaldehyde in the same batch of the drug substance became undetectable (LOD: 3 ppm). All the evidence suggested that the observed formaldehyde in the HS-GC analysis might be due to the decomposition of DMSO, which could be facilitated by the presence of this particular drug substance. In other words, the presence of the drug substance (in the form of HCl salt) would cause a minor decomposition of DMSO to produce formaldehyde. To prove this hypothesis, a GC-MS experiment of the drug substance was conducted in which deuterated DMSO (DMSO-d6) was used in place of regular DMSO; the expected deuterated derivatization product, i.e., diethoxymethane-d2 (C2H5OCD2OC2H5), was observed in the HS-GC-MS analysis. Therefore, it became clear that this drug substance facilitates the minor decomposition of DMSO in the HS-GC analysis. In such a case, formaldehyde is an artifact peak, or ghost peak, rather than a true impurity of the drug substance. The false positive results of formaldehyde were also found in other four compounds (three drug substances and one reagent) which are all in the form of HCl or HBr salts, suggesting that generation of formaldehyde from DMSO could be a widely occurred phenomenon in HS-GC analysis of alkyl amines in the form of HCl or HBr salts, when DMSO-containing diluents are used during sample preparation.