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Soil temperature plays an important role in hydrology, agriculture, and meteorology. In order to improve the accuracy of soil temperature simulation, a soil temperature data assimilation system was developed based on the Ensemble Particle Filter (EnPF) and the Common Land Model (CLM), and then applied in the Walnut Gulch Experimental Watershed (WGEW) in Arizona, United States. Surface soil temperature in situ observations and Moderate Resolution Imaging Spectroradiometer Land Surface Temperature (MODIS LST) data were assimilated into the system. In this study, four different assimilation experiments were conducted: (1) assimilating in situ observations of instantaneous surface soil temperature each hour, (2) assimilating in situ observations of instantaneous surface soil temperature once per day, (3) assimilating verified MODIS LST once per day, and (4) assimilating original MODIS LST once per day. These four experiments reflect a transition from high-quality and more frequent in situ observations to lower quality and less frequent remote sensing data in the data assimilation system. The results from these four experiments show that the assimilated results are better than the simulated results without assimilation at all layers except the bottom layer, while the superiority gradually diminishes as the quality and frequency of the observations decrease. This demonstrates that remote sensing data can be assimilated using the ensemble particle filter in poorly gauged catchments to obtain highly accurate soil variables (e.g., soil moisture, soil temperature). Meanwhile, the results also demonstrate that the ensemble particle filter is effective in assimilating soil temperature observations to improve simulations, but the performance of the data assimilation method is affected by the frequency of assimilation and the quality of the input data. [ABSTRACT FROM AUTHOR]

• High-resolution recharge estimation using a process-based hydrologic model. • Detailed model testing using baseflow measurements. • Recharge occurred year-round in agricultural lands. • Recharge was intermittent in forested lands. • Major recharge pulses occurred in spring, summer and fall (sometimes in late fall). Understanding the timing, location and rates of recharge is important for sustainable groundwater management and effective management of groundwater-dependent ecosystems. This paper explores the spatiotemporal distributions of large- and small-recharge events in a composite watershed in the Great Lakes region and examines the impacts of climate, land use/land cover, soils, and topography on simulated recharge. Novel aspects of the work include recharge estimation using an integrated hydrologic model and constraining the model using field observations of baseflows in both perennial and intermittent streams in the region as well as the United States Geological Survey (USGS) streamflows, groundwater heads, and satellite-based evapotranspiration (ET) products. Simulated high (low) recharge values were associated with high (low) elevations and regions of low (high) ET. The temporal dynamics of recharge are dominated by interannual climate variations, but are also affected by land cover types and soil types. Recharge occurred year-round in agricultural lands but intermittently in forested lands with both recharge and discharge occurring at different times within the same grid cell. Major recharge pulses were associated with spring snowmelt and also occurred in summer and fall and sometimes in late fall but there was considerable variability from year to year depending on the dominant land use and climate. Our approach based on the use of an integrated hydrologic model combined with multi-source data can be used in larger areas and is suitable for studying climate change impacts on groundwater resources. [ABSTRACT FROM AUTHOR]

At present, high-resolution drought indices are scarce, and this problem has restricted the development of refined drought analysis to some extent. This study explored the possibility of calculating the standardized precipitation index (SPI) with short-term precipitation sequences in China, based on data from 2416 precipitation observation stations covering the time period from 1961 to 2019. The result shows that it is feasible for short-sequence stations to calculate SPI index, based on the spatial interpolation of the precipitation distribution parameters of the long-sequence station. Error analysis denoted that the SPI error was small in east China and large in west China, and the SPI was more accurate when the observation stations were denser. The SPI error of short-sequence sites was mostly less than 0.2 in most areas of eastern China and the consistency rate for the drought categories was larger than 80%, which was lower than the error using the 30-year precipitation samples. Further analysis showed that the estimation error of the distribution parameters β and q was the most important cause of SPI error. Two drought monitoring examples show that the SPI of more than 50,000 short-sequence sites can correctly express the spatial distribution of dry and wet and have refined spatial structure characteristics. [ABSTRACT FROM AUTHOR]

• A Nonlinear Joint Hydrological Drought Index (NJHDI) is constructed. • The non-linear relationship between surface water and groundwater is reflected. • Changes in underlying surface is considered when characterizing hydrological drought. • The most-often hydrological drought grades (MHC) in different parts of the YRB are found. • The potential influencing factors on the MHC are analyzed and quantified. It is critical important to accurately evaluate hydrological drought evolutions based on a composite index for the sustainable development of water resources. In this study, a Nonlinear Joint Hydrological Drought Index (NJHDI) is constructed by combining surface water and groundwater to better reflect the multivariate phenomenon in characterizing hydrological drought. The bi-dimensional copula function is applied to describe the complicated and nonlinear relationship between surface water and groundwater due to its dependence structure and flexibility. To reflect the changes in underlying surface, the time-varying parameters are applied in the Soil and Water Assessment Tool (SWAT) model to simulate the surface water and groundwater more accurately. Based on the NJHDI, the spatio-temporal hydrological drought evolutions as well as their potential influencing factors are analyzed in a case study of the Yellow River Basin (YRB). Results indicate that: 1) compared to the single hydrological index, the NJHDI is more sensitive and effective to capture historically droughts; 2) hydrological droughts became increasingly serious during the last few decades, especially in parts of the basin located in the Loess Plateau areas where the ecosystem is extremely fragile; 3) climate and LULC changes have both contributed to the changes in hydrological droughts but their contributions vary significantly spatially. In general, the NJHDI-based hydrological drought evolution can provide more reliable information in hydrological drought decision-making owing to considering changes in underlying land surface, and combining the surface water and groundwater with nonlinear combination method. [ABSTRACT FROM AUTHOR]

Since the skin limits the distribution of intradermal vaccines, a large number of dendritic cells in the skin cannot be fully utilized to elicit a more effective immune response. Here, we loaded the antigen to the surface of the flagellate bacteria that was modified by cationic polymer, thus creating antigen-loaded flagellate bacteria (denoted as 'FB-Ag') to overcome the skin barrier and perform the active delivery of antigen in the skin. The FB-Ag showed fast speed (∼0.2 μm s−1) and strong dendritic cell activation capabilities in the skin model in vitro. In vivo, the FB-Ag promoted the spread of antigen in the skin through active movement, increased the contact between Intradermal dendritic cells and antigen, and effectively activated the internal dendritic cells in the skin. In a mouse of pulmonary metastatic melanoma and in mice bearing subcutaneous melanoma tumor, the FB-Ag effectively increased antigen-specific therapeutic efficacy and produced long-lasting immune memory. More importantly, the FB-Ag also enhanced the level of COVID-19 specific antibodies in the serum and the number of memory B cells in the spleen of mice. The movement of antigen-loaded flagellate bacteria to overcome intradermal constraints may enhance the activation of intradermal dendritic cells, providing new ideas for developing intradermal vaccines. [Display omitted] [ABSTRACT FROM AUTHOR]

Mapping irrigated area, frequency, timing, and amount is important for sustainable management of water resources in semi-arid and arid regions. Various studies exist on the mapping of irrigation using remote sensing and census statistics, but they mainly focus on the mapping of irrigation extent without taking frequency and timing into account. In this study, we proposed a new approach to extract irrigation attributes including irrigation extent, frequency and timing using multi-source data—moderate resolution imaging spectroradiometer (MODIS), Landsat, and ancillary data. A time-series dataset with 30-m spatial resolution was generated by fusing 480-m time-series MODIS and Landsat imagery. We used the greenness index (the ratio of NIR and green spectral bands) to detect irrigation events during the first half of the growing season. Rainfall events were assumed as water supplement events along with irrigation events. The number of water supplement stages were then recorded cumulatively when a water supplement event was detected using a threshold-based model. To estimate the possible dates of each water supplement stage, Gaussian process regression and linear regression models were applied. The new framework was applied to the Hexi Corridor in northwestern China, an intensively irrigated region with a semi-arid climate. Results show that the overall accuracy of water supplement stage using the proposed method is 87%. Validation of the number of water supplement stages and possible dates of water supply by GRP model with a “strict” (or “loose”) assessment method shows an overall accuracy of 55% (94%) and 59% (89%), respectively. The good accuracy of the additional independent validations for different years and sites demonstrates the robustness of the proposed method, suggesting the general applicability to other regions. Overall, this research demonstrates that the proposed method is promising in detecting irrigation attributes such as frequency and timing which have not been explored in previous research. [ABSTRACT FROM AUTHOR]

Disastrous impacts of recent drought events around the world have led to extensive efforts in drought monitoring and prediction. Various drought information systems have been developed with different indicators to provide early drought warning. The climate forecast from North American Multimodel Ensemble (NMME) has been among the most salient progress in climate prediction and its application for drought prediction has been considerably growing. Since its development in 1999, the U.S. Drought Monitor (USDM) has played a critical role in drought monitoring with different drought categories to characterize drought severity, which has been employed to aid decision making by a wealth of users such as natural resource managers and authorities. Due to wide applications of USDM, the development of drought prediction with USDM drought categories would greatly aid decision making. This study presented a categorical drought prediction system for predicting USDM drought categories in the U.S., based on the initial conditions from USDM and seasonal climate forecasts from NMME. Results of USDM drought categories predictions in the U.S. demonstrate the potential of the prediction system, which is expected to contribute to operational early drought warning in the U.S. [ABSTRACT FROM AUTHOR]

To develop an injectable formulation and improve the stability of disulfiram (DSF), DSF was encapsulated into mixed nanoparticles (DSF-NPs) through a high-pressure homogenization method. The Flory-Huggins interaction parameters (χ FH ) were calculated to predict the miscibility between DSF and the hydrophobic core, resulting in PCL 5000 selected as the hydrophobic block to encapsulate the DSF, as PCL 5000 had a lower χ FH 3.39 and the drug loading of the nanoparticles prepared by mPEG 5000 -PCL 5000 was relatively higher. mPEG 5000 -PCL 5000 and PCL 5000 were blended to reduce the leakage of DSF during preparation, as well as increase the stability of the nanoparticles. The cargo-loading capacity of the nanoparticles was improved from 3.35% to 5.50% by reducing the crystallinity of the PCL nanoparticle core, and the crystallinity decreased from 51.13% to 25.15% after adding medium chain triglyceride (MCT). The DSF-NPs prepared by the above method had a small particle size of 98.1 ± 10.54 nm, with a polydispersity index (PDI) of 0.036, as well as drug loading of 5.50%. Furthermore, DSF-NPs containing MCT showed higher stability than DSF-NPs without MCT and DSF-sol (DSF dissolved in Cremophor EL and ethanol) in water and 90% plasma-containing PBS. The pharmacokinetics proved that DSF-NPs containing MCT enhanced the DSF concentration in the blood. Finally, DSF-NPs effectively inhibited H22 xenograft tumor growth in vivo. [ABSTRACT FROM AUTHOR]

The climatology of shallow foehn, also known locally as elevated south-easterly gales (ESEGs), on the northern lee side of the central Tianshan Mountains is analysed using radiosonde data recorded over a period of 10 years at Urumqi, the capital of Xinjiang Uygur Autonomous Region in north-western China. ESEGs are a frequent weather phenomenon in the region, occurring on average 128.5 days/yr and most often in winter (47.0 days), particularly January (17.5 days), and least in summer (18 days). The vertical ESEG structures also undergo seasonal variations, with the height of the maximum ESEG wind and the base and top of the ESEG layer more elevated in the warm half (late spring through early fall) of the year than the cold half. However, the monthly mean maximum wind speeds, which vary around 10 m/s, appear to be independent of season. A typical synoptic pattern accompanying ESEGs is characterized by opposite air masses to the east (cold) and west (warm) of Xinjiang. A strong low-level west-east pressure gradient helps push cold air to enter Xinjiang from the east, which subsequently induces a north-south pressure gradient across the Tianshan Mountains. This regional pressure gradient combined with terrain channelling leads to the development of ESEGs. A comparison of boundary layer structure between days with/without ESEGs in winter shows that the ESEG days are accompanied by deeper (average of 900 m) and more intense (average 6 °C) inversion, but there is little difference in the cold air pool Froude Number between the two types of days. • A climatology of shallow foehn on the lee side of the central Tianshan Mountains in northwestern China is produced; • Regional pressure gradients combined with terrain channelling lead to the development of shallow foehn events • A deeper, more intense surface-based inversion usually accompanies a shallow foehn event [ABSTRACT FROM AUTHOR]

• Developed a new filter method – unscented weighted ensemble Kalman filter (UWEnKF). • UWEnKF is a highly effective and practical assimilation technique. • UWEnKF has better performance than EnKF. A new data assimilation technique, unscented weighted ensemble Kalman filter (UWEnKF) was developed based on the scaled unscented transformation and ensemble Kalman filter (EnKF). In UWEnKF, the individual members selected are unequally weighted and symmetric about the expectation. To investigate the performance of UWEnKF, nine assimilation experiments with different ensemble sizes (161, 1601, 16001) and different assimilation frequencies (every 6 h, every 12 h, every 24 h) were designed to assimilate soil surface (5 cm) moisture data observed at station HY in the upper reaches of the Yellow River, in the northeastern of Tibetan plateau, China into the Richards equation. The results showed that the performance of the filter was greatly affected by random noise, and the filter was sensitive to ensemble size and assimilation frequency. Increasing the ensemble size reduced the effects of random noise on filter performance in several independent assimilation runs (i.e., it decreased the differences between the results of the several independent assimilation runs). Reducing the assimilation frequency also reduced the effects of random noise on filter performance. UWEnKF gave more accurate soil moisture model results than EnKF for all ensemble sizes and assimilation frequencies at all soil depths. Additionally, EnKF may have different performances according to different initial conditions, but not for UWEnKF. Precipitation and soil properties uncertainties had some impact on filter performance. Thus, UWEnKF is a better choice than EnKF, while it is more computationally demanding, for improving soil moisture predictions by assimilating data from many sources, such as satellite-observed soil moisture data, at a low assimilation frequency (e.g., every 24 h). [ABSTRACT FROM AUTHOR]

Improving flood modeling accuracy is crucial for real-time flood monitoring and early warning systems. Knowing the sources, patterns and driving factors of model uncertainty aids the development of more accurate flood predictions. This study investigates the consistency of two global flood inundation products, i.e., the Soil Moisture Active Passive (SMAP) satellite based fractional water (Fw) cover and the Global Flood Monitoring System (GFMS) modeled flood inundation. Using Pearson's correlation coefficient (r) as the indicator of the SMAP-GFMS model consistency, this research documents the spatial and temporal patterns of the correlations between the two flood products, and investigates factors affecting these relationships, including climate, land cover, hydrology and terrain distributions. Results reveal that globally, 64% locations have moderate to strong SMAP-GFMS correlation (r ≥ 0.4). Locations that are dry and have low biomass and high seasonal flood variability tend to have high correlation; for example, 47% locations with r ≥ 0.4 occur in tropical and arid climate zones, and 43% locations with r ≥ 0.4 are observed in Barren , Evergreen Broadleaf Forest , Grasslands , Open Shrubland and Savannahs. Also, larger rivers have higher correlation, and in each Strahler stream order there are 60% to 65% locations having r ≥ 0.4. Larger watersheds show higher SMAP-GFMS consistency in particular watersheds between 1000 and 40,000 km2. Regions with greater urban infrastructure tend to have lower correlation, while locations with lower elevations and relatively flat topography have higher SMAP-GFMS consistency. This study indicates that GFMS and SMAP provide complementary information on surface water storage variations influencing precipitation driven runoff and flooding, which may enable enhanced global flood predictions. • Consistency of SMAP-derived and GFMS-modeled flood inundation is investigated. • 64% locations have moderate to strong SMAP-GFMS correlation. • Rivers with high Strahler stream orders show high SMAP-GFMS consistency. • Areas with dry climate, low/flat topography, low biomass show high consistency. • GFMS and SMAP provide complementary information on surface water dynamics. [ABSTRACT FROM AUTHOR]

Background: Traditional Chinese Medicine (TCM) has gained global attention, particularly after Professor Youyou Tu was awarded the Nobel Prize for her discovery of artemisinin as a treatment for malaria. However, the theory behind TCM is often perceived as a "black-box" with complex components and an unclear structure and mechanism of action. This had hindered the development of TCM within the framework of modern medicine., Aim of Review: The molecular compatibility theory proposed by Professor Tian Xie's team integrates TCM with Western medicine in clinical practice, and provide a feasible direction for TCM modernization. It is necessary to summarize and popularize this theory. This review aims to systematically introduce this theory to provide some new insight for development of TCM., Key Scientific Concepts of Review: According to the molecular compatibility theory, the desired effects can be achieved by organically combining multiple active molecules from TCM. These TCM molecular compounds have specific ingredients, precise mechanisms, and controllable quality that meet the standards of modern medicine. The molecular compatibility theory has guided the development of antitumor new drug elemene emulsions, and has also revealed extensive compatibility between TCM-derived active molecules and other TCM, Western medicine, or biomaterials. This discovery opens up potential TCM-based treatment options. In conclusion, the molecular compatibility theory holds promise as a strategy for modernizing TCM., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Production and hosting by Elsevier B.V.)

Background: The incidence of multiple primary cancers (MPC), especially involving primary lung cancer (PLC) and primary hematologic malignancies (PHM), is rising. This study aims to analyze clinicopathological features, gene abnormalities, and prognostic outcomes in individuals diagnosed with PLC-PHM MPC., Methods: A retrospective analysis included 89 patients diagnosed with PLC-PHM MPC at the Respiratory or Hematology Departments of Ruijin Hospital from 2003 to 2022 (a total of 842,047 people). Next-generation sequencing (NGS) assessed lung cancer specimens, while Polymerase Chain Reaction (PCR) and NGS were used for hematologic malignancy specimens. Statistical analysis involved survival analysis and Cox regression., Results: PLC-PHM MPC incidence surged from 1.67 per year (2011-2013) to 16.3 per year (2020-2022). The primary demographic for PLC-PHM MPC consists predominantly of elderly (average age 66 years) males (59.6%), with a high prevalence of metachronous MPC (89.9%). The prevailing histological types were lung adenocarcinoma (70.8%) in lung cancer (LC) and mature B-cell lymphomas (50.6%) in hematologic malignancies (HM). Notably, in a molecular testing cohort of 38 LC patients, 84.2% of lung cancer cases exhibited driver mutations, in which EGFR mutations frequence prevalent was 74.2%. In total group of 85 cases achieved a median overall survival (mOS) of 46.2 months, with a 5-year survival rate of 37.9% and advanced LC patients with LC gene mutations achieved a mOS was 52.6 months, with a 5-year OS rate of 30.6%. The median progression-free survival (PFS) following first-line treatment of 11 advanced patients with lung cancer-associated driver gene mutations is 26.6 months. Multivariate Cox regression revealed a favorable OS associated with surgery for LC, favorable PS score, adenocarcinoma pathology of LC, and the presence of genetic abnormalities associated with HM., Conclusion: PLC-PHM MPC incidence is rising, characterized by a significant proportion of lung adenocarcinoma and a high prevalence of positive driver genes, especially in EGFR. Despite suffering from two primary tumors, the PLC-PHM MPC patients had superior data of both PFS and OS, suggesting an inherently intricate background of genetic abnormalities between the two kinds of tumors., (© 2024. The Author(s).)

Tumor metastasis contributes to the low overall survival of tumor patients, while transforming growth factor-β (TGFβ) has been recognized as a prominently promoting factor in the development of tumor metastasis. Platelets reserve abundant TGFβ, which will be secreted to peripheral blood after activation, and they are the dominant source of circulating TGFβ. Therefore, downregulation of platelet-derived TGFβ is expected to inhibit the metastasis of circulating tumor cells. Here, unfolded human serum albumin (HSA)-coated perfluorotributylamine (PFTBA) nanoparticles were constructed to display a favorable platelet delivery and an antiplatelet effect to downregulate platelet-derived TGFβ in vitro and in blood plasma. PFTBA@HSA-mediated TGFβ downregulation impaired epithelial-mesenchymal transition of tumor cells as well as their migration and invasion behaviors and enhanced immune surveillance of NK cells. Intravenous injection of PFTBA@HSA effectively reduced tumor metastasis on the lungs or liver to improve the survival rate of mice on multiple metastatic models, including CT26 colon cancer, B16F10 melanoma, and 4T1 breast cancer. Compared with the clinical antiplatelet drug ticagrelor, PFTBA@HSA reduced bleeding risk when displaying a favorable downregulation on platelet-derived TGFβ, thereby obtaining a higher therapy benefit. Together, this study confirmed that downregulation of platelet-derived TGFβ by PFTBA@HSA will be a potential approach and therapeutic candidate for the prevention of tumor metastasis.

Thrombosis is a major contributor to global disease burden. Antiplatelet therapy is the critical approach to prevent thrombosis by reducing platelet reactivity. However, classical antiplatelet strategies generally interfere with platelet integrin α IIb β 3 -mediated platelet activation, thereby facing severe bleeding risk. To break the limitation, we described an integrin α IIb β 3 -independent antiplatelet method by cytosolic delivery of nanoscale perfluorocarbon (PFC) to platelets via albumin carrier. Denatured albumin was found to build high affinity with platelets to mediate cytosolic PFC delivery. While, cytosolic PFC impaired cytoskeleton reorganization during platelet activation to inhibit relevant platelet functions, but avoided to interfere with integrin α IIb β 3 . We proved that this α IIb β 3 -indenpendent antiplatelet pattern showed potential antiplatelet effect with low bleeding risk to prevent thrombosis in various thrombosis models. Together, cytosolic PFC delivery via albumin is a promising antiplatelet approach, and will provide an alternative regimen for current antithrombotic therapy., Competing Interests: Declaration of Competing Interest The authors declare that they have no competing interests., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: The rechallenge of immune checkpoint inhibitors (ICI) is now an optional strategy for patients who discontinued ICI due to immune-related adverse events (irAEs) or disease progression. However, little data is available for the prognosis and prognostic factors of patients receiving ICI rechallenge treatment in advanced lung cancer patients. Our study aimed to explore the efficacy, prognosis and safety of patients who received anti-programmed cell death-1/programmed cell death ligand 1 (anti-PD-1/PD-L1) inhibitor rechallenge., Methods: In our retrospective cohort study, data of advanced lung cancer patients who received anti-PD-1/PD-L1 inhibitor and discontinued due to irAEs or disease progression were collected from December 2016 to August 2021. Enrolled patients were categorized into two groups: rechallenge group (R group) and non-rechallenge group (NR group). Progression-free survival (PFS), overall survival (OS), disease control rate (DCR) and safety data were analyzed. Cox model and subgroup analysis were analyzed according to baseline characteristics, ICI type, the reason for discontinuing ICI, etc. According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1), evaluation was performed routinely every 6-8 weeks after initiating treatment with the PD-1/PD-L1 inhibitor. The last follow-up in the study was on September 20, 2021., Results: Eighty-one patients who met our inclusion criteria were enrolled. In the whole cohort, the R group achieved better OS than the NR group [hazard ratio (HR) =0.176; 95% confidence interval (CI): 0.065-0.477; P=0.001). In the irAEs group, the survival analyses showed a trend toward improved OS in the rechallenge subgroup (HR =0.287; 95% CI: 0.081-1.025; P=0.055), and a promising DCR of 75% after an ICI rechallenge. Additionally, the exploration of safety outcomes indicated an acceptable recurrence rate (22.5%) of irAEs and an early onset of irAEs after an ICI rechallenge. In the disease progression group, the rechallenge subgroup did not improve OS (HR =0.214; 95% CI: 0.027-1.695; P=0.144), and the DCR of the rechallenge subgroup was 40% after ICI rechallenge., Conclusions: ICI rechallenge might be an attractive option for patients who discontinue treatment due to irAEs. For patients with disease progression, further research should be conducted. The recurrence of irAEs and their early onset during the second round of ICI should be considered., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-22-360/coif). DWD reports receiving payment for lectures, presentations, speakers bureaus, manuscript writing or educational events by Roche, BMS, MSD, Pfizer and Astra Zeneca. The other authors have no conflicts of interest to declare., (2022 Translational Lung Cancer Research. All rights reserved.)

This study aimed to evaluate the performance of cisplatin-loaded polymeric micelles (CDDP-PMs) with different drug/copolymer ratios of 1:1, 1:3 and 1:6 (w/w) prepared by coordinated complexation and self-assembly method. The mass ratio influenced the self-assembly behaviors and the complex degree, where both single- and double- complexation existed in CDDP-PMs. With the increase of CDDP/copolymer ratio, the particle size and drug loading increased, while encapsulation efficiency decreased. The PEG density of CDDP-PM 1-6 , CDDP-PM 1-3 and CDDP-PM 1-1 were 0.20, 0.61 and 0.38 PEG/nm 2 , respectively. CDDP-PM 1-3 and CDDP-PM 1-6 had similar sustained release behavior, while CDDP-PM 1-1 showed burst release. Pharmacokinetics showed the AUC of CDDP-PM 1-6 , CDDP-PM 1-3 and CDDP-PM 1-1 was 27.2, 76.6 and 13.0 fold higher than CDDP solution. Tissue distribution presented the platinum concentration of CDDP-PM 1-6 , CDDP-PM 1-3 and CDDP-PM 1-1 was 1.03, 0.80 and 0.48 times of CDDP solution in kidney at 10 min, and 17.61, 28.63 and 16.6 times in tumor at 48 h respectively, indicating CDDP-PMs significantly reduced nephrotoxicity and increased tumor-targeting accumulation. In vivo antitumor test showed that CDDP-PMs exhibited an improved antitumor efficacy and lower systemic toxicity compared with CDDP solution. From CDDP-PM 1-1 to CDDP-PM 1-6 , the toxicity decreased with the increase of copolymer ratio, but the tumor inhibition rate also decreased. CDDP-PM 1-3 had relative high therapeutic effect and low toxicity compared with other formulations. CDDP-PM 1-3 could improve the antitumor efficacy by increasing the dose within systemic tolerability, but CDDP solution cannot. This work provides an effective strategy by modulating drug/copolymer ratio of CDDP-PMs to balance the antitumor efficacy and toxicity for better payoff. STATEMENT OF SIGNIFICANCE: Cancer chemotherapy always exists a contradiction between antitumor efficacy and toxicity. Higher efficacy against tumor often associated with larger toxicity for normal tissues. This work provides an important strategy by modulating the drug/copolymer ratios to balance the antitumor efficacy and toxicity to obtain better payoff. The cisplatin-loaded polymeric micelles (CDDP-PMs) based on the complexation between CDDP and copolymer with different mass ratios make differences in vitro and in vivo because of the single- or double-complexation degree. Most importantly, we found the balance at CDDP/copolymer ratio of 1:3, which has relative high therapeutic effect and low toxicity compared with other formulations. CDDP-PM 1-3 could improve the antitumor efficacy by increasing the dose within systemic tolerability, but CDDP solution cannot., (Copyright © 2019 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

Current research was to evaluate the capacity and molecular interaction of ion pair/phospholipid complex during preparation of clarithromycin intravenous lipid microsphere (CLA-LM) for improving drug-loading, stability and antibacterial activity. The optimum pH range for the presence of ion pair formed by CLA and cholesteryl hemisuccinate (CHEMS) was found to be between 6.4 and 8.2. CLA-LM prepared by ion pair/phospholipid complex possessed improved drug-loading (5-10 mg/ml), plasma stability, storage stability (24 months at 4 ± 2℃) and better activity for multi-drug-resistant Mycobacterium tuberculosis (MIC = 0.058 μg/ml). The release profile in vitro was pH-sensitive and greater in more acidic condition, which was effective for pathological targeting. CLA-LM presented controlled release and low drug leakage in plasma. Langmuir monolayer showed that the incorporation of CHEMS obviously improved interfacial molecular interactions of the mixed monolayer. The ordering and condensing effect of CHEMS resulted in higher collapse surface pressure and smaller limiting area, as well as reduced compression modulus. Close aggregate network distribution with particular micro domains in atomic force microscopy images reflected the enhanced miscibility and thermodynamic stability. The change of the spatial location and protonation degree of CHEMS resulted from the aqueous subphase pH value from 6 to 8 was observed. More acidic environment allowed for better molecular interaction and interface behavior. These results indicated that CHEMS enhances the phospholipid packing to achieve stable CLA-encapsulation in phospholipid interface and identify the preference of ion pair/phospholipid complex as a valuable delivery strategy to develop CLA formulations for improving drug-loading, stability and antibacterial activity., (Copyright © 2018 Elsevier B.V. All rights reserved.)

The clinical application of disulfiram (DSF) in cancer treatments is hindered by its rapid degradation in the blood circulation. In this study, methoxy poly(ethylene glycol)- b-poly(lactide- co-glycolide)/poly(ε-caprolactone) (mPEG 5k - b-PLGA 2k /PCL 3.4k ) micelles were developed for encapsulation of DSF by using the emulsification-solvent diffusion method. Medium chain triglyceride (MCT) was incorporated into the mixed polymeric micelles to improve drug loading by reducing the core crystallinity. Differential scanning calorimetry (DSC) results implied that DSF is likely present in an amorphous form within the micelles, and is well dispersed. DSF is encapsulated within the core and the reservoir is stabilized by the hydrophilic shell to prevent rapid diffusion of DSF from the core. The DSF mixed micelles (DSF-MMs) showed good drug loading (5.90%) and a well-controlled particle size (86.4 ± 13.2 nm). The mixed micelles efficiently protected DSF from degradation in plasma, with 58% remaining after 48 h, while almost 90% of DSF was degraded after the same period for the DSF solution (DSF-sol), which was used as a control. The pharmacokinetics study showed that the maximum plasma concentration and bioavailability of DSF were improved by using the DSF-MMs (2 and 2.5 times that of the DSF-sol). The TIRs (tumor inhibition rates) of 5-FU, DSF-sol, and DSF-MMs were 63.46, 19.57, and 69.98%, respectively, implying that DSF-MMs slowed the growth of a H22 xenograft tumor model effectively.