Application of Nano-Delivery Systems in Lymph Nodes for Tumor Immunotherapy

Immunotherapy has become a promising research“hotspot”in cancer treatment.“Soldier”immune cells are not uniform throughout the body;they accumulate mostly in the immune organs such as the spleen and lymph nodes(LNs),etc.The unique structure of LNs provides the microenvironment suitable for the survival,activation,and proliferation of multiple types of immune cells.LNs play an important role in both the initiation of adaptive immunity and the generation of durable anti-tumor responses.Antigens taken up by antigen-presenting cells in peripheral tissues need to migrate with lymphatic fluid to LNs to activate the lymphocytes therein.Meanwhile,the accumulation and retaining of many immune functional compounds in LNs enhance their efficacy significantly.Therefore,LNs have become a key target for tumor immunotherapy.Unfortunately,the nonspecific distribution of the immune drugs in vivo greatly limits the activation and proliferation of immune cells,which leads to unsatisfactory anti-tumor effects.The efficient nano-delivery system to LNs is an effective strategy to maximize the efficacy of immune drugs.Nano-delivery systems have shown beneficial in improving biodistribution and enhancing accumulation in lymphoid tissues,exhibiting powerful and promising prospects for achieving effective delivery to LNs.Herein,the physiological structure and the delivery barriers of LNs were summarized and the factors affecting LNs accumulation were discussed thoroughly.Moreover,developments in nano-delivery systems were reviewed and the transformation prospects of LNs targeting nanocarriers were summarized and discussed.

ODA二胺单体双酮酐型聚酰亚胺的合成与性能

以4,4'-对苯二甲酰二邻苯二甲酸酐(TDPA)为二酐单体,4,4'-二氨基二苯醚(4,4'-ODA)和3,4'-二氨基二苯醚(3,4'-ODA)为二胺单体,采用两步法低温溶液缩聚分别合成了2种聚酰亚胺(PI)。采用红外光谱、X射线衍射、差示扫描量热分析、热重分析、拉伸强度测试等对聚合物的结构与性能进行了表征。研究结果表明,制得的聚酰亚胺均具有良好的成膜性,PI(4,4'-ODA)膜的拉伸强度达到262 MPa,玻璃化转变温度(Tg)为297℃; PI(3,4'-ODA)膜的拉伸强度为149 MPa,Tg为261℃。热分解温度都在520℃以上,具有优良的耐热性能及力学性能。

可溶性含萘环结构聚醚酮酮醚酮酮的合成

以1-萘酚和1,4-二(4-氟苯羰基)苯为起始原料,经亲核取代反应,合成了一种新的含萘环结构芳醚单体1,4-[4-(1-萘氧基)苯羰基]苯(BNOBB)。以路易斯酸无水三氯化铝(AlCl 3)为催化剂,将该单体与对苯二甲酰氯(TPC)和间苯二甲酰氯(IPC)进行缩聚,合成了一种主链含萘环结构的无规共聚物聚醚酮酮醚酮酮(PEKKEKK)。采用傅里叶变换红外光谱仪、核磁共振、差示扫描量热仪、热重分析仪和广角X射线衍射等技术手段对PEKKEKK树脂的结构和性能进行测试。结果表明,该树脂为非晶态结构,具有较高的玻璃化转变温度(T g>181℃)和热分解温度(T 5%>502℃);易溶解于氯仿、1,2-二氯乙烷、N,N-二甲基乙酰胺等有机溶剂中,可涂膜获得透明薄膜;拉伸强度大于83 MPa,力学性能较好。

含联苯聚芳醚砜醚酮酮无规共聚物的合成与表征

以新合成的含联苯芳醚单体4,4’-二(4-联苯氧基)二苯砜(BBPOPS)与4,4’-二苯氧基二苯砜(DPODPS)、对苯二甲酰氯(TPC)为单体,以路易斯酸无水三氯化铝(AlCl_(3))为催化剂进行三元共缩聚,制备了大分子主链含联苯结构的聚芳醚砜醚酮酮(PESEKK)无规共聚物。通过核磁共振仪、红外光谱仪、差示扫描量热仪、广角X射线衍射和紫外-可见分光光度计等分析方法表征了PESEKK无规共聚物的结构与性能。实验结果表明,在大分子主链引入联苯结构能提高PESEKK无规共聚物的耐热性,玻璃化转变温度(T_(g))高于189℃,且T_(g)随着共聚物中联苯结构含量的增加而升高;PESEKK无规共聚物为非晶态结构,其热分解温度(T_(d))为544℃,具有优异的热性能。无规共聚物可溶解于二甲基亚砜、N-甲基吡咯烷酮、氯仿等有机溶剂,并可涂膜制得柔韧性薄膜,薄膜拉伸强度大于84 MPa,弹性模量大于1.89GPa,力学性能较好。

Design of integrated radar and communication system based on MIMO-OFDM waveform

Orthogonal frequency division multiplexing(OFDM)waveform enables radar and communication functions simultaneously, which encounters low angle resolution and poor data rate for traditional single input single output(SISO) systems. To solve these problems, an integrated radar and communication system(IRCS) with multiple input multiple output(MIMO) OFDM waveform is proposed. The different limitations of radar and communication in designing such a system are investigated. Then, an optimization problem is devised to obtain suitable system parameters, including the number of subcarriers, subcarrier spacing, number of symbols,pulse repetition frequency(PRF) and length of cyclic prefix(CP).Finally, to satisfy the requirements of both radar and communication, the IRCS parameters are derived in three typical cases.Several numerical results are presented to illustrate the demands of radar and communication, inconsistent or consistent, for the IRCS parameters and the superiority of the proposed system.

A Review on Nano-Based Drug Delivery System for Cancer Chemoimmunotherapy

Although notable progress has been made on novel cancer treatments,the overall survival rate and therapeutic effects are still unsatisfactory for cancer patients.Chemoimmunotherapy,combining chemotherapeutics and immunotherapeutic drugs,has emerged as a promising approach for cancer treatment,with the advantages of cooperating two kinds of treatment mechanism,reducing the dosage of the drug and enhancing therapeutic effect.Moreover,nano-based drug delivery system(NDDS)was applied to encapsulate chemotherapeutic agents and exhibited outstanding properties such as targeted delivery,tumor microenvironment response and site-specific release.Several nanocarriers have been approved in clinical cancer chemotherapy and showed significant improvement in therapeutic efficiency compared with traditional formulations,such as liposomes(Doxil R,Lipusu R),nanoparticles(Abraxane R)and micelles(Genexol-PM R).The applications of NDDS to chemoimmunotherapy would be a powerful strategy for future cancer treatment,which could greatly enhance the therapeutic efficacy,reduce the side effects and optimize the clinical outcomes of cancer patients.Herein,the current approaches of cancer immunotherapy and chemoimmunotherapy were discussed,and recent advances of NDDS applied for chemoimmunotherapy were further reviewed.

Nanoparticle‑Loaded Polarized‑Macrophages for Enhanced Tumor Targeting and Cell‑Chemotherapy

Cell therapy is a promising strategy for cancer therapy.However,its therapeutic efficiency remains limited due to the complex and immunosuppressive nature of tumor microenvironments.In this study,the“cell-chemotherapy”strategy was presented to enhance antitumor efficacy.M1-type macrophages,which are therapeutic immune cells with both of immunotherapeutic ability and targeting ability,carried sorafenib(SF)-loaded lipid nanoparticles(M1/SLNPs)were developed.M1-type macrophages were used both as therapeutic tool to provide immunotherapy and as delivery vessel to target deliver SF to tumor tissues for chemotherapy simultaneously.M1-type macrophages were obtained by polarizing macrophages using lipopolysaccharide,and M1/SLNPs were obtained by incubating M1-type macrophages with SLNP.Tumor accumulation of M1/SLNP was increased compared with SLNP(p<0.01),which proved M1/SLNP could enhance tumor targeting of SF.An increased ratio of M1-type macrophages to M2-type macrophages,and the CD3^+CD4^+T cells and CD3^+CD8^+T cell quantities in tumor tissues after treatment with M1/SLNP indicated M1/SLNP could relieve the immunosuppressive tumor microenvironments.The tumor volumes in the M1/SLNP group were significantly smaller than those in the SLNP group(p<0.01),indicating M1/SLNP exhibited enhanced antitumor efficacy.Consequently,M1/SLNP showed great potential as a novel cellchemotherapeutic strategy combining both cell therapy and targeting chemotherapy.

Amphiphilic small molecular mates match hydrophobic drugs to form nanoassemblies based on drug-mate strategy

Nanomedicine has made great progress in the targeted therapy of cancer. Here, we established a novel drug-mate strategy by studying the formulation of nanodrugs at the molecular level. In the drug-mate combination, the drug is a hydrophobic drug that is poorly soluble in water, and the mate is an amphiphilic small molecule (SMA) that has both hydrophilic and lipophilic properties. We proposed that the hydrophobic drug could co-assemble with a suitable SMA on a nanoscale without additive agents. The proof-ofconcept methodology and results were presented to support our hypothesis. We selected five hydrophobic drugs and more than ten amphiphilic small molecules to construct a library. Through molecular dynamic simulation and quantum chemistry computation,we speculated that the formation of nanoassemblies was related to the binding energy of the drug-mate, and the drug-mate interaction must overcome drug-drug interaction.Furthermore, the obtained SF/VECOONa nanoassemblieswas selected as a model, which had an ultra-high drug loading content (46%), improved pharmacokinetics, increased bioavailability, and enhanced therapeutic efficacy. In summary, the drug-mate strategy is an essential resource to design exact SMA for many hydrophobic drugs and provides a reference for the design of a carrier-free drug delivery system.

Gas-blasting nanocapsules to accelerate carboplatin lysosome release and nucleus delivery for prostate cancer treatment

To improve therapeutic effect and reduce severely side effects of carboplatin(CBP),the gas-generating nanocapsules were developed to accelerate CBP lysosome release and nucleus delivery.CBP/SB-NC was prepared by co-loading CBP and NaHCO 3(SB)in nanocapsules using w/o/w emulsification solvent evaporation.They exhibited vesicle-like spherical morphology,uniform particle size and negative zeta potential.Reaching the tumor site with a relatively high concentration is the first step for CBP delivery and the results showed that CBP/SB-NC could effectively increase drug accumulation at tumor site.After that,the drug delivery carriers need to be internalized into tumor cells and the in vitro cellular uptake ability results showed CBP/SB-NC could be internalized into RM-1 cells more efficient than CBP solution.After internalized by RM-1 cells,the gas-blasting release process was tested in acid environment.It was demonstrated that 5 mg/ml NaHCO 3 was optimal to achieve pH-responsive gas-blasting release.In vitro release results showed that CBP significantly rapid release in acid environment(pH 5.0)compared to neutral pH(pH 7.4)(P<0.05).Meanwhile,TEM and the change of the concentration of H+results exhibited that the explosion of CBP/SB 5-NC was more easily happened in lysosome acid environment(pH 5.0).The blasting release can accelerate CBP lysosome release to cytoplasm.Furthermore,the nucleus delivery results showed CBP/SB 5-NC can promote pH-triggered rapid nucleus delivery.And the results of Pt-DNA adduct assay showed that the binding efficiency between CBP and DNA of CBP/SB 5-NC was higher than CBP solution.At last,in vitro and in vivo anti-tumor efficacy proved that CBP/SB 5-NC could enhance anti-tumor activity for prostate cancer therapy.CBP/SB 5-NC also showed superior safety in vitro and in vivo by hemolysis assay and histopathological study.All of the results demonstrate that CBP/SB 5-NC would be an efficient gas-blasting release formulation to enhance prostate cancer treatment.

Dynamic Changes of Tobacco-growing Soil Nutrients and Enzymes After Application of Amelioration Materials

[Objectives]This study was conducted to clarify the improvement effects of different soil amelioration materials such as lime,green manure and bio-organic fertilizer on acidic tobacco-planting soil.[Methods]The dynamic changes of soil pH,soil nutrients and enzyme activity were studied by applying lime,lime+green fertilizer,and lime+green fertilizer+biological organic fertilizer.[Results]①After the application of amelioration materials,the soil pH and available phosphorus content of tobacco-growing soil showed a stepwise change of first increasing and then decreasing,and became stable at 60 d after tobacco transplanting;the soil organic matter,alkali-hydrolyzable nitrogen and available potassium content showed a gradual change trend of"high-low-high";and the soil invertase and urease activity showed a gradual change trend of"low-high-low".②To 90 d after tobacco transplanting,the application of amelioration materials increased soil pH by 1.29-1.62 units,and increased organic matter content by 15.21%-20.86%,alkali-hydrolyzable nitrogen content by 6.83%-18.17%,available phosphorus content by 54.15%-217.85%,rapidly available potassium content by 11.42%-30.86%,soil invertase activity by 70.09%-18.93%,and soil urease activity by 64.07%-130.47%.③The combination of lime+green manure+alkaline microbial organic fertilizer had the best effect on the improvement of acidic tobacco-growing soil,and the effect of lime+green manure+acid microbial organic fertilizer on acidic soil was the second.[Conclusions]When applying lime,green fertilizer and alkaline bio-organic fertilizer should be applied to achieve sustainable improvement of strongly acidic soil.

Characteristics of gas-liquid diaphragm discharge and its application on decolorization of brilliant red B in aqueous solution

A simple gas-liquid diaphragm discharge reactor was designed and characteristics of the discharge and its application on decolorization of brilliant red B in an aqueous solution were investigated. The results showed that strong oxidizing agents such as ·OH and ·O radicals were generated. Average electron temperature of the discharge was 0.72 eV, 1.15 eV and 0.83 eV with air, oxygen and argon as the discharge gas, respectively. Solution p H and conductivity changed little when oxygen or argon was used as the discharge gas; however, these two parameters changed significantly when the discharge was performed in air. During the discharge treatment,the characteristic absorption peaks of brilliant red B gradually decreased where the decolorization followed the first-order kinetics. With 10 min of discharge, the decolorization of brilliant red B(30 mg L^(-1)) can reach 96%, 81% and 62% in the cases of oxygen, argon and air,respectively. The analysis of by-products showed that the brilliant red B molecule can be effectively destroyed in this discharge mode.

The patterns and risks for disease spreading of cattle movement in China

In order to reduce the risks for the spread of disease in cattle movements, we investigated China’s cattle breeding and movement pattern, analyzed risk factors of disease infection caused by long-distance movement, explored the relevant risk management measures and conjectured the direction of cattle movement based on the regional distribution of cattle inventory and beef price. We also constructed a market value chain in live cattle movements and qualitatively analyzed the risks for unapparent infection in the process of movement. Meanwhile, we put forward a long-term policy of reducing the risks for unapparent infection and animal health supervision measures.

Optimization of the Ethanol Extraction Method of Monoester Alkaloids from Radix Aconiti Preparata Based on HPLC-MS and Orthogonal Test

[Objectives] This study was conducted to optimize the ethanol extraction technology of monoester alkaloids from Radix Aconiti Preparata. [Methods]On the basis of defined extraction times,ethanol concentration,ethanol times and extraction time were investigated by HPLC-MS combined with orthogonal test to optimize extraction process using the content of monoester alkaloids( the sum of benzoyl neoaconitine,benzoyl hypoaconitine and benzoyl aconitine) as an index.[Results]The optimum ethanol extraction technology was as follows: 75% ethanol,ethanol amount 25 times of the medicinal material,and each extraction for 1. 5 h.[Conclusions] The optimal extraction technology is simple,feasible,stable and reliable. It can provide reference for the industrial production and quality control of monoester alkaloids from Radix Aconiti Preparata.

High catalytic performance of neodymium modified Co_(3)O_(4) for toluene oxidation

Co-based catalysts are the most promising catalysts in catalytic oxidation of volatile organic compounds(VOCs).Precious metal doping is adopted to improve the catalytic activity of toluene on Co_(3)O_(4) catalysts,but greatly increases its cost along with it.It is found that doping a small amount of rare earth(Ce,Pr,Sm and Nd)can dramatically promote the catalytic activity of Co_(3)O_(4).Especially,the Nd-doped Co_(3)O_(4) catalyst exhibits excellent catalytic activity with a toluene removal rate of 90% at 162.1℃,which is even better than that of Pt-doped Co_(3)O_(4).Compared with other rare earth metal doping,the Nd doping leads to a higher ratio of Co^(3+)/Co^(2+) and has more oxygen vacancies.The in situ diffuse reflectance infrared Fourier transform spectroscopy(DRIFTS)experiments show that the lattice oxygen of Nd-Co sample can be utilized at a quite low temperature,while that of pure Co_(3)O_(4) cannot engage in oxidation reaction when the temperature is below 200℃,which visually demonstrates the main reason for the improved catalytic performance of Nd-Co catalyst.

On-demand integrated nano-engager converting cold tumors to hot via increased DNA damage and dual immune checkpoint inhibition

Cancer immunotherapy has become a promising strategy.However,the effectiveness of immunotherapy is restricted in"cold tumors"characterized with insufficient T cells intratumoral infiltration and failed T cells priming.Herein,an on-demand integrated nano-engager(JOT-Lip)was developed to convert cold tumors to hot via"increased DNA damage and dual immune checkpoint inhibition"strategy.JOT-Lip was engineered by co-loading oxaliplatin(Oxa)and JQ1 into liposomes with T-cell immunoglobulin mucin-3 antibodies(Tim-3 mAb)coupled on the liposomal surface by metalloproteinase-2(MMP-2)-sensitive linker.JQ1 inhibited DNA repair to increase DNA damage and immunogenic cell death(ICD)of Oxa,thus promoting T cells intratumoral infiltration.In addition,JQ1 inhibited PD-1/PD-L1 pathway,achieving dual immune checkpoint inhibition combining with Tim-3 mAb,thus effectively promoting T cells priming.It is demonstrated that JOT-Lip not only increased DNA damage and promoted the release of damage-associated molecular patterns(DAMPs),but also enhanced T cells intratumoral infiltration and promoted T cell priming,which successfully converted cold tumors to hot and showed significant anti-tumor and anti-metastasis effects.Collectively,our study provides a rational design of an effective combination regimen and an ideal co-delivery system to convert cold tumors to hot,which holds great potential in clinical cancer chemoimmunotherapy.

Macrophage-camouflaged epigenetic nanoinducers enhance chemoimmunotherapy in triple negative breast cancer

Chemoimmunotherapy has been approved as standard treatment for triple-negative breast cancer(TNBC),but the clinical outcomes remain unsatisfied.Abnormal epigenetic regulation is associated with acquired drug resistance and T cell exhaustion,which is a critical factor for the poor response to chemoimmunotherapy in TNBC.Herein,macrophage-camouflaged nanoinducers co-loaded with paclitaxel(PTX)and decitabine(DAC)(P/D-mMSNs)were prepared in combination with PD-1 blockade therapy,hoping to improve the efficacy of chemoimmunotherapy through the demethylation of tumor tissue.Camouflage of macrophage vesicle confers P/D-mMSNs with tumor-homing properties.First,DAC can achieve demethylation of tumor tissue and enhance the sensitivity of tumor cells to PTX.Subsequently,PTX induces immunogenic death of tumor cells,promotes phagocytosis of dead cells by dendritic cells,and recruits cytotoxic T cells to infiltrate tumors.Finally,DAC reverses T cell depletion and facilitates immune checkpoint blockade therapy.P/D-mMSNs may be a promising candidate for future drug delivery design and cancer combination therapy in TNBC.

Recent advancements and manipulation strategies of colloidal Cs_(2)B^(I)B^(III)X_(6)lead-free halide double perovskite nanocrystals

Double-metallic lead-free halide perovskites,Cs_(2)B^(I)B^(III)X_(6),sharing three-dimensional crystal structure,have been under the spotlight as the promising alternatives for the toxic and instable lead-based counterparts.Interest in Cs_(2)B^(I)B^(III)X_(6)motivates intense research into their colloidal nanocrystals(NCs).Recently,Cs_(2)B^(I)B^(III)X_(6)NCs have made great progress in the optical performance via alloying or doping,but there are still great challenges for optoelectronic applications.In this review,the latest advances of Cs_(2)B^(I)B^(III)X_(6)NCs in synthesis approaches,bandgap engineering,photoluminescence(PL)optimization,and applications are summarized.The focus is put upon the composition-property relationships of Cs_(2)B^(I)B^(III)X_(6)NCs,which is approached by discussing the influences of composition variation on the electronic states,carrier dynamics,and optical properties.The challenges and the corresponding improving strategies in the development of high-effective and stable Cs_(2)B^(I)B^(III)X_(6)NCs for device applications are also highlighted.It is believed that this review can deepen the understanding on this burgeoning material system and shed light on their future research directions.

Micro/nanomotor: A promising drug delivery system for cancer therapy

Micro/nanomotors(MNMs)are small-scale devices that can effectively convert various forms of energy into mechanical motion.Their controllable motility and good permeability have attracted the interest of researchers as promising drug carriers in cancer therapy.Compared with traditional formulations,micro/nanomotor drug delivery systems can greatly improve therapeutic efficiency and reduce the side effects of antitumor drugs.This review mainly discusses the advantages of micro/nanomotor drug delivery systems and the applications of MNMs propelled by exogenous,endogenous,and biohybrid power in cancer therapy.Finally,the main challenges of the applications of micro/nanomotor drug delivery systems,as well as future development trends and opportunities are discussed.

神经肽Y在人脑局灶性皮层发育不良不同Palmini病理亚型间的表达差异

目的探讨不同Palmini病理亚型局灶性脑皮层发育不良(FCD)与正常人脑中神经肽Y(NPY)表达的差异,以及FCD诱发癫痫的机制。方法收集河北省人民医院神经外科自2007年5月至2011年10月收治的行癫痫手术后病理结果符合FCD的患者58例作为试验组。以Palmini分类标准,按病理亚型分为4组:ⅠA组9例、ⅠB组26例、ⅡA组10例、ⅡB组13例。同时取10例正常人脑组织设为对照组。观察FCD患者癫痫发病临床特点,FCD患者及正常人脑中NPY免疫反应阳性细胞数目差异。结果FCDⅡB组癫痫发作频率明显高于其他病理亚型组。FCDⅡB组NPY免疫反应阳性细胞数目与对照组比较明显增加,差异有统计学意义(P<0.05);FCD组中FCDⅠA、FCDⅠB、FCDⅡA各亚型与对照组比较,差异无统计学意义(P>0.05)。结论FCD各病理亚型中FCDⅡB型的NPY免疫反应阳性细胞反应明显,FCDⅡB致痫机制可能与NPY的表达增高有关。

Hybrid constructed wetlands for highly polluted river water treatment and comparison of surface-and subsurface-flow cells

A series of large pilot constructed wetland(CW) systems were constructed near the confluence of an urban stream to a larger river in Xi'an, a northwestern megacity in China, for treating polluted stream water before it entered the receiving water body. Each CW system is a combination of surfaceand subsurface-flow cells with local gravel, sand or slag as substrates and Phragmites australis and Typha orientalis as plants. During a one-year operation with an average surface loading of 0.053 m3/(m2·day), the overall COD, BOD, NH3-N, total nitrogen(TN) and total phosphorus(TP) removals were 72.7% ± 4.5%, 93.4% ± 2.1%, 54.0% ± 6.3%, 53.9% ± 6.0% and 69.4% ± 4.6%, respectively, which brought about an effective improvement of the river water quality. Surface-flow cells showed better NH3-N removal than their TN removal while subsurface-flow cells showed better TN removal than their NH3-N removal. Using local slag as the substrate, the organic and phosphorus removal could be much improved. Seasonal variation was also found in the removal of all the pollutants and autumn seemed to be the best season for pollutant removal due to the moderate water temperature and well grown plants in the CWs.