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Photo-induced crosslinked and anti-PD-L1 peptide incorporated liposomes to promote PD-L1 multivalent binding for effective immune checkpoint blockade therapy

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Acta Pharmaceutica Sinica B 2024年第3期14卷 1428-1440页

作者： Youngjoo Lee Sukyung Song Suah Yang Jinseong Kim Yujeong Moon Nayeon shim Hong Yeol Yoon Sehoon Kim man kyu shim Kwangmeyung Kim KU-KIST Graduate School of Converging Science and Technology Korea UniversitySeoul 02841Republic of Korea Medicinal Materials Research Center Biomedical Research DivisionKorea Institute of Science and Technology(KIST)Seoul 02792Republic of Korea College of Pharmacy Graduate School of Pharmaceutical SciencesEwha Womans UniversitySeoul 03760Republic of Korea Department of Bioengineering Korea UniversitySeoul 02841Republic of Korea

Immune checkpoint blockade(ICB)therapy targeting PD-L1 via monoclonal antibody(m Ab)has shown extensive clinical benefits in the diverse types of advanced ***,most patients are completely refractory to ICB therapy owing to the PD-L1 recycling ***,we propose photo-induced crosslinked and anti-PD-L1 peptide incorporated liposomes(immune checkpoint blockade liposomes;ICB-LPs)to promote PD-L1 multivalent binding for inducing lysosomal degradation of PD-L1 in tumor *** ICB-LPs are prepared by formulation of DC_(8,9)PC with photo-polymerized diacetylenic moiety,1,2-dipalmitoylphosphatidylcholine(DPPC)and anti-PD-L1peptide(D-form NYSKPTDRQYHF)-conjugated DSPE-PEG_(2k)(anti-PD-L1-DSPE-PEG_(2k))in a molar ratio of 45:45:10,followed by cross-linking of liposomal bilayer upon UV *** 10 mol% antiPD-L1-DSPE-PEG_(2k)incorporated ICB-LPs have a nano-sized lipid bilayer structure with an average diameter of 137.7±1.04 nm,showing a high stability in serum ***,the ICB-LPs efficiently promote the multivalent binding with PD-L1 on the tumor cell membrane,which are endocytosed with aim to deliver PD-L1 to the lysosomes,wherein the durable PD-L1 degradation is observed for72 h,in contrast to anti PD-L1 m Abs showing the rapid PD-L1 recycling within 9 *** in vitro coculture experiments with CD8^(+)T cells show that ICB-LPs effectively enhance the T cell-mediated antitumor immune responses against tumor cells by blocking the PD-L1/PD-1 *** ICB-LPs are intravenously injected into colon tumor-bearing mice,they efficiently accumulate within the targeted tumor tissues via both passive and active tumor targeting,inducing a potent T cell-mediated antitumor immune response by effective and durable PD-L1 ***,this study demonstrates the superior antitumor efficacy of crosslinked and anti-PD-L1 peptide incorporated liposome formulation that promotes PD-L1 multivalent binding for trafficking of PD-L1 toward

关键词： Cancer immunotherapy Immune checkpoint blockade PEGylated liposome Crosslinked lipid nanoparticles Anti-PD-L1 peptide Tumor-targeting PD-L1 multivalent binding Lysosomal PD-L1 degradation

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Cathepsin B-responsive prodrugs for cancer-targeted therapy:Recent advances and progress for clinical translation

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Nano Research 2022年第8期15卷 7247-7266页

作者： Seong Ik Jeon Suah Yang man kyu shim Kwangmeyung Kim Biomedical Research Institute Korea Institute of Science and Technology(KIST)Seoul 02792Republic of Korea KU-KIST Graduate School of Converging Science and Technology Korea UniversitySeoul 02841Republic of Korea

The cathepsin B-responsive prodrugs are promising strategies to reduce the serious adverse effects of anticancer drugs by improving the cancer selectivity that can be specifically activated by overexpressed cathepsin B in targeted cancer ***,clinical translation of such therapeutic approaches has been restricted by low antitumor efficacy that is mainly attributable to undesirable pharmacokinetic profiles and inefficient tumor-targeting of cathepsin B-responsive prodrugs,due to their small-molecule *** recent decades,many researchers have widely investigated the drug delivery system(DDS)to improve the in vivo pharmacokinetic profiles and tumor-targeting efficiency of cathepsin B-responsive prodrugs via the application of polymers,dendrimers,antibodies,lipids,and inorganic nanoparticles as drug *** addition,the potential therapeutic efficacy of DDS for cathepsin B-responsive prodrugs is demonstrated in multiple studies and combinatorial treatment with typical therapeutic modalities can effectively overcome the challenges of tumor heterogeneity and multidrug *** this review,recent advances and progress of new DDS for cathepsin B-responsive prodrugs are outlined,and their clinical trials are ***,potential challenges and the outlooks for clinical translation of cathepsin B-responsive prodrugs are highlighted.

关键词： cathepsin B prodrug chemotherapy drug delivery system targeted cancer therapy

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All-in-one glycol chitosan nanoparticles for co-delivery of doxorubicin and anti-PD-L1 peptide in cancer immunotherapy

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Bioactive Materials 2023年第10期28卷 358-375页

作者： Sukyung Song man kyu shim Suah Yang Jaewan Lee Wan Su Yun Hanhee Cho Yujeong Moon Jin Young Min Eun Hee Han Hong Yeol Yoon Kwangmeyung Kim College of Pharmacy Graduate School of Pharmaceutical SciencesEwha Womans UniversitySeoul03760Republic of Korea Medicinal Materials Research Center Biomedical Research DivisionKorea Institute of Science and Technology(KIST)Seoul02792Republic of Korea KU-KIST Graduate School of Converging Science and Technology Korea UniversitySeoul02841Republic of Korea Department of Bioengineering Korea UniversitySeoul02841Republic of Korea Research Center for Bioconvergence Analysis Korea Basic Science Institute(KBSI)Cheongju28119Republic of Korea Department of Toxicology College of PharmacyChungnam National UniversityDaejeon34134Republic of Korea

Synergistic immunotherapy of immune checkpoint blockade (ICB) and immunogenic cell death (ICD) has shown remarkable therapeutic efficacy in various cancers. However, patients show low response rates and undesirable outcomes to these combination therapies owing to the recycling mechanism of programmed death-ligand 1 (PD-L1) and the systemic toxicity of ICD-inducing chemotherapeutic drugs. Herein, we propose all-in-one glycol chitosan nanoparticles (CNPs) that can deliver anti-PD-L1 peptide (PP) and doxorubicin (DOX) to targeted tumor tissues for a safe and more effective synergistic immunotherapy. The PP-CNPs, which are prepared by conjugating ᴅ-form PP (NYSKPTDRQYHF) to CNPs, form stable nanoparticles that promote multivalent binding with PD-L1 proteins on the targeted tumor cell surface, resulting in effective lysosomal PD-L1 degradation in contrast with anti-PD-L1 antibody, which induces recycling of endocytosed PD-L1. Consequently, PP-CNPs prevent subcellular PD-L1 recycling and eventually destruct immune escape mechanism in CT26 colon tumor-bearing mice. Moreover, the ICD inducer, DOX is loaded into PP-CNPs (DOX-PP-CNPs) for synergistic ICD and ICB therapy, inducing a large number of damage-associated molecular patterns (DAMPs) in targeted tumor tissues with minimal toxicity in normal tissues. When the DOX-PP-CNPs are intravenously injected into CT26 colon tumor-bearing mice, PP and DOX are efficiently delivered to the tumor tissues via nanoparticle-derived passive and active targeting, which eventually induce both lysosomal PD-L1 degradation and substantial ICD, resulting in a high rate of complete tumor regression (CR: 60%) by a strong antitumor immune response. Collectively, this study demonstrates the superior efficacy of synergistic immunotherapy using all-in-one nanoparticles to deliver PP and DOX to targeted tumor tissues.

关键词： Chitosan nanoparticle Synergistic immunotherapy Immune checkpoint blockade Multivalent binding Immunogenic cell death

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Extension and Design of Securc Dynamic Updates in Domain Name Systems

Extension and Design of Securc Dynamic Updates in Domain Nam...

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亚太地区通信会议暨光电子通信会议

作者： Young-Chul shim Hee-Won shim man-Hee Lee OK-Hwan Byeon Hong-Ik University Dept.of Computer Engineering 72-1 Sangsudong Mapogu Seoul Korea 121-791 Hong-Ik University Dept.of Computer Engineering 72-1 Sangsudong Mapogu Seoul Korea 121-791 ETRl Supercomputer Center Taejon Korea ETRl Supercomputer Center Taejon Korea

Recent IETF proposals for the secure dynamic updatesin the DNS dictate that any DNS update requests arerestricted to the same zone as the requester. This limitsthe flexibility and applicability of many servers such asCA servers. In this paper we propose to use two morebits in the DNS header section to define the scope of thezones over which a dynamic update key has an updateaccess right. These bits are called scope control *** also describe how requests for dynamic updates canbe generated and processed in the resolver and the DNSservers using these scope control bits

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Case of Fitz-Hugh-Curtis syndrome in male without presentation of sexually transmitted disease

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World Journal of Clinical Cases 2015年第11期3卷 965-969页

作者： Haram Yi Chan Sup shim Gyu Won Kim Jung Seok Kim In Zoo Choi Department of Internal Medicine Sahmyook Seoul Hospital Global Digestive Disease Center Department of Internal Medicine Konkuk University Medical Center

Fitz-Hugh-Curtis syndrome is a type of perihepatitis that causes liver capsular infection without infecting the hepatic parenchyma or pelvis. Fitz-Hugh-Curtis syndrome is known to occur commonly in women of childbearing age who do not use oral contraceptives and have sexual partners older than 25 years of age. However, the syndrome has been reported to occur rarely in males. The clinical symptoms are right upper quadrant pain and tenderness, and pleuritic right sided chest pain. The clinical presentation is similar in male and female. We experienced a case of Fitz-HughCurtis syndrome in a 60-year-old man with the chief complaint of right upper quadrant abdominal pain. Despite a previous history of gonorrhea, we have also described our experiences of improved symptoms and recovery with allopathic medicines and have thereby reported the present case with a literature review.

关键词： Male Right upper quadrant pain Fitz-Hugh-Curtis syndrome Perihepatitis Sexually transmitted disease Liver capsular infection

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HPLC同时测定槐角丸中生药槐角的4种有效成分

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中国中药杂志 2005年第19期30卷 1513-1515页

作者：边清泉杨振萍刘家琴刘思曼绵阳师范学院四川绵阳621000 西南科技大学四川绵阳621000

目的:建立测定槐角丸中游离染料木苷、芸香苷、槲皮素和染料木素的反相高效液色谱测定法.方法:shim-pack Vp-ODS色谱柱(4.6mm×150mm,5 μm);MeOH-H2O-HAc(40:60:0.25)为流动相;检测波长为256 nm;柱温30℃.结果:染料木苷在0.059～0.352... 详细信息

目的:建立测定槐角丸中游离染料木苷、芸香苷、槲皮素和染料木素的反相高效液色谱测定法.方法:shim-pack Vp-ODS色谱柱(4.6mm×150mm,5 μm);MeOH-H2O-HAc(40:60:0.25)为流动相;检测波长为256 nm;柱温30℃.结果:染料木苷在0.059～0.352μg、芸香苷在0.435～2.610μg、槲皮素在0.020～0.121μg、染料木素在0.053～0.319μg线性关系良好,r分别为0.999 6,0.998 2,0.998 9,0.999 9,4组分平均回收率在98.7%～100.2%,RSD分别为1.21%,1.36%,0.47%,1.54%(n=5).结论:该方法同时测定4种有效成分,方便、准确、灵敏度高,重复性好,可适用于槐角丸质控.

关键词： HPLC 槐角丸芸香苷染料木苷染料木素槲皮素

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固相支持液-液萃取/液相色谱-串联质谱法测定人全血中环孢素A

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分析测试学报 2018年第11期37卷 1371-1375页

作者：利利贾叶青张倩影张爱国王曼曼李冬梅王学生华北理工大学公共卫生学院河北唐山063210 华北理工大学附属医院河北唐山063000 华北理工大学药学院河北唐山063210

采用固相支持液-液萃取/液相色谱-串联质谱(LC-MS/MS)技术建立了人全血中环孢素A的分析方法。全血样品经蛋白沉淀后,上样至固相支持液-液萃取柱,经甲基叔丁基醚洗脱,shim-pack XR-ODS色谱柱(75 mm×3. 0 mm i. d.,2. 2μm)分离,电喷雾... 详细信息

采用固相支持液-液萃取/液相色谱-串联质谱(LC-MS/MS)技术建立了人全血中环孢素A的分析方法。全血样品经蛋白沉淀后,上样至固相支持液-液萃取柱,经甲基叔丁基醚洗脱,shim-pack XR-ODS色谱柱(75 mm×3. 0 mm i. d.,2. 2μm)分离,电喷雾电离源、正离子模式和多反应监测模式下采集数据,以环孢素D为内标物定量。结果表明,环孢素A在1. 5～500μg/L范围内呈良好的线性关系,相关系数(r)为0. 998,检出限和定量下限分别为0. 5μg/L和1. 5μg/L,在50、100、400μg/L 3个加标浓度下的平均回收率为78. 6%～83. 5%,日内和日间相对标准偏差(n=3)分别为3. 1%～5. 6%和4. 5%～8. 3%。该方法操作简便、灵敏度高,可用于全血中环孢素A的分析。

关键词：环孢素A 全血固相支持液-液萃取液相色谱-串联质谱法

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RP-HPLC在线衍生法测定红景天中痕量铅的研究

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化学研究与应用 2006年第5期18卷 588-590页

作者：刘思曼边清泉唐英张进李方绵阳师范学院化学与化学工程系四川绵阳621000 重庆文理学院化学与环境科学系重庆永川402168 四川大学化学学院四川成都610064

A new RP-HPLC method for the determination of lead in Rhodiola species was established on a shim-pack Vp-ODS column（150 mm×4.6 mm I.D.,5μm） at UV 255 *** column temperature is ***（Salicyladehyde）o-phenydnediiminato was used as a on line derivate agent and MeOH-H2O-derivate agent（65:33.5:1.5,v/v） was made use of mobile *** method was applied for the determination of lead and the lineal range of lead is 0.1352-0.6759ng（r=0.9989）.The average recovery is 99.2% with RSD being 2.9%（n=5）.

关键词： RP-HPLC 在线衍生双水杨醛邻苯二胺铅(Ⅱ)络合物红景天

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QuEChERS-超高效液相色谱-串联质谱法快速测定豆制品中二甲基黄和碱性嫩黄O的含量

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食品安全质量检测学报 2016年第12期7卷 4753-4758页

作者：李锦清綦艳廖桂福陈满英广东产品质量监督检验研究院国家食品质量监督检验中心(广东)佛山528300

目的建立QuEChERS结合超高效液相色谱-串联质谱法（QuEChERS-ultra performance liquid chromatography-tandem mass spectrometry,QuEChERS-UPLC-MS/MS）快速测定豆制品中二甲基黄和碱性嫩黄O的含量。方法豆制品经20 m L乙腈-水（1：1,V：V）浸泡,采用QuEChERS方法进行萃取、净化,经shim-pack XR-ODSⅢ色谱柱分离,正离子扫描,多反应监测模式进行质谱分析,外标法定量。结果二甲基黄在添加水平为0.5、1和10μg/kg时,方法回收率为81.6%~97.2%;碱性嫩黄O在添加水平为6、10和50μg/kg时,方法回收率为89.1%~100.7%;二甲基黄和碱性嫩黄O的相对标准偏差均小于12%（n=6）;二甲基黄和碱性嫩黄O的检出限分别为0.5、2μg/kg;定量限分别为1.5、6μg/kg。结论该方法操作简便、快速准确,适用于豆制品中二甲基黄、碱性嫩黄O的快速筛查和定量分析。

关键词： QuEChERS 超高效液相色谱-串联质谱法二甲基黄碱性嫩黄O 豆制品

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高效液相色谱测定广西生鲜乳中的维生素A

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中国乳品工业 2012年第5期40卷 58-60页

作者：段玉林苏骏吴雪张少梅温韬梁梦宇陈小聪蒙泳周曼宗玉英广西产品质量监督检验院南宁530022 广西壮族自治区环境监测中心站南宁530022 广西壮族自治区质量技术监督局南宁530022

为了建立生鲜乳中维生素A的一种快速、准确、灵敏度高的检测方法,样品经皂化后,经石油醚提取,浓缩后采用高效液相色谱法,以shim-pack VP-ODS柱(4.6 mm×150 mm,5μm),柱温35℃,检测波长325 nm,流动相为甲醇∶水(98∶2,体积比),流速1.0 m... 详细信息

为了建立生鲜乳中维生素A的一种快速、准确、灵敏度高的检测方法,样品经皂化后,经石油醚提取,浓缩后采用高效液相色谱法,以shim-pack VP-ODS柱(4.6 mm×150 mm,5μm),柱温35℃,检测波长325 nm,流动相为甲醇∶水(98∶2,体积比),流速1.0 mL/min的条件进行实验。结果维生素A在0.174～87.2μg/mL范围内线性关系良好,相关系数r=0.9999,平均回收率为98.17%,RSD=1.90%。建立的方法准确、可靠,可以用于生鲜乳中维生素A的含量检测。

关键词：生鲜乳维生素A 高效液相色谱

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