PEGylation,the controlled covalent conjugation of polyethylene glycol to therapeutics,enhances therapeutic efficacy through optimized pharmacokinetics.However,to date no high-molecular-weight PEGylated small-molecule ...PEGylation,the controlled covalent conjugation of polyethylene glycol to therapeutics,enhances therapeutic efficacy through optimized pharmacokinetics.However,to date no high-molecular-weight PEGylated small-molecule prodrugs have received regulatory approval.This technological gap can be partially attributed to the exponential proliferation of metabolic intermediates resulting from multi-payload conjugation strategies,which introduces unprecedented analytical complexities in metabolite profiling and pharmacokinetic characterization.To address this challenge,we developed a liquid chromatography-triple-quadrupole/time-of-flight mass spectrometry platform for PEG20k-(irinotecan)3,a Phase III clinical candidate.Our methodology employs payload stoichiometry-based chromatographic resolution for clustering isomeric PEG species.Complementarily,diagnostic product ions at m/z 699.83,569.27,and 587.28 enable systematic differentiation between double-loaded,single-loaded,and released irinotecan payload.This approach successfully identifies eight metabolic clusters spanning from PEG-conjugates,cleaved PEG segments,and released small-molecule species.Its demonstrated capacity to deconvolute complex metabolic profiles—through payload-stoichiometry based chromatographic resolution coupled with diagnostic ion analysis—positions this workflow as an attractive tool for accelerating the development of PEGylated small-molecule therapeutics.展开更多
针对恶劣海况下吊装细长杆件产生的双摆现象而带来的作业效率低、风险高以及难以精确定位等问题,提出了一种新型多柔索减摇定姿系统(multi-tagline anti-swing and positioning system,MTAPS),采用多体动力学和牛顿经典力学方法建立MTAP...针对恶劣海况下吊装细长杆件产生的双摆现象而带来的作业效率低、风险高以及难以精确定位等问题,提出了一种新型多柔索减摇定姿系统(multi-tagline anti-swing and positioning system,MTAPS),采用多体动力学和牛顿经典力学方法建立MTAPS的动力学模型。试验数据表明,MTAPS可以有效抑制规则吊重和细长杆件吊重的摆动,在短时间内可使细长杆件吊重趋于相对稳定状态,在设定工况下MTAPS对规则吊重和细长杆件的平均减摇比分别在90%和85%以上。通过动力学仿真分析比较了船舶运动激励下多柔索减摇系统和MTAPS的减摇效果以及动力学特性。基于多柔索减摇系统研制的起重机防摆装置已完成实船应用,为实现海上细长杆件的快速转运和精确定位提供了一种新思路。展开更多
基金support from the National Natural Science Foundation of China(Nos.82030107,82304443,82373944)the Hainan Provincial Natural Science Foundation of China(No.825QN288).
文摘PEGylation,the controlled covalent conjugation of polyethylene glycol to therapeutics,enhances therapeutic efficacy through optimized pharmacokinetics.However,to date no high-molecular-weight PEGylated small-molecule prodrugs have received regulatory approval.This technological gap can be partially attributed to the exponential proliferation of metabolic intermediates resulting from multi-payload conjugation strategies,which introduces unprecedented analytical complexities in metabolite profiling and pharmacokinetic characterization.To address this challenge,we developed a liquid chromatography-triple-quadrupole/time-of-flight mass spectrometry platform for PEG20k-(irinotecan)3,a Phase III clinical candidate.Our methodology employs payload stoichiometry-based chromatographic resolution for clustering isomeric PEG species.Complementarily,diagnostic product ions at m/z 699.83,569.27,and 587.28 enable systematic differentiation between double-loaded,single-loaded,and released irinotecan payload.This approach successfully identifies eight metabolic clusters spanning from PEG-conjugates,cleaved PEG segments,and released small-molecule species.Its demonstrated capacity to deconvolute complex metabolic profiles—through payload-stoichiometry based chromatographic resolution coupled with diagnostic ion analysis—positions this workflow as an attractive tool for accelerating the development of PEGylated small-molecule therapeutics.
文摘针对恶劣海况下吊装细长杆件产生的双摆现象而带来的作业效率低、风险高以及难以精确定位等问题,提出了一种新型多柔索减摇定姿系统(multi-tagline anti-swing and positioning system,MTAPS),采用多体动力学和牛顿经典力学方法建立MTAPS的动力学模型。试验数据表明,MTAPS可以有效抑制规则吊重和细长杆件吊重的摆动,在短时间内可使细长杆件吊重趋于相对稳定状态,在设定工况下MTAPS对规则吊重和细长杆件的平均减摇比分别在90%和85%以上。通过动力学仿真分析比较了船舶运动激励下多柔索减摇系统和MTAPS的减摇效果以及动力学特性。基于多柔索减摇系统研制的起重机防摆装置已完成实船应用,为实现海上细长杆件的快速转运和精确定位提供了一种新思路。
