已入深夜,您辛苦了!由于当前在线用户较少,发布求助请尽量完整地填写文献信息,科研通机器人24小时在线,伴您度过漫漫科研夜!祝你早点完成任务,早点休息,好梦!

Increasing Linker Chain Length and Intestinal Stability Enhances Lymphatic Transport and Lymph Node Exposure of Triglyceride Mimetic Prodrugs of a Model Immunomodulator Mycophenolic Acid

前药 化学 淋巴 淋巴系统 连接器 药理学 生物化学 亲脂性 生物 免疫学 医学 病理 计算机科学 操作系统
作者
Sifei Han,Tim Quach,Luojuan Hu,Shea F. Lim,Dan Zheng,Nathania Leong,Garima Sharma,Daniel K. Bonner,Jamie S. Simpson,Natalie L. Trevaskis,Christopher J. H. Porter
出处
期刊:Molecular Pharmaceutics [American Chemical Society]
卷期号:20 (5): 2675-2685 被引量:3
标识
DOI:10.1021/acs.molpharmaceut.3c00099
摘要

Targeted delivery of immunomodulators to the lymphatic system has the potential to enhance therapeutic efficacy by increasing colocalization of drugs with immune targets such as lymphocytes. A triglyceride (TG)-mimetic prodrug strategy has been recently shown to enhance the lymphatic delivery of a model immunomodulator, mycophenolic acid (MPA), via incorporation into the intestinal TG deacylation–reacylation and lymph lipoprotein transport pathways. In the current study, a series of structurally related TG prodrugs of MPA were examined to optimize structure–lymphatic transport relationships for lymph-directing lipid-mimetic prodrugs. MPA was conjugated to the sn-2 position of the glyceride backbone of the prodrugs using linkers of different chain length (5–21 carbons) and the effect of methyl substitutions at the alpha and/or beta carbons to the glyceride end of the linker was examined. Lymphatic transport was assessed in mesenteric lymph duct cannulated rats, and drug exposure in lymph nodes was examined following oral administration to mice. Prodrug stability in simulated intestinal digestive fluid was also evaluated. Prodrugs with straight chain linkers were relatively unstable in simulated intestinal fluid; however, co-administration of lipase inhibitors (JZL184 and orlistat) was able to reduce instability and increase lymphatic transport (2-fold for a prodrug with a 6-carbon spacer, i.e., MPA-C6-TG). Methyl substitutions to the chain resulted in similar trends in improving intestinal stability and lymphatic transport. Medium- to long-chain spacers (C12, C15) between MPA and the glyceride backbone were most effective in promoting lymphatic transport, consistent with increases in lipophilicity. In contrast, short-chain (C6–C10) linkers appeared to be too unstable in the intestine and insufficiently lipophilic to associate with lymph lipid transport pathways, while very long-chain (C18, C21) linkers were also not preferred, likely as a result of increases in molecular weight reducing solubility or permeability. In addition to more effectively promoting drug transport into mesenteric lymph, TG-mimetic prodrugs based on a C12 linker resulted in marked increases (>40 fold) in the exposure of MPA in the mesenteric lymph nodes in mice when compared to administration of MPA alone, suggesting that optimizing prodrug design has the potential to provide benefit in targeting and modulating immune cells.
最长约 10秒,即可获得该文献文件

科研通智能强力驱动
Strongly Powered by AbleSci AI
更新
PDF的下载单位、IP信息已删除 (2025-6-4)

科研通是完全免费的文献互助平台,具备全网最快的应助速度,最高的求助完成率。 对每一个文献求助,科研通都将尽心尽力,给求助人一个满意的交代。
实时播报
zty123发布了新的文献求助10
1秒前
lQ发布了新的文献求助20
2秒前
EvaHo完成签到,获得积分10
3秒前
小新爱看文献完成签到,获得积分10
3秒前
寒天完成签到 ,获得积分10
4秒前
桃子牛肉酱完成签到 ,获得积分10
9秒前
joker完成签到 ,获得积分10
14秒前
16秒前
科目三应助CheetahAzure采纳,获得10
16秒前
leclerc完成签到,获得积分10
17秒前
李李发布了新的文献求助30
17秒前
19秒前
19秒前
20秒前
72101394发布了新的文献求助10
21秒前
junyang发布了新的文献求助10
23秒前
HoHo完成签到 ,获得积分10
23秒前
量子星尘发布了新的文献求助10
24秒前
李李完成签到,获得积分20
24秒前
Guesss发布了新的文献求助10
26秒前
26秒前
平淡如天完成签到,获得积分10
27秒前
fufufu123完成签到 ,获得积分10
28秒前
fogsea完成签到,获得积分0
29秒前
孙意冉完成签到,获得积分10
31秒前
健康的大门完成签到,获得积分10
31秒前
SOESAN完成签到,获得积分10
32秒前
drzz发布了新的文献求助10
32秒前
Raunio完成签到,获得积分10
36秒前
tt完成签到 ,获得积分10
40秒前
72101394完成签到,获得积分20
40秒前
haha完成签到,获得积分10
41秒前
芯之痕发布了新的文献求助10
41秒前
Orange应助科研通管家采纳,获得10
43秒前
星辰大海应助科研通管家采纳,获得10
43秒前
传奇3应助科研通管家采纳,获得10
43秒前
Hayat应助科研通管家采纳,获得10
43秒前
半城微凉应助科研通管家采纳,获得10
43秒前
在水一方应助科研通管家采纳,获得10
43秒前
科研通AI2S应助科研通管家采纳,获得10
43秒前
高分求助中
A new approach to the extrapolation of accelerated life test data 1000
Picture Books with Same-sex Parented Families: Unintentional Censorship 700
ACSM’s Guidelines for Exercise Testing and Prescription, 12th edition 500
Nucleophilic substitution in azasydnone-modified dinitroanisoles 500
不知道标题是什么 500
Indomethacinのヒトにおける経皮吸収 400
Phylogenetic study of the order Polydesmida (Myriapoda: Diplopoda) 370
热门求助领域 (近24小时)
化学 材料科学 医学 生物 工程类 有机化学 生物化学 物理 内科学 纳米技术 计算机科学 化学工程 复合材料 遗传学 基因 物理化学 催化作用 冶金 细胞生物学 免疫学
热门帖子
关注 科研通微信公众号,转发送积分 3976600
求助须知:如何正确求助?哪些是违规求助? 3520674
关于积分的说明 11204422
捐赠科研通 3257298
什么是DOI,文献DOI怎么找? 1798683
邀请新用户注册赠送积分活动 877842
科研通“疑难数据库(出版商)”最低求助积分说明 806595