The enhanced intestinal permeability of infant mice enables oral protein and macromolecular absorption without delivery technology.
The enhanced intestinal permeability of infant mice enables oral protein and macromolecular absorption without delivery technology.
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增强的幼鼠肠道渗透性使口服蛋白质和大分子吸收无需递送技术。
DOI：
10.1016/j.ijpharm.2020.120120
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发表时间：
2021-01-25
影响因子：
5.8
通讯作者：
Whitehead KA
中科院分区：
文献类型：
--
作者：
Gleeson JP;Fein KC;Chaudhary N;Doerfler R;Newby AN;Whitehead KA
大分子药物的口服给药是患者最喜欢的给药途径，因为它是无痛和方便的。在过去的30年里，人们对成人口服蛋白质递送给予了极大的关注。不幸的是，在婴儿中存在对类似努力的突出需求，婴儿是具有不同肠道生理学和治疗需求的患者群体。在这里，我们评估了新生和婴儿小鼠的肠道通透性，以确定口服递送肽和蛋白质药物而不使用渗透促进剂或其他辅助的可行性。使用非外翻肠囊模型，我们发现大分子渗透性依赖于分子大小，小鼠年龄和肠组织类型使用模型葡聚糖。例如，70 kDa FITC-葡聚糖（FD 70）在婴儿小肠组织中的表观渗透性是成人组织的2-5倍。随着小鼠年龄的增长，屏障形成和孔形成紧密连接蛋白的表达分别增加和减少。4 kDa FITC-葡聚糖（FD 4）和FD 70的体内口服吸收在年轻小鼠中显著更高，与成年小鼠相比，80 kDa蛋白质乳铁蛋白的口服吸收增加了4倍。口服灌胃胰岛素（5 IU/kg）可使婴儿2小时和3小时的血糖水平降低20%以上，但对成人无影响。口服胰岛素在婴儿和成人中具有1 IU/kg皮下剂量的药效学效应的35%和<1%，如通过曲线下面积测量的。这些数据表明，婴儿肠道独特的渗漏性质可能支持生物制剂的口服给药，而不需要传统的口服给药技术。
Oral delivery of macromolecular drugs is the most patient-preferred route of administration because it is painless and convenient. Over the past 30 years, significant attention has been paid to oral protein delivery in adults. Unfortunately, there is an outstanding need for similar efforts in infants, a patient population with distinct intestinal physiology and treatment needs. Here, we assess the intestinal permeability of neonatal and infant mice to determine the feasibility of orally delivering peptide and protein drugs without permeation enhancers or other assistance. Using the non-everted gut sac model, we found that macromolecular permeability depended on molecular size, mouse age, and intestinal tissue type using model dextrans. For example, the apparent permeability of 70 kDa FITC-Dextran (FD70) in infant small intestinal tissue was 2–5-fold higher than in adult tissue. As mice aged, the expression of barrier-forming and pore-forming tight junction proteins increased and decreased, respectively. The in vivo oral absorption of 4 kDa FITC-Dextran (FD4) and FD70 was significantly higher in younger mice, and there was a fourfold increase in oral absorption of the 80 kDa protein lactoferrin compared to adults. Oral gavage of insulin (5 IU/kg) reduced blood glucose levels in infants by >20% at 2 and 3 hours but had no effect in adults. Oral insulin had 35% and <1% of the pharmacodynamic effect of a 1 IU/kg subcutaneous dose in infants and adults, as measured by area above the curve. These data indicate that the uniquely leaky nature of the infantile intestine may support the oral delivery of biologics without the need for traditional oral delivery technology.
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影响因子：
5.9
作者：
Hurley WL;Theil PK
通讯作者：
Theil PK
影响因子：
14
作者：
Krug, Susanne M.;Amasheh, Maren;Amasheh, Salah
通讯作者：
Amasheh, Salah
影响因子：
5.3
作者：
Jaramillo, Claudia A. Castro;Belli, Sara;Simon, Silke
通讯作者：
Simon, Silke
DOI：
10.1111/j.1651-2227.1989.tb17932.x
发表时间：
1989-07-01
期刊：
ACTA PAEDIATRICA SCANDINAVICA
影响因子：
--
作者：
AXELSSON, I;JAKOBSSON, I;RAIHA, N
通讯作者：
RAIHA, N
影响因子：
17.1
作者：
Buckley, Stephen T.;Baekdal, Tine A.;Knudsen, Lotte Bjerre
通讯作者：
Knudsen, Lotte Bjerre