In Vivo Brain Delivery and Brain Deposition of Proteins with Various Sizes.
In Vivo Brain Delivery and Brain Deposition of Proteins with Various Sizes.
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不同大小蛋白质的体内脑输送和脑沉积。
DOI：
10.1021/acs.molpharmaceut.9b00763
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发表时间：
2019
影响因子：
4.9
通讯作者：
Siahaan,TerunaJ
中科院分区：
文献类型：
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作者：
Ulapane,KavishaR;Kopec,BrianM;Siahaan,TerunaJ
开发治疗脑部疾病的蛋白质药物是非常具有挑战性的；这是因为由于血脑屏障(BBB)的原因，将它们输送到大脑中是困难的。因此，替代的递送方式需要进一步探索脑内递送蛋白质以诊断和治疗脑部疾病。此前，ADTC5和HAV6多肽已被证明可以促进小分子和中型分子在血脑屏障中的活体输送。本研究评价了ADTC5和HAV6多肽对C57BL/6小鼠脑内15 kDa溶菌酶、65 kDa白蛋白、150 kDa免疫球蛋白单抗和220 kDa纤维连接蛋白等不同大小蛋白质的转运能力。每种蛋白质都被标记了IRdy800CW，并建立了一种使用近红外荧光(NIRF)成像的定量方法来确定进入大脑的蛋白质的量。与对照组相比，ADTC5多肽显著增加了溶菌酶、白蛋白和免疫球蛋白单抗的脑递送，但对纤维连接蛋白的影响不明显。相反，HAV6多肽显著增加溶菌酶的脑递送，但不增加白蛋白和Ig G单抗。因此，每种多肽都有一个可以输送的蛋白质的截止大小。HAV6和ADTC5可影响蛋白在肝、脾、肺、肾、心脏等器官的分布。综上所述，在将不同大小的蛋白质输送到大脑中时，ADTC5是一种比HAV6更好的BBB调节剂，而蛋白质的大小会影响其大脑输送。
It is very challenging to develop protein drugs for the treatment of brain diseases; this is due to the difficulty in delivering them into the brain because of the blood–brain barrier (BBB). Thus, alternative delivery methods need further exploration for brain delivery of proteins to diagnose and treat brain diseases. Previously, ADTC5 and HAV6 peptides have been shown to enhance thein vivobrain delivery of small- and medium-size molecules across the BBB. This study was carried out to evaluate the ability of ADTC5 and HAV6 peptides to enhance delivery of proteins of various sizes, such as 15 kDa lysozyme, 65 kDa albumin, 150 kDa IgG mAb, and 220 kDa fibronectin, into the brains of C57BL/6 mice. Each protein was labeled with IRdye800CW, and a quantitative method using near IR fluorescence (NIRF) imaging was developed to determine the amount of protein delivered into the brain. ADTC5 peptide significantly enhanced brain delivery of lysozyme, albumin, and IgG mAb but not fibronectin compared to controls. In contrast, HAV6 peptide significantly enhanced the brain delivery of lysozyme but not albumin and IgG mAb. Thus, there is a cutoff size of proteins that can be delivered by each peptide. The distribution of delivered protein in other organs such as liver, spleen, lung, kidney, and heart could be influenced by HAV6 and ADTC5. In summary, ADTC5 is a better BBB modulator than HAV6 in delivering various sizes of proteins into the brain, and the size of the protein affects its brain delivery.