Ulapane Kavisha R, On Ngoc, Kiptoo Paul, Williams Todd D, Miller Donald W, Siahaan Teruna J
Department of Chemistry, The University of Kansas, Lawrence, KS 66047, USA.
Department of Pharmaceutical Chemistry, The University of Kansas, Lawrence, KS 66047, USA.
Nanotheranostics. 2017;1(2):217-231. doi: 10.7150/ntno.19158. Epub 2017 Jun 8.
There is an urgent need to develop new and alternative methods to deliver functional biomolecules to the brain for diagnosis and treatment of brain diseases. The goal of this study was to evaluate the activity of blood-brain barrier (BBB) modulators (, HAV and ADT peptides) to deliver functional biomolecules (, galbumin, IRdye800cw-cLABL, and cIBR7) to the brains of mice and rats. HAV6, cHAVc3, and ADTC5 peptides but not HAV4 peptide significantly enhanced the brain delivery of 65 kDa galbumin compared to control in Balb/c mice as quantified by magnetic resonance imaging (MRI). Ten-minute pretreatment with ADTC5 peptide still significantly increased brain delivery of galbumin; however, no enhancement was observed after 10-min pretreatment with HAV6. There was no enhancement of galbumin deposition following 40-min pretreatment with ADTC5 or HAV6, suggesting a short duration of the BBB opening for large molecules. ADTC5 peptide also improved the brain delivery of IRdye800cw-cLABL peptide about 3.5-fold compared to control in Balb/c mice as detected by near infrared fluorescence (NIRF). The BBB modulator activity of ADTC5 to deliver cIBR7 peptide was also evaluated using Sprague-Dawley rats. The amount of cIBR7 in the brain was detected by LC-MS/MS. ADTC5 peptide enhanced the delivery of cIBR7 peptide into rat brain about 4-fold compared to control and the intact cIBR7 can be efficiently extracted and detected in rat brain. In conclusion, HAV and ADT peptides enhance the brain delivery of functional peptides (, cLABL and cIBR7) and protein (, 65 kDa galbumin) in two animal models, and the duration of the BBB opening for a large molecule (, galbumin) was short.
迫切需要开发新的和替代方法，将功能性生物分子输送到大脑，用于脑部疾病的诊断和治疗。本研究的目的是评估血脑屏障（BBB）调节剂（HAV和ADT肽）将功能性生物分子（如白蛋白、IRdye800cw-cLABL和cIBR7）输送到小鼠和大鼠大脑的活性。通过磁共振成像（MRI）定量分析，与对照组相比，HAV6、cHAVc3和ADTC5肽而非HAV4肽显著增强了Balb/c小鼠大脑对65 kDa白蛋白的摄取。用ADTC5肽预处理10分钟仍能显著增加大脑对白蛋白的摄取；然而，用HAV6预处理10分钟后未观察到增强作用。用ADTC5或HAV6预处理40分钟后，白蛋白沉积没有增强，这表明大分子打开血脑屏障的持续时间较短。通过近红外荧光（NIRF）检测，与对照组相比，ADTC5肽还使Balb/c小鼠大脑对IRdye800cw-cLABL肽的摄取提高了约3.5倍。还使用Sprague-Dawley大鼠评估了ADTC5输送cIBR7肽的血脑屏障调节活性。通过LC-MS/MS检测大脑中cIBR7的含量。与对照组相比，ADTC5肽使cIBR7肽向大鼠大脑的输送增加了约4倍，并且完整的cIBR7可以在大鼠大脑中有效提取和检测。总之，在两种动物模型中，HAV和ADT肽增强了功能性肽（如cLABL和cIBR7）和蛋白质（如65 kDa白蛋白）向大脑的输送，并且大分子（如白蛋白）打开血脑屏障的持续时间较短。
