マイクロ波誘発脳損傷の治療のためのテトラジン温度感受性in situハイドロゲルの経鼻投与

Intranasal tetrandrine temperature-sensitive in situ hydrogels for the treatment of microwave-induced brain injury.

• Lihua Zhang
• Lulu Pang
• Siqing Zhu
• Jinqiu Ma
• Ruiteng Li
• Yijing Liu
• Lin Zhu
• Xiaomei Zhuang
• Weijia Zhi
• Xiang Yu
• Lina Du
• Hongyan Zuo
• Yiguang Jin

抄録

脳はマイクロ波の影響を最も受けやすい臓器です。しかし、脳内への薬剤の浸透性が悪いため、マイクロ波誘発脳損傷の治療に有効な薬剤はほとんどありません。ここでは、ポロキサマー407と188を用いて経鼻的テトラジン(TET)温度感受性in situハイドロゲル(ISG)を調製した。その特性は、レオロジー特性、in vitroでの薬物放出、粘膜刺激性を含めて評価された。また、薬理作用や脳へのターゲッティング効果についても検討した。高粘性の ISG は鼻腔内に長時間残存し、TET の持続的な放出と明らかな毛様体毒性は認められなかった。鼻腔内温度感受性TET ISGは、マイクロ波によって誘発される空間記憶と自発的探索行動を、モデルと比較してMorris water maze（MWM）とopen field test（OFT）で顕著に改善しました。また、マイクロ波によって誘発された脳損傷を緩和し、脳内カルシウムチャネルの特定のmRNA発現を抑制した。経鼻投与された温度感受性TET ISGsは、経口投与されたTET(8.4h)に比べて短いT(4.8h)で急速に吸収された。経鼻温度感受性TET ISGの脳内ターゲティング指数は経口TETの2.26倍であった。経鼻温度感受性TET ISGは、マイクロ波誘発脳損傷の治療のための有望な脳標的薬であると考えられます。

The brain is the most sensitive organ to microwave radiation. However, few effective drugs are available for the treatment of microwave-induced brain injury due to the poor drug permeation into the brain. Here, intranasal tetrandrine (TET) temperature-sensitive in situ hydrogels (ISGs) were prepared with poloxamers 407 and 188. Its characteristics were evaluated, including rheological properties, drug release in vitro, and mucosal irritation. The pharmacodynamics and brain-targeting effects were also studied. The highly viscous ISGs remained in the nasal cavity for a long time with the sustained release of TET and no obvious ciliary toxicity. Intranasal temperature-sensitive TET ISGs markedly improved the spatial memory and spontaneous exploratory behavior induced by microwave with the Morris water maze (MWM) and the open field test (OFT) compared to the model. The ISGs alleviated the microwave-induced brain damage and inhibited the certain mRNA expressions of calcium channels in the brain. Intranasal temperature-sensitive TET ISGs was rapidly absorbed with a shorter T (4.8 h) compared to that of oral TET (8.4 h). The brain targeting index of intranasal temperature-sensitive TET ISGs was as 2.26 times as that of the oral TET. Intranasal temperature-sensitive TET ISGs are a promising brain-targeted medication for the treatment of microwave-induced brain injury.

Copyright © 2020 Elsevier B.V. All rights reserved.