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Gemini quaternary ammonium-incorporated biodegradable multiblock polyurethane micelles for brain drug delivery

机译：Gemini季铵掺入的可生物降解多嵌段用于脑药递送的聚氨酯胶束

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摘要

Brain drug delivery is still facing significant challenges due to the low permeability of the blood-brain barrier (BBB). To overcome such an insurmountable obstacle, we developed gemini quaternary ammonium (GQA) as a cell penetrating molecule incorporated into biodegradable multiblock poly(epsilon-caprolactone urethanes)s(BMPUs) drug nanocarriers for improvement of drug accumulation in brain parenchyma. The zeta potential of Dox-loaded GQA-BMPUs micelles was around 26 mV with a mean particle size near 100 nm. It was found that GQA-BMPUs micelles achieved steadily time-dependent and concentration-dependent Dox accumulation in human brain microvascular endothelial cells (HBMECs) much higher than GQA-free BMPUs micelles and free Dox, as confirmed by flow cytometry and confocal laser scanning microscopy (CLSM) experiments. Meanwhile, no pronounced cytotoxicity was noticed in GQA-BMPUs micelles and GQA-free BMPUs micelles, and Dox associated cytotoxicity might be reduced once encapsulated into micelles. More importantly, CLSM of brain sections showed higher accumulation of Dox-loaded GQABMPUs micelles in the subcortical area after administrated intravenously, while no Dox accumulation was observed in either Dox-BMPUs micelles or free Dox formulation. Coupling with in vivo pharmacokinetics, biodistribution and histological toxicity studies, the results show that GQA introduced into drug nanocarriers is a promising avenue to transport therapeutic agents across BBB and improve brain drug accumulation.
机译：由于血脑屏障（BBB）的低渗透性，脑药输送仍面临重大挑战。为了克服这种难以克服的障碍，我们开发了Gemini季铵（GQA）作为一种细胞穿透分子，其掺入可生物降解的多嵌段聚（ε-己内酯氨基甲酸酯）的（BMPU）药物纳米载体，用于改善脑实质的药物积累。 DOX加载的GQA-BMPU胶束的Zeta电位约为26mV，平均粒度接近100nm。发现GQA-BMPU胶束在人脑微血管内皮细胞（HBMEC）中稳定地依赖于依赖于时间依赖性和浓度依赖性的DOX积累，远高于GQA的BMPU胶束和游离DOX，如流式细胞术和共聚焦激光扫描显微镜证实（CLSM）实验。同时，在GQA-BMPU胶束中没有发现明显的细胞毒性，并且可以在胶束中封装成胶束后减少DOX相关的细胞毒性。更重要的是，在静脉内施用后，脑切片的CLSM在皮下面积中显示出在皮下区域中的DOX加载的GQABMPU胶束积聚，同时在DOX-BMPU胶束或自由DOX制剂中没有观察到DOX积累。结果与体内药代动力学，生物分布和组织学毒性研究相结合，结果表明，GQA引入药物纳米载体是一种有前途的途径，用于在BBB上运送治疗剂并改善脑药积累。

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  • 来源
    《RSC Advances》 |2015年第8期|共12页
  • 作者

    Liang Rui-Chao; Fang Fang; Wang Yan-Chao; Song Ni-Jia; Li Jie-Hua; Zhao Cheng-Jian; Peng Xing-Chen; Tong Ai-Ping; Fang Yuan; He Min; You Chao; Tan Hong;

  • 作者单位

    Sichuan Univ West China Hosp Dept Neurosurg Chengdu 610041 Sichuan Peoples R China;

    Sichuan Univ West China Hosp Dept Neurosurg Chengdu 610041 Sichuan Peoples R China;

    Sichuan Univ West China Hosp Dept Neurosurg Chengdu 610041 Sichuan Peoples R China;

    Sichuan Univ Coll Polymer Sci &

    Engn State Key Lab Polymer Mat Engn Chengdu 610065 Peoples R China;

    Sichuan Univ Coll Polymer Sci &

    Engn State Key Lab Polymer Mat Engn Chengdu 610065 Peoples R China;

    Sichuan Univ West China Hosp State Key Lab Biotherapy &

    Canc Ctr Chengdu 610041 Peoples R China;

    Sichuan Univ West China Hosp State Key Lab Biotherapy &

    Canc Ctr Chengdu 610041 Peoples R China;

    Sichuan Univ West China Hosp State Key Lab Biotherapy &

    Canc Ctr Chengdu 610041 Peoples R China;

    Sichuan Univ West China Hosp Dept Neurosurg Chengdu 610041 Sichuan Peoples R China;

    Sichuan Univ West China Hosp Dept Neurosurg Chengdu 610041 Sichuan Peoples R China;

    Sichuan Univ West China Hosp Dept Neurosurg Chengdu 610041 Sichuan Peoples R China;

    Sichuan Univ Coll Polymer Sci &

    Engn State Key Lab Polymer Mat Engn Chengdu 610065 Peoples R China;

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