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一种基于聚酰胺-胺（PAMAM）树枝状大分子的纳米复合材料经原位凝胶实现鼻脑转运的可行策略。

An Available Strategy for Nasal Brain Transport of Nanocomposite Based on PAMAM Dendrimers via In Situ Gel.

作者信息

Xie Huichao, Li Lingjun, Sun Yue, Wang Yuzhen, Gao Shuang, Tian Yuan, Ma Xuemei, Guo Chengcheng, Bo Fumin, Zhang Li

机构信息

College of Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan 250355, China.

College of Graduate, Shandong University of Traditional Chinese Medicine, Jinan 250355, China.

出版信息

Nanomaterials (Basel). 2019 Jan 24;9(2):147. doi: 10.3390/nano9020147.

DOI:10.3390/nano9020147
PMID:30682799
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6409925/
Abstract

Polyamidoamine (PAMAM) dendrimers are efficient drug carriers. The presence of a physiological pathway for nasal brain transport provides a potential path for direct brain-targeted delivery of dendrimer nanocomposites. In this study, we synthesized PAMAM dendrimer composites with a nanoscale size; the particle size of PAE (Paeonol)/mPEG (the heterofunctional PEG polymer with a methoxy)-PAMAM G5.NHAc and mPEG-PAMAM G5.NH₂-FITC were 72.41 ± 11.58 nm and 96.51 ± 7.77 nm, and the zeta potential of PAE/mPEG-PAMAM G5.NHAc and mPEG-PAMAM G5.NH₂-FITC were + 0.57 ± 0.11 mv and + 9.60 ± 0.41 mv, respectively. The EE% and DL% of PAE in PAE/mPEG-PAMAM G5.NHAc were 53.77% and 13.92%, respectively. PAE/mPEG-PAMAM G5.NHAc/DGG ionic-sensitive in situ gel was prepared, the viscosity of solution and gel state were 112 ± 3.2 mPa and 1403 ± 38.5 mPa, respectively. The in vitro goat mucoadhesive strength of the gel was 4763.36 ± 85.39 dyne/cm². In situ gel system was proven to be a non-Newtonian pseudo-plastic fluid with shear thinning, thixotropy and yield stress. The optimal model of PAE released from PAE/mPEG-PAMAM G5.NHAc and PAE/mPEG-PAMAM G5.NHAc/DGG were the Higuchi equation and the Korsmeyer-Peppas equation, respectively. The cytotoxicity of the nanocomposites showed a concentration-dependence, and the cell viabilities of PAE/mPEG-PAMAM G5.NHAc were both higher than 95% between 0.0001 μM and 10 μM. mPEG-PAMAM G5.NH₂-FITC was efficiently taken up by cells and exhibited strong fluorescence in the cytoplasm and nucleus. Significant accumulation of nanocomposites was observed in the brain after administration of the in situ gel group, and maximum accumulation was reached at 12 h. A small amount of accumulation was observed in the nanocomposite solution group only at 2 h. Therefore, the direct nasal brain transport efficiency of PAMAM dendrimer nanocomposites can be significantly improved after combining with in situ gel. PAMAM dendrimer nanocomposite/DGG is a potential drug delivery system for nasal brain transport.

摘要

聚酰胺-胺（PAMAM）树枝状大分子是高效的药物载体。存在经鼻脑转运的生理途径为树枝状大分子纳米复合材料的直接脑靶向递送提供了一条潜在途径。在本研究中，我们合成了纳米级尺寸的PAMAM树枝状大分子复合材料；丹皮酚（PAE）/甲氧基聚乙二醇（mPEG，具有甲氧基的异功能聚乙二醇聚合物）-PAMAM G5.NHAc和mPEG-PAMAM G5.NH₂-FITC的粒径分别为72.41±11.58nm和96.51±7.77nm，PAE/mPEG-PAMAM G5.NHAc和mPEG-PAMAM G5.NH₂-FITC的ζ电位分别为+0.57±0.11mV和+9.60±0.41mV。PAE在PAE/mPEG-PAMAM G5.NHAc中的包封率（EE%）和载药量（DL%）分别为53.77%和13.92%。制备了PAE/mPEG-PAMAM G5.NHAc/DGG离子敏感型原位凝胶，溶液和凝胶态的黏度分别为112±3.2mPa和1403±38.5mPa。该凝胶在体外山羊鼻黏膜的黏附强度为4763.36±85.39达因/cm²。原位凝胶体系被证明是一种具有剪切变稀、触变性和屈服应力的非牛顿假塑性流体。PAE从PAE/mPEG-PAMAM G5.NHAc和PAE/mPEG-PAMAM G5.NHAc/DGG中释放的最佳模型分别为Higuchi方程和Korsmeyer-Peppas方程。纳米复合材料的细胞毒性呈浓度依赖性，在0.0001μM至10μM之间，PAE/mPEG-PAMAM G5.NHAc的细胞活力均高于95%。mPEG-PAMAM G5.NH₂-FITC被细胞有效摄取，并在细胞质和细胞核中呈现强荧光。原位凝胶组给药后在脑中观察到纳米复合材料的显著蓄积，在12h达到最大蓄积量。纳米复合材料溶液组仅在2h观察到少量蓄积。因此，与原位凝胶联合后，PAMAM树枝状大分子纳米复合材料的经鼻脑直接转运效率可显著提高。PAMAM树枝状大分子纳米复合材料/DGG是一种潜在的经鼻脑转运药物递送系统。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/54f3/6409925/0e1bee3aff4c/nanomaterials-09-00147-g010.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/54f3/6409925/c3c0ef6a607b/nanomaterials-09-00147-sch002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/54f3/6409925/5d6435391169/nanomaterials-09-00147-sch003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/54f3/6409925/cdb7ee418141/nanomaterials-09-00147-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/54f3/6409925/0e7be151cc87/nanomaterials-09-00147-g002.jpg
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