载低分子肝素（LMWH）的大孔 PEG-PLGA 颗粒用于哮喘治疗。
Low-molecular-weight heparin (LMWH)-loaded large porous PEG-PLGA particles for the treatment of asthma.
机构信息
Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Science Center , Amarillo, TX 79106.
出版信息
J Aerosol Med Pulm Drug Deliv. 2014 Feb;27(1):12-20. doi: 10.1089/jamp.2013.1073. Epub 2013 Nov 28.
BACKGROUND
Heparin-like compounds interrupt leukocyte adhesion and migration, and prevent release of chemical mediators during the process of inflammation. However, little is known whether the anti-inflammatory property of smaller heparin fragments, low-molecular-weight heparin (LMWH), plays any role in the process of airway inflammation. In this study, we sought to evaluate the efficacy of LMWH-loaded large porous polyethylene glycol-poly(D,L-lactide-co-glycolide) (PEG-PLGA) particulate formulations in alleviating the cellular and biochemical changes associated with asthma.
METHODS
To study the pharmacological efficacy of LMWH for the treatment of asthma, we have used a previously optimized polymeric formulation of LMWH. The anti-asthmatic efficacy of the optimized formulation was studied in an ovalbumin-sensitized rat model of asthma. The influence of the formulation on asthmatic lungs was assessed by measuring the total protein content and number of inflammatory cells in the bronchoalveolar lavage fluid (BALF). Lungs were also examined for morphological and structural changes that may occur in asthmatic lungs.
RESULTS
Compared with healthy animals, asthmatic animals showed a seven- and threefold increase in the protein content and number of inflammatory cells in BALF, respectively. However, intratracheal LMWH particles reduced the protein content by 2.5-fold and the number of inflammatory cells by 1.8-fold-comparable to those of sham animals. Similarly, LMWH particles reduced the lactate dehydrogenase levels by 2.8- and threefold in BALF and plasma, respectively. The airway wall thickness also decreased from 47.37±6.02 μm to 21.35±3.60 μm upon treatment with PEG-PLGA particles of LMWH. Goblet cell hyperplasia was also reduced in asthmatic rats treated with LMWH particles.
CONCLUSION
PLGA particles of LMWH were efficacious in improving cellular and histological changes associated with asthma, and thus this polymeric formulation has the potential for further development into a clinically viable anti-asthma therapy.
背景
肝素样化合物可阻断白细胞黏附和迁移，并在炎症过程中阻止化学介质的释放。然而，人们对于小分子肝素片段（低分子肝素，LMWH）的抗炎特性是否在气道炎症过程中发挥作用知之甚少。在本研究中，我们旨在评估载有 LMWH 的大孔聚乙二醇-聚（D，L-丙交酯-co-乙交酯）（PEG-PLGA）颗粒制剂在缓解与哮喘相关的细胞和生化变化方面的疗效。
方法
为了研究 LMWH 治疗哮喘的药效学，我们使用了先前优化的 LMWH 聚合物制剂。在卵清蛋白致敏的哮喘大鼠模型中研究了该优化制剂的抗哮喘疗效。通过测量支气管肺泡灌洗液（BALF）中的总蛋白含量和炎症细胞数来评估该制剂对哮喘肺的影响。还检查了肺部的形态和结构变化，这些变化可能发生在哮喘肺中。
结果
与健康动物相比，哮喘动物的 BALF 中的蛋白含量和炎症细胞数分别增加了七倍和三倍。然而，与哮喘动物相比，LMWH 颗粒经气管内给药可使蛋白含量降低 2.5 倍，炎症细胞数降低 1.8 倍。同样，LMWH 颗粒分别使 BALF 和血浆中的乳酸脱氢酶水平降低 2.8 倍和 3 倍。气道壁厚度也从 47.37±6.02μm 降低至 LMWH 的 PEG-PLGA 颗粒治疗后的 21.35±3.60μm。用 LMWH 颗粒治疗后，哮喘大鼠的杯状细胞增生也减少了。
结论
LMWH 的 PLGA 颗粒在改善与哮喘相关的细胞和组织学变化方面是有效的，因此该聚合物制剂具有进一步开发为可行的抗哮喘治疗方法的潜力。
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