Dual pH- and temperature-responsive microparticles for protein delivery to ischemic tissues.
Dual pH- and temperature-responsive microparticles for protein delivery to ischemic tissues.
复制标题
DOI：
10.1016/j.actbio.2013.01.041
复制
发表时间：
2013-05
影响因子：
9.7
通讯作者：
Duvall, Craig L.
中科院分区：
文献类型：
--
作者：
Joshi, Rucha V.;Nelson, Christopher E.;Poole, Kristin M.;Skala, Melissa C.;Duvall, Craig L.
关键词：
可注射的、对温度和pH都敏感的“智能”微球已经被制造出来，并被用于控制向缺血骨骼肌输送治疗性蛋白质。利用N-异丙基丙烯酰胺(NIPAAm)、丙基丙烯酸(PAA)和丙烯酸丁酯(BA)组成的共聚物文库，采用复乳法制备了微球，确定了由57%NIPAAm、18%PAA和25%BA组成的共聚物的最佳配方。在37℃和代表缺血肌的pH(即pH 5.2-7.2)下，这些微球产生持续的、扩散控制的释放，在正常的生理pH(即pH 7.4)下，它们被溶解和快速清除。利用成纤维细胞生长因子2(FGF-2)的传递来证实微球包裹/释放微球后保持了蛋白质的生物活性，这是基于体外培养的NIH3T3成纤维细胞的增殖呈剂量依赖性增加。采用小鼠一侧后肢缺血模型，将微球负载或游离Cy5.5标记的白蛋白注射到缺血小鼠和对照小鼠的腓肠肌中，建立外周动脉疾病模型。在缺血肢体中，在3.5天和7天，通过微球传递的蛋白比注射的游离蛋白有更高的局部滞留(p<；0.05)。然而，在该模型中，通过微球传递的蛋白质的清除量相当于在随后的时间点上对应于缺血恢复的游离蛋白质。最后，对腓肠肌的组织学分析表明，聚合物微球在注射部位附近没有产生任何微观毒性迹象。这些综合结果表明，本文提出的pH和温度响应型微球是一种有希望的可控蛋白输送到缺血组织的技术平台。
Injectable, “smart” microspheres that are sensitive to both temperature and pH have been fabricated and tested for controlled delivery of therapeutic proteins to ischemic skeletal muscle. A library of copolymers composed of N-isopropyl acrylamide (NIPAAm), propyl acrylic acid (PAA), and butyl acrylate (BA) was used to fabricate microspheres using a double emulsion method, and an optimal formulation made from copolymers composed of 57 mol% NIPAAm, 18 mol% PAA, and 25 mol% BA copolymers was identified. At 37°C and pH representative of ischemic muscle (i.e., pH 5.2–7.2), these microspheres produced sustained, diffusion-controlled release, and at normal, physiologic pH (i.e. pH 7.4), they underwent dissolution and rapid clearance. Delivery of fibroblast growth factor 2 (FGF-2) was used to confirm that protein bioactivity was retained following microsphere encapsulation/release based on a dose-dependent increase in NIH3T3 fibroblast proliferation in vitro. Microsphere-loaded or free Cy5.5-labeled albumin was injected into ischemic and control gastrocnemii of mice following unilateral induction of hind limb ischemia to model peripheral arterial disease. In the ischemic limb at day 3.5 and day 7, there was higher local retention of the protein delivered via microspheres relative to injected free protein (p<0.05). However, clearance of protein delivered via microspheres was equivalent to free protein at later time points that correspond to ischemic recovery in this model. Finally, histological analysis of the gastrocnemius revealed that the polymeric microspheres did not produce any microscopic signs of toxicity near the injection site. These combined results suggest that the pH- and temperature-responsive microspheres presented herein are a promising technological platform for controlled protein delivery to ischemic tissue.
登录
查看更多内容
DOI：
10.1111/j.1532-5415.1985.tb02853.x
发表时间：
1985-01-01
影响因子：
6.3
作者：
KANNEL, WB;MCGEE, DL
通讯作者：
MCGEE, DL
影响因子：
5.8
作者：
Leo, Eliana;Ruozi, Barbara;Vandelli, Maria Angela
通讯作者：
Vandelli, Maria Angela
影响因子：
3.3
作者：
Marcinek, David J.;Kushmerick, Martin J.;Conley, Kevin E.
通讯作者：
Conley, Kevin E.
DOI：
10.1016/j.jconrel.2012.07.042
发表时间：
2012-09-28
期刊：
Journal of controlled release : official journal of the Controlled Release Society
影响因子：
--
作者：
Gupta MK;Meyer TA;Nelson CE;Duvall CL
通讯作者：
Duvall CL
DOI：
10.1038/nrd2792
发表时间：
2009-03
期刊：
Nature reviews. Drug discovery
影响因子：
--
作者：
通讯作者：
--