N-acetylglucosamine conjugated to nanoparticles enhances myocyte uptake and improves delivery of a small molecule p38 inhibitor for post-infarct healing.
N-acetylglucosamine conjugated to nanoparticles enhances myocyte uptake and improves delivery of a small molecule p38 inhibitor for post-infarct healing.
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DOI：
10.1007/s12265-011-9292-0
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发表时间：
2011-10
影响因子：
3.4
通讯作者：
Davis ME
中科院分区：
文献类型：
--
作者：
Gray WD;Che P;Brown M;Ning X;Murthy N;Davis ME
据估计，2011 年美国将发生 985,000 起新的心肌梗塞 (MI)。虽然许多人能在最初的损伤中幸存下来，但早期的损害最终将导致心力衰竭，而唯一确定的治疗方法是移植。 CM（CM）细胞凋亡是导致心脏功能障碍的重要因素，尽管存在抑制细胞凋亡途径的潜在治疗分子，但缺乏药物递送方法。这种损害主要是区域性的，因此局部治疗具有巨大的潜力；然而，CM 相对不具有吞噬作用，这限制了依赖吞噬作用的现有选择。最近，糖 N-乙酰氨基葡萄糖 (GlcNAc) 被证明可以被 CM 结合并内化，为药物输送提供了潜在的机制。在这里，我们展示了药物递送系统的功效，该系统包含表面用 GlcNAc 修饰的载药可生物降解聚缩酮纳米颗粒。通过细胞内激活荧光测量，糖的加入增强了 CM 的吸收。当缺血再灌注损伤后在体内递送时，负载有 p38 抑制剂 SB239063 的 GlcNAc 修饰的颗粒减少了细胞凋亡事件和梗塞面积，并改善了急性心脏功能。这与我们发表的数据形成鲜明对比，该数据表明非糖修饰的负载 p38 抑制剂的颗粒没有急性作用。这些数据提出了一种新的治疗选择，可以增强 CM 对载药纳米颗粒的吸收，并可能减少心肌损伤后大量的 CM 细胞死亡。
An estimated 985,000 new myocardial infarctions (MI) will occur in the U.S. in 2011. While many will survive the initial insult, the early damage will eventually lead to heart failure for which the only definitive cure is transplantation. CM (CM) apoptosis is a large contributor to cardiac dysfunction, and although potential therapeutic molecules exist to inhibit apoptotic pathways, drug delivery methods are lacking. This damage is largely regional and thus localized delivery of therapeutics holds great potential; however CMs are relatively non-phagocytic, which limits existing options that rely on phagocytosis. Recently, the sugar N-acetyl-glucosamine (GlcNAc) was shown to be bound and internalized by CMs, providing a potential mechanism for drug delivery. Here we demonstrate efficacy of a drug delivery system comprising a drug-loaded biodegradable polyketal nanoparticle that is surface-decorated with GlcNAc. Inclusion of the sugar enhanced uptake by CMs as measured by intracellular activated fluorescence. When delivered in vivo following ischemia-reperfusion injury, GlcNAc-decorated particles loaded with the p38 inhibitor SB239063 reduced apoptotic events and infarct size, and improved acute cardiac function. This was in contrast to our published data demonstrating no acute effect of non-sugar decorated, p38 inhibitor-loaded particles. These data suggest a novel therapeutic option to enhance uptake of drug-loaded nanoparticles to CMs, and perhaps reduce the large amount of CM cell death following myocardial injury.
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影响因子：
4.7
作者：
Lee, Sungmun;Yang, Stephen C.;Murthy, Niren
通讯作者：
Murthy, Niren
影响因子：
10.8
作者：
Aso, Shin-ichi;Ise, Hirohiko;Ikeda, Uichi
通讯作者：
Ikeda, Uichi
影响因子：
4.3
作者：
Ise, Hirohiko;Kobayashi, Satoshi;Akaike, Toshihiro
通讯作者：
Akaike, Toshihiro
DOI：
10.1073/pnas.94.12.6541
发表时间：
1997-06-10
影响因子：
11.1
作者：
Matherne, GP;Linden, J;Headrick, JP
通讯作者：
Headrick, JP
影响因子：
5
作者：
Chen, ZY;Siu, B;Chua, BHL
通讯作者：
Chua, BHL