Development of target-specific liposomes for delivering small molecule drugs after reperfused myocardial infarction.
Development of target-specific liposomes for delivering small molecule drugs after reperfused myocardial infarction.
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DOI：
10.1016/j.jconrel.2015.06.017
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发表时间：
2015-12-28
期刊：
影响因子：
--
通讯作者：
Kelly KA
中科院分区：
文献类型：
--
作者：
Dasa SSK;Suzuki R;Gutknecht M;Brinton LT;Tian Y;Michaelsson E;Lindfors L;Klibanov AL;French BA;Kelly KA
虽然再灌注对于恢复缺血心肌的循环至关重要，但它也会导致不可逆的事件，包括再灌注损伤、心功能下降和最终形成疤痕。多种细胞类型参与多阶段修复过程，包括炎症细胞、血管细胞和心脏成纤维细胞。针对梗死边界区这些细胞类型的治疗可以改善心功能，但受到全身副作用的限制。这项工作的目的是开发具有表面修饰的脂质体，包括对梗死后心肌中存在的细胞类型具有亲和力的肽。为了鉴定梗死区/边界区特异性肽，我们使用了活体噬菌体展示方法和光学成像方法：荧光分子断层扫描（FMT）。我们鉴定了重构梗死边界区存在的心肌细胞、内皮细胞、肌成纤维细胞和c-Kit+细胞特异性肽。然后将这些肽偶联到脂质体上，并测定体内特异性和药代动力学。作为概念的证明，心肌细胞特异性（I-1）脂质体被用来递送PARP-1（聚[adp核糖]聚合酶1）抑制剂：AZ7379。使用靶向脂质体方法，与游离AZ7379相比，我们能够在注射后24小时增加梗死区/边界区AZ7379的可用性。我们观察到，与阴性对照肽脂质体（NCP）相比，当使用I-1脂质体评估所有细胞类型时，PARP-1抑制效率提高了约3倍。进一步分析发现，与NCP脂质体相比，I-1脂质体在心肌细胞和巨噬细胞中的效率分别高出9倍和1.5倍。总之，我们已经开发了一种模块化的药物输送系统，可以针对梗死边界区治疗感兴趣的细胞类型。
Although reperfusion is essential in restoring circulation to ischemic myocardium, it also leads to irreversible events including reperfusion injury, decreased cardiac function and ultimately scar formation. Various cell types are involved in the multi-phase repair process including inflammatory cells, vascular cells and cardiac fibroblasts. Therapies targeting these cell types in the infarct border zone can improve cardiac function but are limited by systemic side effects. The aim of this work was to develop liposomes with surface modifications to include peptides with affinity for cell types present in the post-infarct myocardium. To identify peptides specific for the infarct/border zone, we used in vivo phage display methods and an optical imaging approach: fluorescence molecular tomography (FMT). We identified peptides specific for cardiomyocytes, endothelial cells, myofibroblasts, and c-Kit+ cells present in the border zone of the remodeling infarct. These peptides were then conjugated to liposomes and in vivo specificity and pharmacokinetics were determined. As a proof of concept, cardiomyocyte specific (I-1) liposomes were used to deliver a PARP-1 (Poly [ADP-ribose] polymerase 1) inhibitor: AZ7379. Using a targeted liposomal approach, we were able to increase AZ7379 availability in the infarct/border zone at 24 h post-injection as compared to free AZ7379. We observed ~3-fold higher efficiency of PARP-1 inhibition when all cell types were assessed using I-1 liposomes as compared to negative control peptide liposomes (NCP). When analyzed further, I-1 liposomes had a 9-fold and 1.5-fold higher efficiency in cardiomyocytes and macrophages, respectively, as compared to NCP liposomes. In conclusion, we have developed a modular drug delivery system that can be targeted to cell types of therapeutic interest in the infarct border zone.
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DOI：
10.1016/j.ddmec.2007.12.006
发表时间：
2007-01-01
期刊：
Drug discovery today. Disease mechanisms
影响因子：
--
作者：
French, Brent A;Kramer, Christopher M
通讯作者：
Kramer, Christopher M
影响因子：
3
作者：
Bornmann, C.;Graeser, R.;Von Dobschuetz, E.
通讯作者：
Von Dobschuetz, E.
影响因子：
15.8
作者：
Kelly, Kimberly A.;Bardeesy, Nabeel;Anbazhagan, Rajesh;Gurumurthy, Sushma;Berger, Justin;Alencar, Herlen;DePinho, Ronald A.;Mahmood, Umar;Weissleder, Ralph
通讯作者：
Weissleder, Ralph
影响因子：
5.4
作者：
Nag OK;Awasthi V
通讯作者：
Awasthi V
影响因子：
37.8
作者：
Nahrendorf M;Pittet MJ;Swirski FK
通讯作者：
Swirski FK