Enzyme-Responsive Nanoparticles for the Targeted Delivery of an MMP Inhibitor to Acute Myocardial Infarction.
Enzyme-Responsive Nanoparticles for the Targeted Delivery of an MMP Inhibitor to Acute Myocardial Infarction.
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DOI：
10.1021/acs.biomac.3c00421
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发表时间：
2023-11-13
影响因子：
6.2
通讯作者：
Christman, Karen L.
中科院分区：
文献类型：
--
作者：
Sullivan, Holly L.;Liang, Yifei;Worthington, Kendra;Luo, Colin;Gianneschi, Nathan C.;Christman, Karen L.
在此，我们开发了一种药物负载的基质金属蛋白酶（MMP）反应胶束纳米颗粒（NP），用于心肌梗死（MI）急性期的微创静脉注射，并在心脏中长期保留小分子药物递送。采用开环复分解聚合（ROMP）法制备了含有小分子MMP抑制剂（MMPi） PD166793的肽-聚合物两亲体（PPAs），并将其转化为球形胶束。得到的胶束NPs经过mmp诱导的聚集，表现出酶的反应性。通过大鼠心肌梗死模型，我们观察到这些NPs能够成功地外渗到心脏梗死区域，由于活性的酶介导的靶向作用，它们被保留在那里，在给药后1周仍可检测到，而不增加巨噬细胞的募集。此外，体外研究表明，这些NPs在MMP治疗后成功释放药物，并保持药物生物活性，MMP抑制作用与游离MMPi相当。这项工作建立了一个靶向NP平台，将小分子治疗药物输送到心肌梗死后的心脏，为心肌梗死治疗开辟了可能性。
Herein, we have developed a drug-loaded matrix metalloproteinase (MMP)-responsive micellar nanoparticle (NP) intended for minimally invasive intravenous injection during the acute phase of myocardial infarction (MI) and prolonged retention in the heart for small-molecule drug delivery. Peptide-polymer amphiphiles (PPAs) bearing a small-molecule MMP inhibitor (MMPi), PD166793, were synthesized via ring-opening metathesis polymerization (ROMP) and formulated into spherical micelles by transitioning to aqueous solution. The resulting micellar NPs underwent MMP-induced aggregation, demonstrating enzyme responsiveness. Using a rat MI model, we observed that these NPs were capable of successfully extravasating into the infarcted region of the heart where they were retained due to the active, enzyme-mediated targeting, remaining detectable after 1 week post administration without increasing macrophage recruitment. Furthermore, in vitro studies show that these NPs demonstrated successful drug release following MMP treatment and maintained drug bioactivity as evidenced by comparable MMP inhibition to free MMPi. This work establishes a targeted NP platform for delivering small-molecule therapeutics to the heart after MI, opening possibilities for myocardial infarction treatment.
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心肌梗塞和心力衰竭中的基质金属蛋白酶。
DOI：
10.1016/bs.pmbts.2017.02.001
发表时间：
2017
影响因子：
--
作者：
DeLeon-Pennell KY;Meschiari CA;Jung M;Lindsey ML
通讯作者：
Lindsey ML
影响因子：
29.4
作者：
Chien, Miao-Ping;Thompson, Matthew P.;Barback, Christopher V.;Ku, Ti-Hsuan;Hall, David J.;Gianneschi, Nathan C.
通讯作者：
Gianneschi, Nathan C.
影响因子：
2.4
作者：
Park, JC;Park, BJ;Kwon, OH
通讯作者：
Kwon, OH
持续释放基于肽的基质金属蛋白酶 2 抑制剂可减轻心肌梗死后的不良心脏重塑并改善心脏功能
影响因子：
6.2
作者：
Fan Z;Fu M;Xu Z;Zhang B;Li Z;Li H;Zhou X;Liu X;Duan Y;Lin PH;Duann P;Xie X;Ma J;Liu Z;Guan J
通讯作者：
Guan J
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