Inflammation-Responsive Micellar Nanoparticles from Degradable Polyphosphoramidates for Targeted Delivery to Myocardial Infarction.
Inflammation-Responsive Micellar Nanoparticles from Degradable Polyphosphoramidates for Targeted Delivery to Myocardial Infarction.
复制标题
来自可降解聚磷酸酰胺的炎症响应性胶束纳米颗粒用于靶向递送至心肌梗塞。
DOI：
10.1021/jacs.3c01054
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发表时间：
2023
影响因子：
15
通讯作者：
Gianneschi,NathanC
中科院分区：
文献类型：
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作者：
Liang,Yifei;Sullivan,HollyL;Carrow,Kendal;Mesfin,JoshuaM;Korpanty,Joanna;Worthington,Kendra;Luo,Colin;Christman,KarenL;Gianneschi,NathanC
先前已经开发了经历局部形态变化以靶向炎症区域的纳米颗粒，但受到其缺乏生物降解性的限制。在本文中，我们描述了一种低环应变的环烯烃单体，1，3-二甲基-2-苯氧基-1，3，4，7-四氢-1，3，2-二氮磷杂庚烯2-氧化物（MePTDO），该单体在室温下通过开环易位聚合快速聚合，以高单体转化率（>84%）生成定义明确的可降解聚氨基磷酸酯。有效的MePTDO共聚与基于异戊烯的单体，包括一个异戊烯单体官能化的肽底物炎症相关的基质金属蛋白酶（MMP）。所得两亲性肽刷共聚物在水溶液中自组装以产生胶束纳米颗粒（直径30 nm），其表现出优异的细胞和血液相容性，并经历MMP诱导的组装成微米级聚集体。由于MMPs在心肌梗死后（MI）的心脏中上调，因此在MI大鼠模型中静脉内给药后，将MMP-响应性胶束应用于靶向梗死心脏并在梗死心脏中积累。与不可降解的类似物相比，这些颗粒显示出不同的生物分布和清除模式。具体而言，MI部位的蓄积主要通过肾脏而非肝脏与消除竞争。总之，这些结果表明这是一种有前途的新的可生物降解的炎症靶向递送平台。
Nanoparticles that undergo a localized morphology change to target areas of inflammation have been previously developed but are limited by their lack of biodegradability. In this paper, we describe a low-ring-strain cyclic olefin monomer, 1,3-dimethyl-2-phenoxy-1,3,4,7-tetrahydro-1,3,2-diazaphosphepine 2-oxide (MePTDO), that rapidly polymerizes via ring-opening metathesis polymerization at room temperature to generate well-defined degradable polyphosphoramidates with high monomer conversion (>84%). Efficient MePTDO copolymerizations with norbornene-based monomers are demonstrated, including a norbornenyl monomer functionalized with a peptide substrate for inflammation-associated matrix metalloproteinases (MMPs). The resulting amphiphilic peptide brush copolymers self-assembled in aqueous solution to generate micellar nanoparticles (30 nm in diameter) which exhibit excellent cyto- and hemocompatibility and undergo MMP-induced assembly into micron-scale aggregates. As MMPs are upregulated in the heart postmyocardial infarction (MI), the MMP-responsive micelles were applied to target and accumulate in the infarcted heart following intravenous administration in a rat model of MI. These particles displayed a distinct biodistribution and clearance pattern in comparison to nondegradable analogues. Specifically, accumulation at the site of MI competed with elimination predominantly through the kidney rather than the liver. Together, these results suggest this as a promising new biodegradable platform for inflammation targeted delivery.