Development of Nanodroplets for Histotripsy-Mediated Cell Ablation
Development of Nanodroplets for Histotripsy-Mediated Cell Ablation
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DOI：
10.1021/mp500419w
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发表时间：
2014-10-01
影响因子：
4.9
通讯作者：
ElSayed, Mohamed
中科院分区：
文献类型：
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作者：
Durmaz, Yasemin Yuksel;Vlaisavljevich, Eli;ElSayed, Mohamed
本报告描述了由亲水性聚（乙二醇）（PEG）嵌段、中心聚（丙烯酸）（PAA）嵌段以及形成疏水性嵌段的甲基丙烯酸十七烷酯（HDFMA）和甲基丙烯酸甲酯（MMA）的无规共聚物组成的两亲性共聚物（ABC-1和ABC-2）的合成，其用于形成用于超声介导的细胞消融的纳米液滴。具体地，研究了PEG和P（HDFMA-co-MMA）嵌段的分子量对聚合物围绕可变量（096、1%和296 v/v）的全氟戊烷（PFP）自组装形成纳米液滴的能力的影响。还研究了在组织模拟琼脂糖模型中嵌入单层红细胞（RBC）的不同纳米液滴制剂响应于具有不同声压的超声处理和RBC的相关消融而引发和维持气泡云的能力。结果显示，与由5 kDa PEG嵌段和11.4kDa P（HDFMA-co-MMA）嵌段组成的ABC-2聚合物相比，由2kDa PEG嵌段和6.7kDa P（HDFMA-co-MMA）嵌段组成的ABC-1聚合物更好地包封PFP核心。此外，由RBC单层中的损伤面积指示的消融能力随着PFP含量的增加而增加，并且在使用ABC-1聚合物配制并包封w2%v/v PFP的纳米液滴的情况下达到其最大值。使用ABC-1聚合物配制并装载有2%PFP的纳米液滴产生空化云，并在比使用组织破坏术产生相同效果所需的声压低2.5倍的声压下表现出它们的消融效果（超声波）单独脉冲，这表明这些纳米液滴能够实现靶向和自我-限制疾病细胞的分级分离，同时保留邻近的健康细胞。结果还显示，有效的纳米液滴在与牛血清白蛋白在37 ° C下孵育24小时后保持其大小和浓度，这表明其在生理条件下的稳定性及其用于体内癌细胞消融的前景。
This report describes the synthesis of amphiphilic copolymers (ABC-1 and ABC-2) composed of a hydrophilic poly(ethylene glycol) (PEG) block, a central poly(acrylic acid) (PAA) block, and a random copolymer of heptadecafluorodecyl methacrylate (HDFMA) and methyl methacrylate (MMA) forming the hydrophobic block, which are used to form nanodroplets for ultrasound-mediated cell ablation. Specifically, the effect of molecular weight of PEG and P(HDFMA-co-MMA) blocks on polymer's ability to self-assemble around a variable amount (096, 1%, and 296 v/v) of perfluoropentane (PFP) forming nanodroplets is investigated. The ability of different nanodroplets formulations embedded with a monolayer of red blood cells (RBCs) in tissue-mimicking agarose phantoms to initiate and sustain a bubble cloud in response to ultrasound treatments with different acoustic pressures and the associated ablation of RBCs were also investigated. Results show that ABC-1 polymer composed of a 2 kDa PEG block and a 6.7 kDa P(HDFMA-co-MMA) block better encapsulate the PFP core compared to ABC-2 polymer composed of a 5 kDa PEG block and 11.4 kDa P(HDFMA-co-MMA) block. Further, the ablative capacity indicated by the damage area in the RBCs monolayer increased with the increase in PFP content and reached its maximum with the nanodroplets formulated using ABC-1 polymer and encapsulating w2% v/v PFP. The nanodroplets formulated using ABC-1 polymer and loaded with 2% PFP produced the cavitation cloud and exhibited their ablative effect at an acoustic pressure that is 2.5-fold lower than the acoustic pressure needed to generate the same effect using a histotripsy (ultrasound) pulse alone, which indicates the ability of these nanodroplets to achieve targeted and self-limiting fractionation of disease cells while sparing neighboring healthy ones. Results also show that effective nanodroplets maintained their size and concentration upon incubation with bovine serum albumin at 37 degrees C for 24 h, which indicates their stability in physiologic conditions and their promise for in vivo cancer cell ablation.