Polymer-assisted intratumoral delivery of ethanol: Preclinical investigation of safety and efficacy in a murine breast cancer model.
Polymer-assisted intratumoral delivery of ethanol: Preclinical investigation of safety and efficacy in a murine breast cancer model.
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DOI：
10.1371/journal.pone.0234535
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发表时间：
2021
期刊：
影响因子：
3.7
通讯作者：
Ramanujam N
中科院分区：
文献类型：
--
作者：
Nief C;Morhard R;Chelales E;Adrianzen Alvarez D;Bourla Bs I;Lam CT;Sag AA;Crouch BT;Mueller JL;Katz D;Dewhirst MW;Everitt JI;Ramanujam N
使用乙醇的局灶性肿瘤消融术可以在低资源环境中提供益处，因为其总体成本低，成像技术要求最低，临床结局可接受。不幸的是，乙醇消融并不常用，因为缺乏消融区的可预测性，这是由乙醇在注射部位的低效保留引起的。为了创建一个可预测的消融区域，我们开发了一种使用乙基纤维素（EC）与乙醇混合的聚合物辅助消融方法。EC是乙醇可溶的和水不溶性的，允许EC-乙醇作为液体注射并沉淀成固体，从而在与组织接触时堵塞乙醇的泄漏。本研究的目的是在小鼠乳腺肿瘤模型中比较EC-乙醇与传统乙醇消融的1）安全性、2）释放动力学、3）空间分布、4）坏死体积和5）总生存期。通过局部不良事件记录、拉曼光谱的乙醇释放动力学、体内成像的注射液分布、NADH-黄递酶染色的靶组织坏死和肿瘤生长的替代物的总存活率来监测非靶组织损伤。与相同体积的纯乙醇相比，EC-乙醇表现出局部不良事件减少，乙醇释放速率减慢，注射区更紧凑，靶组织坏死增加5倍，总生存率更长。单次150 μL剂量的6% EC-乙醇达到了与每日6次50 μL剂量的纯乙醇相似的生存概率，用于模拟6天内乙醇的缓慢释放。总之，这些结果表明EC-乙醇比单独的乙醇更安全和更有效地消融肿瘤。
Focal tumor ablation with ethanol could provide benefits in low-resource settings because of its low overall cost, minimal imaging technology requirements, and acceptable clinical outcomes. Unfortunately, ethanol ablation is not commonly utilized because of a lack of predictability of the ablation zone, caused by inefficient retention of ethanol at the injection site. To create a predictable zone of ablation, we have developed a polymer-assisted ablation method using ethyl cellulose (EC) mixed with ethanol. EC is ethanol-soluble and water-insoluble, allowing for EC-ethanol to be injected as a liquid and precipitate into a solid, occluding the leakage of ethanol upon contact with tissue. The aims of this study were to compare the 1) safety, 2) release kinetics, 3) spatial distribution, 4) necrotic volume, and 5) overall survival of EC-ethanol to conventional ethanol ablation in a murine breast tumor model. Non-target tissue damage was monitored through localized adverse events recording, ethanol release kinetics with Raman spectroscopy, injectate distribution with in vivo imaging, target-tissue necrosis with NADH-diaphorase staining, and overall survival by proxy of tumor growth. EC-ethanol exhibited decreased localized adverse events, a slowing of the release rate of ethanol, more compact injection zones, 5-fold increase in target-tissue necrosis, and longer overall survival rates compared to the same volume of pure ethanol. A single 150 μL dose of 6% EC-ethanol achieved a similar survival probability rates to six daily 50 μL doses of pure ethanol used to simulate a slow-release of ethanol over 6 days. Taken together, these results demonstrate that EC-ethanol is safer and more effective than ethanol alone for ablating tumors.