Ultrasound-targeted photodynamic and gene dual therapy for effectively inhibiting triple negative breast cancer by cationic porphyrin lipid microbubbles loaded with HIF1α-siRNA
Ultrasound-targeted photodynamic and gene dual therapy for effectively inhibiting triple negative breast cancer by cationic porphyrin lipid microbubbles loaded with HIF1α-siRNA
复制标题
超声靶向光动力和基因双重疗法通过负载 HIF1 α-siRNA 的阳离子卟啉脂质微泡有效抑制三阴性乳腺癌
DOI：
10.1039/c8nr03074j
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发表时间：
2018-11-14
期刊：
影响因子：
6.7
通讯作者：
Wang, Shumin
中科院分区：
文献类型：
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作者：
Sun, Sujuan;Xu, Yunxue;Wang, Shumin
三阴性乳腺癌（Triple-negative breast cancer，TNBC）是一种侵袭性乳腺癌，由于其孕激素受体（progesterone receptor，PR）、雌激素受体（estrogen receptor，ER）和HER 2的表达缺失，与其他乳腺癌亚型相比，其复发率更高，总生存率更低。为了提高TNBC的治疗效果，我们研制了一种新型的载HIF 1 α siRNA的多功能阳离子卟啉接枝脂质（CPGL）微泡（siHIF@CpMB）。由于CPGL的两亲性结构，它可以与常规脂质自组装成微泡（MBs），卟啉基团可以作为光敏剂用于光动力学治疗（PDT），而氨基可以通过静电吸附作用吸附HIF 1 alpha siRNA（siHIF）。这样的MB具有显著高的药物负载含量和较少的过早药物释放。通过实时超声成像（3-12 MHz）可以很容易地监测MB的分布。此外，在超声靶向微泡破坏（UTMD）的辅助下，siHIF@CpMBs可以有效地原位转化为纳米颗粒，通过空化效应促进卟啉和siRNA在肿瘤部位的积累。HIF 1 α siRNA可下调肿瘤组织中常见的低氧环境或PDT产生的ROS诱导的HIF 1 α水平，增强PDT的疗效，部分抑制肿瘤的进展。因此，UTMD辅助PDT和基因治疗的组合被认为是TNBC的有效治疗策略。
Triple-negative breast cancer (TNBC), which is a kind of aggressive breast cancer, has a much higher recurrence rate and a shorter overall survival rate than other breast cancer subtypes owing to its lack of expression of the progesterone receptor (PR), estrogen receptor (ER) and HER2. For improving the therapeutic efficacy of TNBC, we developed a new kind of multifunctional cationic porphyrin-grafted lipid (CPGL) microbubble loaded with HIF 1 alpha siRNA (siHIF@CpMB). Owing to the amphiphilic structure of CPGL, it can be self-assembled into microbubbles (MBs) with conventional lipids and the porphyrin group could be used as a photosensitizer for photodynamic therapy (PDT), while the amino group could adsorb HIF 1 alpha siRNA (siHIF) through electrostatic adsorption. Such MBs possess a remarkably high drug loading content and less premature drug release. Distribution of MBs could be easily monitored by real-time US imaging (3-12 MHz). Furthermore, with the assistance of ultrasound targeted microbubble destruction (UTMD), siHIF@CpMBs could be efficiently converted into nanoparticles in situ, facilitating the accumulation of porphyrin and siRNA at the tumor site through the cavitation effect. HIF 1 alpha siRNA down-regulated the HIF 1 alpha level, which was induced by the common hypoxic tumor environment or the ROS (generated by PDT), enhanced the PDT efficacy and partly inhibited the tumor progression. Therefore, UTMD assisted combination of PDT and gene therapy was believed to be an effective therapeutic strategy for TNBC.