Antosh Michael P, Wijesinghe Dayanjali D, Shrestha Samana, Lanou Robert, Huang Yun Hu, Hasselbacher Thomas, Fox David, Neretti Nicola, Sun Shouheng, Katenka Natallia, Cooper Leon N, Andreev Oleg A, Reshetnyak Yana K
Institute for Brain and Neural Systems and Department of Physics, Brown University, Providence, RI 02912;
Physics Department, University of Rhode Island, Kingston, RI 02881;
Proc Natl Acad Sci U S A. 2015 Apr 28;112(17):5372-6. doi: 10.1073/pnas.1501628112. Epub 2015 Apr 13.
Previous research has shown that gold nanoparticles can increase the effectiveness of radiation on cancer cells. Improved radiation effectiveness would allow lower radiation doses given to patients, reducing adverse effects; alternatively, it would provide more cancer killing at current radiation doses. Damage from radiation and gold nanoparticles depends in part on the Auger effect, which is very localized; thus, it is important to place the gold nanoparticles on or in the cancer cells. In this work, we use the pH-sensitive, tumor-targeting agent, pH Low-Insertion Peptide (pHLIP), to tether 1.4-nm gold nanoparticles to cancer cells. We find that the conjugation of pHLIP to gold nanoparticles increases gold uptake in cells compared with gold nanoparticles without pHLIP, with the nanoparticles distributed mostly on the cellular membranes. We further find that gold nanoparticles conjugated to pHLIP produce a statistically significant decrease in cell survival with radiation compared with cells without gold nanoparticles and cells with gold alone. In the context of our previous findings demonstrating efficient pHLIP-mediated delivery of gold nanoparticles to tumors, the obtained results serve as a foundation for further preclinical evaluation of dose enhancement.
先前的研究表明，金纳米颗粒可以提高辐射对癌细胞的有效性。提高辐射有效性将使给予患者的辐射剂量降低，减少不良反应；或者，在当前辐射剂量下能杀死更多癌细胞。辐射和金纳米颗粒造成的损伤部分取决于俄歇效应，该效应非常局限；因此，将金纳米颗粒置于癌细胞上或癌细胞内很重要。在这项工作中，我们使用对pH敏感的肿瘤靶向剂——低pH插入肽（pHLIP），将1.4纳米的金纳米颗粒连接到癌细胞上。我们发现，与未连接pHLIP的金纳米颗粒相比，pHLIP与金纳米颗粒的结合增加了细胞对金的摄取，且纳米颗粒大多分布在细胞膜上。我们进一步发现，与未加金纳米颗粒的细胞和仅加金的细胞相比，连接pHLIP的金纳米颗粒在辐射后使细胞存活率出现统计学上的显著下降。鉴于我们之前的研究结果表明pHLIP能有效地将金纳米颗粒递送至肿瘤，所获得的结果为进一步的剂量增强临床前评估奠定了基础。
