Enhancement of radiation effect on cancer cells by gold-pHLIP

• Published in: Proceedings of the National Academy of Sciences - PNAS 2015-04, Vol.112 (17), p.5372-5376
• Main Authors: 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.
• Format: Article
• Language: English
• Subjects: Biological Sciences; Cancer; Cell Line, Tumor; Cell Survival - drug effects; Cell Survival - radiation effects; Cells; Gamma Rays; Gold - chemistry; Gold - pharmacology; Humans; Membrane Proteins - chemistry; Membrane Proteins - pharmacology; Membranes; Metal Nanoparticles - chemistry; Nanoparticles; Neoplasms - metabolism; Neoplasms - pathology; Neoplasms - therapy; Radiation; Tumors
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1501628112

Significance Nanometer-sized gold particles are shown to increase the effectiveness of radiation in killing cancer cells. Improved radiation effectiveness allows less radiation to be used, reducing adverse effects to patients. Alternatively, more cancer killing could be possible while using current radiation doses. Here we used pH Low-Insertion Peptide (pHLIP) to tether gold nanoparticles to membranes of cancer cells. This increases their effectiveness because the radiation/particle effect is very localized. We find that pHLIP significantly increases the amount of gold particles in cancer cells, as well as the amount of cancer cell death from radiation. This methodology is promising for clinical research, as previous results show efficient targeting of gold nanoparticles to tumors by pHLIP. 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.