Room: Track 3
Purpose: The efficacy of dose-enhancing agents such as gold nanoparticles (AuNP) is negatively impacted by low tumor uptake, low cell membrane penetration, and short range of nanoparticle-generated secondary particles, thus making the spatial distribution of the nanoparticles an important factor. To overcome these limitations, we have developed a novel AuNP system capable of radiation-triggered release of nitrate, a precursor of reactive nitrogen species (RNS), and report here on the in vivo characterization of this system.
Methods: To increase the in vivo circulation time, the cell membrane-penetrating ability, and reduce dependence on the intra-cellular spatial distribution of the AuNPs, AuNPs were functionalized through PEGylation, cell-penetrating peptides (CPP; AuNP@CPP), and nitroimidazole (nIm; AuNP@nIm-CPP), respectively. NU/NU mice with subcutaneous radioresistant 4T1 tumors were injected with AuNP@nIm-CPP or AuNP@CPP. Tumor and normal tissue uptake were evaluated. Another cohort was injected and irradiated 24h post NP injection (18Gy) and followed to evaluate tumor response.
Results: The mean physical/hydrodynamic size of the NP systems was 5/15 nm, respectively. NP nIm-loading of 1 wt% was determined. Tumor accumulation of AuNP@nIm-CPP was significantly lower than that of AuNP@CPP (0.2%ID/g vs 1.2%ID/g, respectively). In contrast, AuNP@nIm-CPP showed higher accumulation in liver and spleen compared to AuNP@CPP. With respect to tumor response, no differential effect was found in un-irradiated mice injected with either saline or AuNP@nIm-CPP alone. Furthermore, the combination of AuNP@CPP with radiation showed no differential effect from radiation alone. A significant tumor growth delay was observed in the irradiated AuNP@nIm-CPP group compared to irradiated controls.
Conclusion: AuNP@nIm-CPP showed an order of magnitude less accumulation in the tumor volumes compared to AuNP@CPP, yet resulted in significantly higher therapeutic response. Our data suggest that by improving the biokinetics of AuNP@nIm-CPP, this novel NP system could be a promising radiosensitizer for radioresistant and hypoxic tumors.