Radiotherapy is commonly used for treating cancer. Novel sensitizers, such as gold nanoparticles (GNPs), are being used to enhance the local radiation dose. It is not known how the uptake and radiation dose enhancement of GNPs vary in synchronized vs unsynchronized (control) tumor cell populations. Successful application of GNPs in radiation therapy requires NPs to be accumulated within individual tumor cells at clinically feasible NP concentrations. Use of small GNPs as a radiation dose enhancer in the past required very high NP concentration, since the driving force for the uptake of smaller GNPs is low. We used a novel lipid-based NP of 50 nm diameter system as a Trojan horse to deliver smaller GNPs of size 5 nm (LNP–GNP) at 0.2 nM concentration. We investigated the changes in GNP uptake and survival fraction with the LNP delivery at different cell stages using human breast cancer as our tumor model and choosing the triple-negative MDA-MB-231 cell line. Using the LNP–GNP system resulted in a 39- and 73-fold enhancement in uptake of 5 nm GNPs in unsynchronized and synchronized tumor cell populations, respectively. The NP uptake per cell increased from 800 to 1200 and from 30,841 to 88,477 for individual 5 nm GNPs and 5 nm GNPs incorporated in LNPs, respectively. After a radiation dose of 2 Gy with 6 MeV photons, synchronized tumor cell populations incorporated with LNP–GNPs produced a 27% enhancement in tumor cell death compared to the control (unsynchronized; no GNPs; 2 Gy). The findings of our experimental results were supported by modeling predictions based on Monte Carlo calculations. This study clearly shows that the cell cycle, GNPs, and radiation therapy can be combined to improve outcome of cancer therapy. Using the experimental data, we estimated the predicted improvement for a clinical treatment plan where 30 fractions of 2 Gy radiation dose were given over a period of time. Enhanced uptake and radiation sensitivity of a synchronous tumor cell population would produce a significant improvement in cell killing. For example, synchronizing cells and the addition of LNP–GNPs into tumor cells produced a 1000-fold enhancement in cell killing. Because the agents used for cell synchronization are in clinical practice, this approach may be a simple and cost-effective way to further enhance local radiation dose. Finally, this study provides a novel lipid-based NP platform to further improve GNP-mediated radiation therapy through synchronization of breast cancer cell population.

中文翻译：

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使用脂质纳米颗粒系统作为特洛伊木马，将金纳米颗粒递送至人乳腺癌细胞，以改善放射治疗的结果

放射疗法通常用于治疗癌症。新型敏化剂，例如金纳米颗粒（GNP），正在用于增强局部辐射剂量。尚不了解同步和非同步（对照）肿瘤细胞群中GNP的摄取和辐射剂量增加如何变化。GNP在放射治疗中的成功应用要求NP以临床上可行的NP浓度积累在单个肿瘤细胞中。过去使用小GNP作为辐射剂量增强剂需要非常高的NP浓度，因为摄取小GNP的驱动力很低。我们使用了一种新型的基于脂质的NP，直径为50 nm的系统作为特洛伊木马，以0.2 nM的浓度提供了5 nm大小的较小GNP（LNP–GNP）。我们使用人类乳腺癌作为我们的肿瘤模型并选择三阴性MDA-MB-231细胞系，研究了在不同细胞阶段LNP传递时GNP摄取和存活分数的变化。使用LNP–GNP系统分别在未同步和同步的肿瘤细胞群体中对5 nm GNP的吸收分别增加了39倍和73倍。对于掺入LNP中的单个5 nm GNP和5 nm GNP，每个细胞的NP摄取量分别从800增加到1200，从30,841增加到88,477。与6 MeV光子一起以2 Gy的辐射剂量照射后，与对照组相比，与LNP–GNPs结合的同步肿瘤细胞群体的肿瘤细胞死亡增加了27％（未同步；无GNP； 2 Gy）。我们的实验结果的发现得到了基于蒙特卡洛计算的模型预测的支持。这项研究清楚地表明，细胞周期，GNP和放射疗法可以结合起来改善癌症疗法的疗效。使用实验数据，我们估算了临床治疗计划的预期改进，该计划在一段时间内给予了30份2 Gy辐射剂量。同步肿瘤细胞群吸收和辐射敏感性的提高将在细胞杀伤力方面产生显着改善。例如，同步细胞和向肿瘤细胞中添加LNP-GNP可以使细胞杀伤力提高1000倍。因为用于细胞同步的药物是在临床实践中，所以该方法可能是进一步提高局部辐射剂量的简单且经济高效的方法。最后，