In situ cancer cell specific synthesis of gold nanoclusters for radiosensitization of pancreatic cancer

抽象的。胰腺癌是最具侵袭性的人类恶性肿瘤之一， 等同于死亡率放射治疗（RT）是局部晚期肿瘤的现代治疗的组成部分。 无法切除的胰腺癌然而，它的最终效用受到一些癌症 细胞对RT有抵抗力。这个问题被胃肠粘膜的存在进一步放大， 这使得剂量递增变得困难并且通常不容易实现。一种新的方法来 增强递送到肿瘤的辐射剂量是通过瞬时增加辐射相互作用概率 的靶组织使用高原子序数（Z）纳米材料。然而，胰腺癌的特征是 在致密的基质成分作为强大的生理屏障的情况下， 到药物和纳米颗粒的输送。治疗策略，可以绕过结缔组织增生“堡垒” 在不显著影响健康细胞和组织的情况下进行治疗， 是胰腺癌固有的症状在这里，我们建议通过一个范例来解决这个交付挑战 从递送预制的高Z纳米颗粒转变为递送原子尺寸的金前体（即，金离子）用于肿瘤 放射增敏，从而实现治疗剂尺寸的最终减小-原子级。我们 假设小的金离子（i）将均匀地分布在整个肿瘤中，因为它们的扩散是不可能的 被基质阻碍，以及（ii）将被癌细胞还原为金纳米颗粒（GNP），（iii）将 这一假设是基于我们令人信服的初步数据， 证明了在胰腺癌细胞而不是正常细胞内从金离子有效合成GNP。 此外，生物合成的GNP表现出高的核定位，这对于高效的细胞内定位至关重要。 由于次级俄歇电子向原子核的较高剂量递送，放射增敏。此外，一些 最近的报道表明，哺乳动物细胞可以从氯金酸合成GNP， 纳米颗粒的优先核定位进一步支持我们的假设。有趣的是， 这种现象以前没有考虑过在放射治疗中的应用。我们把它看作是一个高度 这是一个创新和令人兴奋的机会，可以大大提高原位癌细胞的放射增敏效率。我们 设想我们的方法的临床实施作为一个额外的推动，以显着提高疗效， 胰腺肿瘤患者的立体定向放射治疗。我们小组和其他人的最新临床数据 显示放射剂量增强可提高局部晚期胰腺癌的总体生存率 患者然而，在许多情况下，胃肠道粘膜与肿瘤的接近排除了该剂量 在临床实践中不断升级。我们期望改变目前的模式，由提供预先制作的居民生产总值， 通过癌细胞原位合成GNP将克服胰腺肿瘤中的递送障碍， 胰腺癌细胞对RT的高度显著的敏感性可以极大地改善治疗结果。

Abstract. Pancreatic cancer is one of the most aggressive human malignancies, with a yearly incidence that equals its mortality. Radiation therapy (RT) is an integral component of modern therapy for locally advanced unresectable pancreatic cancers. However, its ultimate utility is severely limited by the fact that some cancer cells are resistant to RT. This problem is further amplified by the presence of gastrointestinal mucosa immediately adjacent to the tumor that makes dose escalation difficult and often not readily achievable. A novel approach to enhancing the radiation dose delivered to tumors is by transiently increasing the radiation-interaction probability of the target tissues using high atomic number (Z) nanomaterials. However, pancreatic cancer is characterized by hypovascularity in the setting of a dense stromal component that serves as a formidable physiological barrier to the delivery of drugs and nanoparticles. Therapeutic strategies, which can bypass the desmoplasia `fortress' and apply therapy without significantly affecting healthy cells and tissues would address the critical issues inherently presented by the pancreatic cancer. Here we propose to solve this delivery challenge by a paradigm shift from delivery of pre-made high-Z nanoparticles to an atomic size gold precursors (i.e., gold ions) for tumor radiosensitization thus achieving the ultimate reduction in size of a therapeutic agent – an atomic scale. Our hypothesis is that small gold ions (i) will uniformly distribute throughout the tumor as their diffusion is not likely to be impeded by the stroma, and (ii) will be reduced to gold nanoparticles (GNPs) by cancer cells that (iii) will result in cancer cell radiosensitization to RT. This hypothesis is based on our compelling preliminary data demonstrating efficient synthesis of GNPs from gold ions inside pancreatic cancer cells but not normal cells. Further, the biosynthesized GNPs exhibited a high nuclear localization that is critical for efficient radiosensitization due to a higher dose delivery to nuclei by the secondary Auger electrons. In addition, a number of recent reports demonstrated intracellular synthesis of GNPs from chloroauric acid by mammalian cells with a preferential nuclear localization of the nanoparticles further supporting our hypothesis. Interestingly, this phenomenon has not been previously considered for applications in radiotherapy. We see it as a highly innovative and exciting opportunity to greatly improve radiosensitization efficiency of cancer cells in situ. We envision clinical implementation of our approach as an added boost to significantly increase efficacy of stereotactic body radiotherapy in patients with a pancreatic tumor. Recent clinical data from our group and others shows that radiation dose enhancement increases overall survival of locally advanced pancreatic cancer patients. However, the proximity of gastrointestinal mucosa to the tumor in many instances precludes this dose escalation in clinical practice. We expect that changing the current paradigm from delivery of pre-made GNPs to in situ synthesis of GNPs by cancer cells will overcame delivery barriers in pancreatic tumors and will result in a highly significant sensitization of pancreatic cancer cells to RT that can greatly improve treatment outcomes.