Radiation response modulation of tumors using biocongjugated gold nanoparticles

描述（由申请人提供）：具有定制形状、大小和表面修饰的金属纳米颗粒在癌症治疗中显示出巨大的潜力。众所周知，当光子与高原子序数元素（如金）相互作用时，光电子的影响显著增加，因此，金纳米颗粒在肿瘤中的被动积累可以增强沉积在肿瘤内的物理辐射剂量。然而，临床相关的辐射质量要求较低（低能量千伏特x射线）和临床无法达到的（不直接注射）金浓度降低了对该方法的热情。本研究旨在克服这些挑战，通过采用金纳米棒（gnr）的主动靶向策略，并提供针对主动靶向下特定临床场景优化的光子源选项，在肿瘤内实现更具肿瘤细胞特异性的金纳米颗粒浓度。在初步数据中，我们证明了主动靶向策略可导致显著的体内放射致敏，尽管肿瘤内gnr的浓度远低于先前认为的金纳米颗粒在肿瘤中被动积累后放射致敏所需的浓度。主动靶向还导致体外放射致敏，减少辐射诱导的DNA双链断裂的修复，并克服肿瘤对传统靶向治疗的固有治疗抗性。我们的中心假设是，主动靶向通过直接调节肿瘤辐射反应，显著提高了gnr介导的放射增敏的效率，这是由于gnr附近存在于肿瘤细胞和血管内皮细胞附近的大量微观剂量增强的结果。一个必然的假设是，gnr作为载体，将靶向部分最佳递送到其他耐药的肿瘤，这一特征可以进一步用于治疗有效载荷的递送。关键的未解决的问题涉及到放射性致敏的分子机制、gnr的生物分布和动力学，以及它们在整个动物、肿瘤和细胞水平的命运。我们将通过三个具体目标来验证我们的假设并回答上述问题：(a)确定gnr介导的体外和体内放射致敏的分子机制，(b)在纳米/细胞尺度上量化gnr在不同临床照射情景下的辐射剂量增强，以及(c)确定gnr在肿瘤内的浓度。我们期望这一建议将导致一种全面的物理，生物学和临床特征的辐射反应调节策略的发展，可以广泛应用于多种肿瘤类型的类解决方案，为更有效，更低毒性的临床放疗奠定基础。

DESCRIPTION (provided by applicant): Metal nanoparticles with customized shapes, sizes, and surface modification have demonstrated tremendous potential for cancer therapy. It is well recognized that physical radiation dose deposited within tumors can be enhanced by passive accumulation of gold nanoparticles in tumors due to the remarkable increase in the fluence of photoelectrons when photons interact with high atomic number elements such as gold. However, the requirements of less clinically relevant radiation quality (low energy kilovolt x-rays) and clinically unachievable (without direct injection) gold concentration reduce enthusiasm for this approach. This proposal seeks to surmount these challenges by achieving a more tumor cell-specific concentration of gold nanoparticles within tumors by adopting an active targeting strategy using gold nanorods (GNRs) and providing photon source options optimized for specific clinical scenarios under active targeting. In preliminary data, we demonstrate that an active targeting strategy results in remarkable in vivo radiosensitization despite a much lower concentration of GNRs within tumors than the concentration previously believed to be necessary for radiosensitization following passive accumulation of gold nanoparticles in tumors. Active targeting also leads to radiosensitization in vitro, reduced repair of radiation-induced DNA double-strand breaks, and overcomes the inherent treatment resistance of tumors to traditional targeted therapies. Our central hypothesis is that active targeting significantly improves the efficiency of GNR-mediated radiosensitization by directly modulating tumor radiation response as a result of substantial microscopic dose enhancement in the vicinity of GNRs that reside in close proximity to tumor cells and vascular endothelial cells in vivo. A corollary hypothesis is that the GNRs serve as vectors for optimal delivery of the targeting moiety to an otherwise resistant tumor, a feature that can be further exploited for therapeutic payload delivery. Critical unanswered questions relate to the molecular mechanism of radiosensitization, biodistribution and kinetics of GNRs, and their fate at the whole animal, tumor and cellular levels. We will test our hypotheses and provide answers to the questions posed above by pursuing three Specific Aims: (a) to determine the molecular mechanism of GNR-mediated radiosensitization in vitro and in vivo, (b) to quantify the radiation dose enhancement by GNRs on a nano-/cellular-scale for different clinical irradiation scenarios, and (c) to determine the intratumoral concentration of GNRs. We anticipate that this proposal will lead to development of a comprehensive physically, biologically and clinically characterized radiation response modulation strategy that can be widely applied as a class solution across multiple tumor types, laying the foundation for more effective clinical radiotherapy with less toxicity. PUBLIC HEALTH RELEVANCE: This proposal builds upon strong preliminary data supporting a new paradigm in gold nanoparticle (GNP)-mediated radiosensitization of tumors using tumor-specific targeting of the GNP and optimized photon source options to develop a new paradigm for treatment of cancer. Using novel experimental and theoretical/computational techniques, this proposal seeks to understand the mechanistic underpinnings of the observed effect and define the operating constraints for maximal clinical impact of this paradigm. Eventually, this multidisciplinary collaborative effort seeks to develop a comprehensive physically, biologically and clinically characterized radiation response modulation strategy that can be widely applied as a class solution across multiple tumor types.