Radiation response modulation of tumors using biocongjugated gold nanoparticles

描述（由申请人提供）：具有定制形状、尺寸和表面改性的金属纳米颗粒已显示出用于癌症治疗的巨大潜力。众所周知，当光子与高原子序数元素如金相互作用时，由于光电子的注量显着增加，肿瘤内沉积的物理辐射剂量可以通过金纳米颗粒在肿瘤中的被动积累而增强。然而，临床相关性较低的辐射质量（低能量千伏X射线）和临床上无法实现的（没有直接注射）金浓度的要求降低了这种方法的热情。该提案旨在通过采用使用金纳米棒（GNR）的主动靶向策略并提供针对主动靶向下的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，从而克服这些挑战。在初步的数据中，我们证明，一个积极的靶向策略的结果显着的体内放射增敏，尽管低得多的浓度GNRs在肿瘤内的浓度比以前认为是必要的放射增敏后，被动积累的金纳米粒子在肿瘤。主动靶向还导致体外放射增敏，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，主动靶向显着提高GNR介导的放射增敏的效率，直接调节肿瘤的辐射反应，作为一个结果，大量的微观剂量增强附近的GNR驻留在靠近肿瘤细胞和血管内皮细胞在体内。一个必然的假设是GNR作为载体，用于将靶向部分最佳递送至其他抗性肿瘤，这是一个可以进一步用于治疗有效载荷递送的特征。关键的未解问题涉及GNR放射增敏的分子机制、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。我们将通过以下三个具体目标来检验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增敏的分子机制，（B）在纳米/细胞尺度上量化GNR对不同临床照射场景的辐射剂量增强，以及（c）确定GNR的瘤内浓度。我们预计，这一提议将导致开发一种全面的物理、生物学和临床特征的辐射反应调节策略，该策略可以作为一种类解决方案广泛应用于多种肿瘤类型，为更有效的临床放射治疗奠定基础，毒性更低。 公共卫生相关性：该提议建立在强有力的初步数据基础上，该数据支持使用GNP的肿瘤特异性靶向和优化的光子源选项的金纳米颗粒（GNP）介导的肿瘤放射增敏的新范例，以开发用于治疗癌症的新范例。使用新的实验和理论/计算技术，该提案旨在了解所观察到的效果的机制基础，并定义该范例的最大临床影响的操作限制。最终，这种多学科的合作努力旨在开发一种全面的物理，生物和临床特征的辐射反应调节策略，可以广泛应用于多种肿瘤类型的类解决方案。

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.