Radiation response modulation of tumors using biocongjugated gold nanoparticles

描述(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，当光子与金等高原子序数元素相互作用时，由于光电子注量的显着增加，金纳米颗粒在肿瘤中的被动积累可以增加沉积在肿瘤内的物理辐射剂量。然而，临床上不太相关的辐射质量(低能量千伏X射线)和临床上无法达到的金浓度(没有直接注射)的要求降低了人们对这种方法的热情。这项建议寻求克服这些挑战，通过采用使用金纳米棒(GNR)的主动靶向策略，并在主动靶向下提供针对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导致了显著的体内放射增敏，尽管肿瘤内的GNRs浓度比先前认为的放射增敏所需的浓度要低得多，因为金纳米粒子在肿瘤中被动积累。主动靶向还能在体外导致放射增敏，减少辐射引起的DNA双链断裂的修复，并克服肿瘤对传统靶向治疗的固有耐药性。我们的中心假设是，主动靶向通过直接调节肿瘤放射反应，显著提高了GNR介导的放射增敏的效率，这是由于体内靠近肿瘤细胞和血管内皮细胞的GNR附近的显着微观剂量增加的结果。一个必然的假设是，GNR作为载体将靶向部分最佳地输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输送。关于GNRs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、肿瘤和细胞水平上的去向，都是一些关键的悬而未决的问题。我们将通过追求三个具体目标来检验我们的假设并提供上述问题的答案：(A)确定GNR在体外和体内介导的放射增敏的分子机制；(B)在纳米/细胞尺度上量化GNR在不同临床照射场景下的辐射剂量增强；以及(C)确定GNR在肿瘤内的浓度。我们预计，这一建议将导致开发一种全面的物理、生物和临床特征的放射反应调节策略，该策略可作为跨多种肿瘤类型的分类解决方案广泛应用，为更有效、毒性更低的临床放射治疗奠定基础。 与公共健康相关：这项建议建立在强有力的初步数据基础上，支持利用肿瘤特异性靶向的纳米金(GNP)介导的肿瘤放射增敏的新范式，以及优化的光子源选项，以开发治疗癌症的新范式。使用新的实验和理论/计算技术，这项建议试图了解观察到的效应的机制基础，并定义该范例最大临床影响的操作限制。最终，这项多学科合作努力寻求开发一种全面的物理、生物和临床特征的放射反应调制策略，该策略可以作为一种类别解决方案广泛应用于多种肿瘤类型。

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.