PSMA-targeted AuNPs for MR guided radiotherapy and radiosensitization

临床放射治疗是一种非侵入性的方法来减缓癌症的进展，这是处方为 超过50%的前列腺癌患者。辐射技术的发展，例如利用强度- 调制放射治疗(IMRT)提供高度适形辐射剂量分布和图像引导 放射治疗(IGRT)考虑到靶区解剖和定位的日常变化，允许前所未有的水平 准确性和治疗结果。前列腺周围有许多神经和肌肉纤维控制。 不同的排泄和勃起功能是困难的但必须避免的，但仍然是一个挑战 精确地向前列腺癌提供辐射剂量，而不会损害正常的周围组织，即使在 图像制导。为了避免过量的辐射剂量，辐射增敏剂已经被开发出来，以放大 肿瘤细胞内的辐射效应。前列腺癌靶向放射增敏剂可能为进一步 相对生物剂量随正常组织的保留而增加。然而，有有限的临床前和 前列腺癌靶向放射增敏剂的临床研究。为了应对挑战，我们的目标是 开发一种纳米颗粒技术，通过以下方式提高前列腺癌组织的可视化和分辨率 MRI，在MRI引导的放射治疗中允许更高的准确性，并在癌症内提供放射增敏 细胞。 前列腺特异性膜抗原(PSMA)是检测前列腺癌的理想靶点 在大多数前列腺癌中大量表达。我们合成了一种新型的聚甲基丙烯酸甲酯高亲和力配体 靶向，并将靶向配体和Gd(III)配合物连接到金纳米颗粒和纳米团簇上 (AUNP/NCS)。我们已经证明了这些以PSMA为靶标的AuNP/NC-Gd(III)具有更高的弛豫度 提供磁共振图像引导的放射治疗。将Gd(III)偶联AuNP/NCS直接输送到前列腺 将更多的Gd(III)试剂输送到靶组织，而将更少的Gd(III)试剂输送到非特异性或非靶部位；2) 改善R1弛豫度和MR敏感性，这可能会减少给患者的剂量，并可能 Gd(III)试剂的毒性；3)区分癌症、正常、神经和肌肉细胞和组织 核磁共振成像，使前列腺癌的准确诊断和精确的放射治疗成为可能；4)将黄金和 使用较低剂量的Gd来增强前列腺癌潜在消融的放射增敏效应 辐射剂量；以及5)使用MRI直线加速器设备实现MRI引导的放射治疗，以提高辐射精度 并避免对正常组织造成附带损害。我们相信，这种做法将影响到质量和成功 放射治疗的结果。此外，PSMA也表达在许多不同实体肿瘤的新生血管上， 因此，这种方法是放射治疗和其他癌症消融的原则证明。

Clinical radiation therapy is a noninvasive means to mitigate cancer progression, which is prescribed for more than 50% of prostate cancer patients. Development of radiation technology, such as utilizing intensity- modulated radiotherapy (IMRT) to deliver highly conformal radiation dose distributions and image-guided radiotherapy (IGRT) to account for daily changes in target anatomy and positioning, allows unprecedented levels of accuracy and therapy outcome. The prostate is surrounded by many nerves and muscle fibers controlling different excretory and erectile functions that are difficult but necessary to avoid, it still remains a challenge to precisely deliver radiation doses to prostate cancer without damaging the normal surrounding tissues even with image guidance. To avoid excessive irradiation doses, radiosensitizers have been developed to amplify the effects of radiation within tumor cells. Prostate cancer targeted radiosensitizers may offer a means for further relative biological dose escalation with sparing of normal tissue. However, there has been limited preclinical and clinical investigation of targeted radiosensitizers for prostate cancer. To address the challenge, we aim to develop a nanoparticle technology that will improve prostate cancer tissue visualization and discrimination by MRI, allowing greater accuracy in MRI-guided radiation therapy, and provide radiosensitization within the cancer cells. Prostate specific membrane antigen (PSMA) is an ideal target to detect prostate cancer due to its abundant expression in most prostate cancers. We have synthesized a novel high-affinity ligand for PSMA targeting, and conjugated both targeting ligand and Gd(III) complex to gold nanoparticles and nanoclusters (AuNP/NCs). We have demonstrated that these PSMA-targeted AuNP/NC-Gd(III) have a much higher relaxivity than free Gd(III) agents and the NP/NCs can be selectively delivered to PSMA-expressing prostate tumor cells, providing MR image-guided radiation therapy. By delivering Gd(III) conjugated AuNP/NCs directly to prostate cancer cells we will 1) concentrate the Gd(III) agent to the nanoparticle surface while simultaneously calibrating the delivery of more Gd(III) agent to target tissues and less of the agent to non-specific or off-target sites; 2) improve r1 relaxivity and MR sensitivity, which potentially can reduce the given doses to patients and potentially toxicity of Gd(III) agents; 3) discriminate among cancerous, normal, neural, and muscle cells and tissues with MRI, enabling precise diagnosis of prostate cancer and precision radiation therapy; 4) combine gold and gadolinium together to enhance the radiosensitizing effect for potential ablation of prostate cancer using a lower radiation dose; and 5) enable MRI-guided radiotherapy using MRI LINAC device to enhance radiation accuracy and avoid collateral damage to normal tissues. We believe that this approach will impact the quality and success of radiotherapy. Further, PSMA is also expressed on the neovasculature of a number of different solid tumors, so this approach is proof-of-principal for radiation therapy and ablation for other cancers as well.