PSMA-targeted AuNPs for MR guided radiotherapy and radiosensitization

临床放射治疗是一种缓解癌症进展的非侵入性手段， 超过50%的前列腺癌患者。辐射技术的发展，如利用强度- 调强放射治疗（IMRT）提供高度适形的辐射剂量分布和图像引导 放射治疗（IGRT），以解决目标解剖结构和定位的日常变化，允许前所未有的水平 准确性和治疗效果。前列腺周围有许多神经和肌肉纤维， 不同的排泄和勃起功能是困难的，但必须避免，它仍然是一个挑战， 精确地将辐射剂量输送到前列腺癌，而不损伤正常的周围组织， 图像制导为了避免过量的辐射剂量，已经开发了放射增敏剂来放大辐射剂量。 辐射对肿瘤细胞的影响。前列腺癌靶向放射增敏剂可能提供进一步治疗的手段。 相对生物剂量递增，但不影响正常组织。然而，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 开发纳米颗粒技术，通过以下方式改善前列腺癌组织的可视化和识别 MRI，使MRI引导的放射治疗更准确，并在癌症内提供放射增敏作用 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高亲和力的PSMA配体 靶向，并将靶向配体和Gd（III）络合物结合到金纳米颗粒和纳米团簇上 (AuNP/NCs）。我们已经证明，这些PSMA靶向的AuNP/NC-Gd（III）具有高得多的弛豫率， 游离Gd（III）试剂和NP/NC可以选择性地递送至表达PSMA的前列腺肿瘤细胞， 提供MR图像引导的放射治疗。通过将Gd（III）缀合的AuNP/NC直接递送至前列腺， 我们将1）将Gd（III）剂浓缩到纳米颗粒表面，同时校准 将更多的Gd（III）药剂递送到靶组织，而将更少的药剂递送到非特异性或脱靶位点; 2） 改善r1弛豫率和MR灵敏度，这可能会降低患者的给定剂量， Gd（III）试剂的毒性; 3）区分癌性、正常、神经和肌肉细胞和组织， 磁共振成像，能够精确诊断前列腺癌和精确放射治疗; 4）将联合收割机与 钆一起使用，以增强放射增敏作用，用于使用较低的 辐射剂量;以及5）使用MRI LINAC设备实现MRI引导的放射治疗，以提高辐射准确性 并避免对正常组织的附带伤害。我们相信，这种方法将影响质量和成功 放射治疗。此外，PSMA还在许多不同实体瘤的新生血管上表达， 因此该方法也是用于其它癌症的放射治疗和消融的原理证明。

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.