Department of Radiation Oncology, Miller School of Medicine, University of Miami, Miami, Florida; Department of Biomedical Engineering, College of Engineering, University of Miami, Miami, Florida.
Department of Radiation Oncology, Miller School of Medicine, University of Miami, Miami, Florida.
Int J Radiat Oncol Biol Phys. 2021 Sep 1;111(1):220-232. doi: 10.1016/j.ijrobp.2021.04.032. Epub 2021 May 6.
The gold nanoparticle (GNP) as a promising theranostic probe has been increasingly studied. The tumor-targeting efficiency of GNPs is crucial to increase the therapeutic ratio. In this study, we developed PSMA-targeted GNPs to enhance GNP uptake in prostate cancer and developed an x-ray fluorescence imaging system to noninvasively monitor and assess GNP delivery.
For targeted therapy of prostate cancer, anti-prostate-specific membrane antigen (PSMA) antibodies were conjugated onto PEGylated GNPs through 1-ethyl-3-(-3-dimethylaminopropyl) carbodiimide (EDC) and N-hydroxysuccinimide (NHS) (EDC/NHS) chemistry. In vivo imaging was implemented using an in-house-developed dual-modality computed tomography (CT) and x-ray fluorescence CT (XFCT) system on mice bearing subcutaneous LNCaP prostate tumors. After intravenous administration of GNPs (15 mg/mL, 200 μL), the x-ray fluorescence signals from the tumor were collected at various time points (5 minutes to approximately 30 hours) for GNP pharmacokinetics analysis. At 24 hours after administration, x-ray fluorescence projection (XRFproj) and XFCT imaging were conducted to evaluate the prostate tumor uptake of active- and passive-targeting GNPs. Inductively coupled plasma mass spectrometry analysis was adopted as a benchmark to verify the quantification accuracy of XRFproj/XFCT imaging.
Fluorescence microscopic imaging confirmed the enhanced (approximately 4 times) targeting efficiency of PSMA-targeted GNPs in vitro. The pharmacokinetics analysis showed enhanced tumor uptake/retention of PSMA-targeted GNPs and revealed that the peak tumor accumulation appeared at approximately 24 hours after intravenous administration. Both XRFproj and XFCT imaging presented their accuracy in quantifying GNPs within tumors noninvasively. Moreover, XFCT imaging verified its unique capabilities to simultaneously determine the heterogeneous spatial distribution and the concentration of GNPs within tumors in vivo.
In conjunction with PSMA-targeted GNPs, XRFproj/XFCT would be a highly sensitive tool for targeted imaging of prostate cancer, benefiting the elucidation of mechanisms of GNP-assisted prostate-cancer therapy.
金纳米颗粒（GNP）作为一种很有前途的治疗诊断探针，越来越受到研究关注。GNP 的肿瘤靶向效率对提高治疗比率至关重要。在这项研究中，我们开发了 PSMA 靶向 GNP，以增强前列腺癌中的 GNP 摄取，并开发了一种 X 射线荧光成像系统，以非侵入性地监测和评估 GNP 递送。
为了对前列腺癌进行靶向治疗，通过 1-乙基-3-(-3-二甲基氨基丙基)碳化二亚胺（EDC）和 N-羟基琥珀酰亚胺（NHS）（EDC/NHS）化学将抗前列腺特异性膜抗原（PSMA）抗体偶联到聚乙二醇化 GNP 上。在携带皮下 LNCaP 前列腺肿瘤的小鼠上使用内部开发的双模态计算机断层扫描（CT）和 X 射线荧光 CT（XFCT）系统进行体内成像。在静脉内给予 GNP（15 mg/mL，200 μL）后，在不同时间点（5 分钟至约 30 小时）采集肿瘤的 X 射线荧光信号，以进行 GNP 药代动力学分析。给药后 24 小时，进行 X 射线荧光投影（XRFproj）和 XFCT 成像，以评估主动和被动靶向 GNP 的前列腺肿瘤摄取。采用电感耦合等离子体质谱分析作为基准，以验证 XRFproj/XFCT 成像的定量准确性。
荧光显微镜成像证实了 PSMA 靶向 GNP 的体外靶向效率提高了（约 4 倍）。药代动力学分析显示 PSMA 靶向 GNP 的肿瘤摄取/保留增强，并表明静脉内给药后约 24 小时达到肿瘤峰值积累。XRFproj 和 XFCT 成像都可以准确地无创定量肿瘤内的 GNP。此外，XFCT 成像验证了其同时确定肿瘤内 GNP 不均匀空间分布和浓度的独特能力。
结合 PSMA 靶向 GNP，XRFproj/XFCT 将成为前列腺癌靶向成像的一种高灵敏度工具，有助于阐明 GNP 辅助前列腺癌治疗的机制。
