Surasinghe Sharmane, Liatsou Ioanna, Nováková Zora, Bařinka Cyril, Artemov Dmitri, Hapuarachchige Sudath
Department of Radiology and Radiological Science, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, United States.
Department of Neuroscience, Johns Hopkins University, Baltimore, Maryland 21205, United States.
ACS Appl Mater Interfaces. 2025 Feb 26;17(8):11611-11623. doi: 10.1021/acsami.4c16009. Epub 2025 Feb 11.
Active targeting is more effective than conventional passive targeted drug delivery systems in increasing therapeutic efficacy and minimizing systemic toxicities. Importantly, the nanoparticle-based targeted drug delivery systems combine active and passive targeting properties and significantly enhance therapeutic efficacy. In this study, we utilized ultrasmall superparamagnetic iron oxide (uSPIO) nanoparticles conjugated with anti-prostate-specific membrane antigen (PSMA) 5D3 monoclonal antibody, mertansine (DM1) antitubulin agent, and fluorophore to develop a targeted uSPIO-5D3-DM1-AF488/CF750 nanotheranostic for PSMA(+) prostate cancer (PC) therapy. This agent enables multimodality imaging using near-infrared (NIR) fluorescence and magnetic resonance imaging (MRI). uSPIO-5D3-DM1-AF488 is selectively internalized into PSMA-positive cells by receptor-mediated endocytosis, and uSPIO-5D3-DM1-CF750 exhibited 1.62 and 166.2 ng/mL IC values in PSMA(+) and PSMA(-) cells, respectively. The image-guided therapeutic study was conducted in human PC xenograft mouse models bearing bilateral PSMA(±) tumors ( = 10, two 10 mg/kg doses on days 1 and 14). The therapeutic results exhibited a significant control of the growth of PSMA(+) tumors starting at day 5 ( = 0.05) and significantly improved efficacy after day 9 ( = 0.0005) during the treatment period ( = 21 days). We observed the PSMA-specific uptake of uSPIO-5D3-DM1-CF750 in tumors in NIR IVIS Xenogen images and - and -weighted MRI with 20.6% and 42% reduction of overall and , respectively. Approximately 70% of mice with PSMA(+) tumors treated with uSPIO-5D3-DM1-CF750 survived or did not exceed the threshold level of the tumor size during the treatment. biodistribution study proved 50% and 45% higher uptake of uSPIO-5D3-DM1-CF750 by PSMA(+) tumors compared to untargeted uSPIO-DM1-CF750 by PSMA(+) tumors and uSPIO-5D3-DM1-CF750 by PSMA(-) tumors, respectively. ICP-MS analysis demonstrated a 73% increase in uSPIO-5D3-DM1-CF750 uptake by PSMA(+) tumors compared to PSMA(+) tumors treated with pure uSPIO. The toxicological results reveal the safe profile in systemic toxicities without life-threatening changes in the complete blood count and clinical chemistry profile of toxicology.
主动靶向在提高治疗效果和最小化全身毒性方面比传统的被动靶向给药系统更有效。重要的是，基于纳米颗粒的靶向给药系统结合了主动和被动靶向特性，并显著提高了治疗效果。在本研究中，我们利用与抗前列腺特异性膜抗原（PSMA）5D3单克隆抗体、美登素（DM1）抗微管蛋白剂和荧光团偶联的超小超顺磁性氧化铁（uSPIO）纳米颗粒，开发了一种用于PSMA（+）前列腺癌（PC）治疗的靶向uSPIO-5D3-DM1-AF488/CF750纳米诊疗剂。该制剂能够使用近红外（NIR）荧光和磁共振成像（MRI）进行多模态成像。uSPIO-5D3-DM1-AF488通过受体介导的内吞作用选择性地内化到PSMA阳性细胞中，并且uSPIO-5D3-DM1-CF750在PSMA（+）和PSMA（-）细胞中的IC值分别为1.62和166.2 ng/mL。在携带双侧PSMA（±）肿瘤的人PC异种移植小鼠模型中进行了图像引导的治疗研究（n = 10，在第1天和第14天给予两个10 mg/kg剂量）。治疗结果显示，从第5天开始对PSMA（+）肿瘤的生长有显著控制（p = 0.05），并且在治疗期（n = 21天）第9天后疗效显著改善（p = 0.0005）。我们在NIR IVIS Xenogen图像以及T2加权和T1加权MRI中观察到uSPIO-5D3-DM1-CF750在肿瘤中的PSMA特异性摄取，总体T2和T1分别降低了20.6%和42%。用uSPIO-5D3-DM1-CF750治疗的PSMA（+）肿瘤小鼠中，约70%在治疗期间存活或肿瘤大小未超过阈值水平。生物分布研究证明，与未靶向的uSPIO-DM1-CF750在PSMA（+）肿瘤中的摄取以及uSPIO-5D3-DM1-CF750在PSMA（-）肿瘤中的摄取相比，uSPIO-5D3-DM1-CF750在PSMA（+）肿瘤中的摄取分别高50%和45%。电感耦合等离子体质谱（ICP-MS）分析表明，与用纯uSPIO治疗的PSMA（+）肿瘤相比，PSMA（+）肿瘤对uSPIO-5D3-DM1-CF750的摄取增加了73%。毒理学结果显示在全身毒性方面具有安全特征，全血细胞计数和毒理学临床化学指标没有危及生命的变化。
