Department of Nanomedicine and Theranostics, Institute for Experimental Molecular Imaging, Faculty of Medicine, RWTH Aachen University, Aachen, Germany.
Department of Nanomedicine and Theranostics, Institute for Experimental Molecular Imaging, Faculty of Medicine, RWTH Aachen University, Aachen, Germany; Gremse-IT GmbH, Aachen, Germany.
J Control Release. 2020 Dec 10;328:805-816. doi: 10.1016/j.jconrel.2020.09.046. Epub 2020 Sep 30.
Core-crosslinked polymeric micelles (CCPM) based on PEG-b-pHPMA-lactate are clinically evaluated for the treatment of cancer. We macroscopically and microscopically investigated the biodistribution and target site accumulation of CCPM. To this end, fluorophore-labeled CCPM were intravenously injected in mice bearing 4T1 triple-negative breast cancer (TNBC) tumors, and their localization at the whole-body, tissue and cellular level was analyzed using multimodal and multiscale optical imaging. At the organism level, we performed non-invasive 3D micro-computed tomography-fluorescence tomography (μCT-FLT) and 2D fluorescence reflectance imaging (FRI). At the tissue and cellular level, we performed extensive immunohistochemistry, focusing primarily on cancer, endothelial and phagocytic immune cells. The CCPM achieved highly efficient tumor targeting in the 4T1 TNBC mouse model (18.6 %ID/g), with values twice as high as those in liver and spleen (9.1 and 8.9 %ID/g, respectively). Microscopic analysis of tissue slices revealed that at 48 h post injection, 67% of intratumoral CCPM were localized extracellularly. Phenotypic analyses on the remaining 33% of intracellularly accumulated CCPM showed that predominantly F4/80 phagocytes had taken up the nanocarrier formulation. Similar uptake patterns were observed for liver and spleen. The propensity of CCPM to primarily accumulate in the extracellular space in tumors suggests that the anticancer efficacy of the formulation mainly results from sustained release of the chemotherapeutic payload in the tumor microenvironment. In addition, their high uptake by phagocytic immune cells encourages potential use for immunomodulatory anticancer therapy. Altogether, the beneficial biodistribution, efficient tumor targeting and prominent engagement of PEG-b-pHPMA-lactate-based CCPM with key cell populations underline the clinical versatility of this clinical-stage nanocarrier formulation.
基于 PEG-b-pHPMA-乳酸的核交联聚合物胶束（CCPM）已在癌症治疗的临床评估中进行研究。我们从宏观和微观角度研究了 CCPM 的生物分布和靶位积累。为此，我们将荧光标记的 CCPM 静脉注射到患有 4T1 三阴性乳腺癌（TNBC）的小鼠体内，并使用多模态和多尺度光学成像分析它们在全身、组织和细胞水平的定位。在机体水平上，我们进行了非侵入性的 3D 微计算机断层荧光成像（μCT-FLT）和 2D 荧光反射成像（FRI）。在组织和细胞水平上，我们进行了广泛的免疫组织化学分析，主要关注癌症、内皮和吞噬免疫细胞。CCPM 在 4T1 TNBC 小鼠模型中实现了高效的肿瘤靶向（18.6%ID/g），其值是肝脏和脾脏的两倍（9.1%ID/g 和 8.9%ID/g）。注射后 48 小时对组织切片进行的微观分析表明，67%的肿瘤内 CCPM 定位于细胞外。对剩余 33%的细胞内积累的 CCPM 进行表型分析表明，主要是 F4/80 吞噬细胞摄取了纳米载体制剂。在肝脏和脾脏中也观察到类似的摄取模式。CCPM 主要在肿瘤的细胞外空间中积累的倾向表明，该制剂的抗癌疗效主要源于在肿瘤微环境中持续释放化疗药物。此外，它们被吞噬免疫细胞大量摄取，这鼓励了将其用于免疫调节抗癌治疗的潜在用途。总之，CCPM 具有有利的生物分布、高效的肿瘤靶向和与关键细胞群的显著结合，突出了这种临床阶段纳米载体制剂的临床多功能性。
