Biancacci Ilaria, De Santis Daniele, Rama Elena, Benderski Karina, Momoh Jeffrey, Pohlberger Robert, Moeckel Diana, Kaps Leonard, Rijcken Cristianne Jf, Prakash Jai, Thewissen Marielle, Kiessling Fabian, Shi Yang, Peña Quim, Sofias Alexandros Marios, Consolino Lorena, Lammers Twan
RWTH Aachen University, Department of Nanomedicine and Theranostics, Institute for Experimental Molecular Imaging, Forckenbeckstrasse 55, 52074, Aachen, Germany.
University of Urbino, Department of Biomolecular Sciences, Piazza Rinascimento 6, 61029, Urbino, Italy.
Adv Ther (Weinh). 2023 Jul 19;6(11). doi: 10.1002/adtp.202300098. eCollection 2023 Nov.
The dense stromal matrix in fibrotic tumors hinders tumor-targeted drug delivery. Tamoxifen (TMX), an estrogen receptor modulator that is clinically used for the treatment of breast cancer, has been shown to reprogram the tumor microenvironment (TME) and to alleviate desmoplasia. We here investigated if TMX, administered in free and nano-formulated form, can be repurposed as a TME remodeling agent to improve tumor accumulation of nano-formulations in pancreatic ductal adenocarcinoma and triple-negative breast cancer mouse models, evaluated using clinical-stage Cy7-labeled core-crosslinked polymeric micelles (CCPM). Under control conditions, we found higher levels of Cy7-CCPM in PANC-1 tumors (16.7 % ID g at 48 h post i.v. injection) than in 4T1 tumors (11.0 % ID g). In both models, free and nano-formulated TMX failed to improve CCPM delivery. These findings were congruent with the results from histopathological immunofluorescence analysis of tumor tissue, which indicated that TMX treatment did not significantly change vascularization, perfusion, macrophage infiltration, collagen density, and collagen fiber thickness. Altogether, our results demonstrate that in PANC-1 and 4T1 mouse models, TMX treatment does not contribute to beneficial TME priming and enhanced tumor-targeted drug delivery.
纤维化肿瘤中致密的基质会阻碍肿瘤靶向药物递送。他莫昔芬（TMX）是一种临床上用于治疗乳腺癌的雌激素受体调节剂，已被证明可重塑肿瘤微环境（TME）并减轻纤维组织增生。我们在此研究了以游离形式和纳米制剂形式给药的TMX是否可重新用作TME重塑剂，以改善纳米制剂在胰腺导管腺癌和三阴性乳腺癌小鼠模型中的肿瘤蓄积，使用临床阶段的Cy7标记的核心交联聚合物胶束（CCPM）进行评估。在对照条件下，我们发现PANC-1肿瘤中Cy7-CCPM的水平（静脉注射后48小时为16.7% ID/g）高于4T1肿瘤（11.0% ID/g）。在两种模型中，游离形式和纳米制剂形式的TMX均未能改善CCPM递送。这些发现与肿瘤组织的组织病理学免疫荧光分析结果一致，该分析表明TMX治疗并未显著改变血管生成、灌注、巨噬细胞浸润、胶原密度和胶原纤维厚度。总之，我们的结果表明，在PANC-1和4T1小鼠模型中，TMX治疗无助于有益的TME启动和增强的肿瘤靶向药物递送。
