Rodponthukwaji Kamonlatth, Thongchot Suyanee, Deureh Suttikiat, Thongkleang Tanva, Thaweesuvannasak Mattika, Srichan Kornrawee, Srisawat Chatchawan, Thuwajit Peti, Nguyen Kytai T, Tadpetch Kwanruthai, Thuwajit Chanitra, Punnakitikashem Primana
Department of Biochemistry, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand.
Siriraj Center of Research Excellence in Theranostic Nanomedicine, Research Department, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand.
Int J Pharm X. 2024 Oct 17;8:100294. doi: 10.1016/j.ijpx.2024.100294. eCollection 2024 Dec.
Cancer-associated fibroblasts (CAFs) are abundant stromal cells residing in a tumor microenvironment (TME) which are associated with the progression of tumor. Herein, we developed novel CAFs-targeting polymeric nanoparticles encapsulating a synthetic 8--methylfusarubin (OMF) compound (OMF@NPs-anti-FAP). Anti-FAP/fibroblast activation protein antibody was employed as a CAFs-targeting ligand. The physicochemical properties of the synthesized nanomaterials were firstly investigated with various techniques. The cytocompatibility of polymeric nanoparticles (NPs) was elicited through cell viability of CAFs and human breast epithelial cells, MCF-10A. Additionally, the anti-FAP-conjugated NPs displayed different degrees of cellular internalization regarding the FAP expression level on the CAFs' surface. However, CAFs exposed to NPs containing OMF demonstrated significant cell death which were associated with the apoptotic pathway as confirmed by caspase-3/7 activity. Upon OMF@NPs-anti-FAP treatment, an enhanced toxicity was clearly observed in 3D spheroid models. High FAP-expressed PC-B-132CAFs demonstrated a high percentage of cell death compared to other cells with a low level of FAP expression analyzed by flow cytometry (e.g. MCF-10A, HDFa, and PC-B-142CAFs). This result emphasized the importance of anti-FAP antibody as a targeting ligand. These findings suggest that the fabricated nanosystem of OMF-loaded polymeric NPs with CAFs' high specificity holds a potential NP-based platform for improvement in breast cancer treatment.
癌症相关成纤维细胞（CAFs）是存在于肿瘤微环境（TME）中的丰富基质细胞，与肿瘤进展相关。在此，我们开发了一种新型的靶向CAFs的聚合物纳米颗粒，其包裹了一种合成的8-甲基夫沙罗汀（OMF）化合物（OMF@NPs-anti-FAP）。抗FAP/成纤维细胞活化蛋白抗体被用作靶向CAFs的配体。首先用各种技术研究了合成纳米材料的物理化学性质。通过CAFs和人乳腺上皮细胞MCF-10A的细胞活力来评估聚合物纳米颗粒（NPs）的细胞相容性。此外，抗FAP偶联的NPs在CAFs表面FAP表达水平方面表现出不同程度的细胞内化。然而，暴露于含有OMF的NPs的CAFs表现出明显的细胞死亡，这与凋亡途径相关，这通过caspase-3/7活性得到证实。在OMF@NPs-anti-FAP处理后，在3D球体模型中明显观察到毒性增强。通过流式细胞术分析，高FAP表达的PC-B-132CAFs与其他低FAP表达水平的细胞（如MCF-10A、HDFa和PC-B-142CAFs）相比，表现出高比例的细胞死亡。这一结果强调了抗FAP抗体作为靶向配体的重要性。这些发现表明，所制备的具有高CAFs特异性的负载OMF的聚合物NPs纳米系统是一种潜在的基于NP的乳腺癌治疗改进平台。
