Development of cancer-associated fibroblasts-targeting polymeric nanoparticles loaded with 8-O-methylfusarubin for breast cancer treatment

IF 5.2 2区 医学 Q1 PHARMACOLOGY & PHARMACY International Journal of Pharmaceutics: X Pub Date : 2024-10-17 DOI:10.1016/j.ijpx.2024.100294
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Abstract

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-O-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.

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开发癌症相关成纤维细胞靶向聚合物纳米颗粒,载入 8-O-甲基扶桑黄素用于乳腺癌治疗
癌症相关成纤维细胞(CAFs)是肿瘤微环境(TME)中大量存在的基质细胞,与肿瘤的进展有关。在此,我们开发了新型的CAFs靶向聚合物纳米颗粒,其中封装了一种合成的8-O-甲基木糖醇(OMF)化合物(OMF@NPs-anti-FAP)。抗 FAP/成纤维细胞活化蛋白抗体被用作 CAFs 靶向配体。首先利用各种技术研究了合成纳米材料的理化性质。通过测定 CAFs 和人乳腺上皮细胞 MCF-10A 的细胞活力,研究了聚合物纳米颗粒(NPs)的细胞相容性。此外,根据 CAFs 表面 FAP 的表达水平,抗 FAP 结合物 NPs 显示出不同程度的细胞内化。然而,暴露于含有 OMF 的 NPs 的 CAF 表现出明显的细胞死亡,这与细胞凋亡途径有关,并通过 caspase-3/7 活性得到证实。经 OMF@NPs-anti-FAP 处理后,在三维球状模型中明显观察到毒性增强。与流式细胞术分析的其他FAP表达水平较低的细胞(如MCF-10A、HDFa和PC-B-142CAFs)相比,FAP表达水平较高的PC-B-132CAFs表现出较高的细胞死亡比例。这一结果强调了抗 FAP 抗体作为靶向配体的重要性。这些研究结果表明,利用 CAFs 的高特异性制造出的负载 OMF 的聚合物 NP 纳米系统是一种潜在的基于 NP 的平台,可改善乳腺癌的治疗。
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来源期刊
International Journal of Pharmaceutics: X
International Journal of Pharmaceutics: X Pharmacology, Toxicology and Pharmaceutics-Pharmaceutical Science
CiteScore
6.60
自引率
0.00%
发文量
32
审稿时长
24 days
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