PO.CH01.04 · 化学
使用组合药物递送增强三阴性乳腺癌(TNBC)的治疗
Enhanced therapy for triple-negative breast cancer (TNBC) using combinatorial drug delivery
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
乳腺癌(BrCa)是女性中最常见的癌症。尽管在早期检测和特异性治疗方面取得了进展,但长期成功仍然有限,尤其是三阴性乳腺癌(TNBC)。这一挑战源于复发、耐药以及与治疗相关的副作用等问题。化学预防即使用天然化合物来延缓、抑制或预防高危个体的癌症发展,显示出前景,但临床成功因生物利用度差而受限。Hedgehog(Hh)信号通路正被研究用于BrCa的生长和转移;因此,靶向Hh代表一种有前景的治疗策略。为应对这些挑战,我们研究了联合两种药物的效果:honokiol(HNK,一种源自厚朴Magnolia officinalis的天然化合物)与化疗药物docetaxel(DTX)联用治疗TNBC。为此,我们采用了金纳米颗粒(AuNPs)。我们的结果显示,双药递送(HNK+DTX)与sonic hedgehog(Shh)DNA适配体(AP32)偶联的AuNPs相结合,可有效靶向高表达Hh通路的TNBC细胞。在将其应用于TNBC细胞(MDA-MB-468和MDA-MB-231)之前,我们对所制备的AuNPs进行了表征,包括使用Zetasizer进行电荷和粒径分析、透射电子显微镜(TEM)、傅里叶变换红外光谱(FTIR)、核磁共振(NMR)和纳米颗粒追踪分析(NTA)。进行了细胞活力/细胞毒性检测以确定IC50值并评估药物联用协同作用。此外,3D细胞模型证实了AuNPs的内化,以及联合AuNPs相较于单药或乱序适配体AuNPs(对照)的疗效。使用免疫荧光、流式细胞术、qRT-PCR和Western blot分析的机制研究显示,Shh靶向递送抑制了下游信号分子Gli1和Ptch1的表达,诱导细胞周期停滞于G0/G1期,并触发凋亡。此外,分子动力学模拟结果提示,HNK同时影响NF-κB驱动的转录和Shh介导的信号传导,进而影响肿瘤细胞与环境的相互作用。这些发现凸显了联合AuNPs在应对TNBC的通路特异性干预中的潜力,为该领域的进一步研究奠定了基础。
查看英文原文 English abstract
Breast cancer (BrCa) is the most common cancer among women. Although there has been progress in early detection and specific therapies, long-term success is still limited, especially for triple-negative breast cancer (TNBC). This challenge arises from issues such as recurrence, drug resistance, and side effects associated with treatments. Chemoprevention, which involves using natural compounds to delay, suppress, or prevent cancer development in individuals at high risk, shows promise, but clinical success is limited by poor bioavailability. Hedgehog (Hh) signaling pathways are being studied for the growth and metastasis of BrCa; thus, targeting Hh represents a promising therapeutic strategy. To address these challenges, we studied the effects of combining two drugs: honokiol (HNK), a natural compound derived from Magnolia officinalis , alongside the chemotherapy drug docetaxel (DTX) for treating TNBC. For this purpose, we employed gold nanoparticles (AuNPs). Our results show that dual drug delivery (HNK+DTX), combined with sonic hedgehog (Shh) DNA aptamer (AP32)- conjugated AuNPs, effectively targets the Hh pathway in TNBC cells that express it at high levels. We characterized the formulated AuNPs, including a Zetasizer for charge and size analysis, Transmission Electron Microscope (TEM), Fourier-Transform Infrared Spectroscopy (FTIR), Nuclear Magnetic Resonance (NMR), and Nanoparticle Tracking Analysis (NTA), before applying them to TNBC cells (MDA-MB-468 and MDA-MB-231). A cell viability/ cytotoxicity assay was performed to determine the IC 50 values and assess drug combination synergy. Additionally, 3D cell models confirmed the internalization of AuNPs and the efficacy of combination AuNPs compared to single-drug or scramble aptamer AuNPs (control). Mechanistic studies using immunofluorescence, flow cytometry, qRT-PCR, and Western blot analysis show that Shh-targeted delivery suppresses the expression of downstream signaling molecules, Gli1 and Ptch1, induces cell cycle arrest at the G 0 /G 1 phase, and triggers apoptosis. Furthermore, results from molecular dynamics simulations suggest that HNK influences both NF-κB-driven transcription and Shh-mediated signaling, subsequently affecting tumor cell-environment interactions. These findings highlight the potential of combination AuNPs for pathway-specific intervention in addressing TNBC, providing a foundation for further research in this area.
利益披露 Disclosure
S. K. Singh, None..
M. Dababneh, None.