Pharmacodynamic Studies of Fluorescent Diamond Carriers of Doxorubicin in Liver Cancer Cells and Colorectal Cancer Organoids.

IF 4.9 Q2 NANOSCIENCE & NANOTECHNOLOGY

Nanotechnology, Science and Applications Pub Date : 2021-01-01 DOI:10.2147/NSA.S321725

Ron Firestein, Cezary Marcinkiewicz, Linyan Nie, Hui Kheng Chua, Ines Velazquez Quesada, Marco Torelli, Mark Sternberg, Bojana Gligorijevic, Olga Shenderova, Romana Schirhagl, Giora Z Feuerstein

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引用次数: 1

Abstract

Background: We recently reported on preferential deposition of bare fluorescent diamond particles FDP-NV-700/800nm (FDP-NV) in the liver following intravenous administration to rats. The pharmacokinetics of FDP-NV in that species indicated short residency in the circulation by rapid clearance by the liver. Retention of FDP-NV in the liver was not associated with any pathology. These observations suggested that cancer therapeutics, such as doxorubicin, linked to FDP-NV, could potentially serve for anti-cancer treatment while sparing toxicities of peripheral organs.

Purpose: To generate proof-of-concept (POC) and detail mechanisms of action of doxorubicin-coated FDP-NV-700/800nm (FDP-DOX) as a prospective chemotherapeutic for metastatic liver cancer.

Methods: FDP-DOX was generated by adsorption chemistry. Experimental design included concentration and time-dependent efficacy studies as compared with naïve (baren) FDP-NV in in vitro liver cancer cells models. Uptake of FDP-NV and FDP-DOX by HepG-2, Hep-3B and hCRC organoids were demonstrated by flow-cytometry and fluorescent microscopy. FDP-DOX pharmacodynamic effects included metabolic as well as cell death biomarkers Annexin V, TUNEL and LDH leakage. DOX desorpted from FDP-DOX was assessed by confocal microscopy and chemical assay of cells fractions.

Results: FDP-DOX efficacy was dose- and time-dependent and manifested in both liver cancer cell lines and human CRC organoids. FDP-DOX was rapidly internalized into cancer cells/organoids leading to cancer growth inhibition and apoptosis. FDP-DOX disrupted cell membrane integrity as evident by LDH release and suppressing mitochondrial metabolic pathways (AlamarBlue assay). Access of free DOX to the nuclei was confirmed by direct UV-Visible fluorescent assay and confocal microscopy of DOX fluorescence.

Conclusion: The rapid uptake and profound cancer inhibition observed using FDP-DOX in clinically relevant cancer models, highlight FDP-DOX promise for cancer chemotherapeutics. We also conclude that the in vitro data justify further investment in in vivo POC studies.

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阿霉素荧光金刚石载体在肝癌细胞和结直肠癌类器官中的药效学研究。

背景:我们最近报道了裸荧光金刚石颗粒FDP-NV-700/800nm (FDP-NV)在大鼠静脉注射后在肝脏中的优先沉积。FDP-NV在该物种中的药代动力学表明，FDP-NV在循环中停留时间短，被肝脏迅速清除。FDP-NV在肝脏中的滞留与任何病理无关。这些观察结果表明，与FDP-NV相关的癌症治疗药物，如阿霉素，可能潜在地用于抗癌治疗，同时保留周围器官的毒性。目的:研究阿霉素包被FDP-NV-700/800nm (FDP-DOX)作为转移性肝癌的前瞻性化疗药物的概念验证(POC)和详细的作用机制。方法:采用吸附化学法制备FDP-DOX。实验设计包括浓度和时间依赖性的疗效研究，比较naïve (baren) FDP-NV在体外肝癌细胞模型中的作用。流式细胞术和荧光显微镜显示HepG-2、Hep-3B和hCRC类器官对FDP-NV和FDP-DOX的摄取。FDP-DOX的药效学效应包括代谢和细胞死亡生物标志物膜联蛋白V、TUNEL和LDH渗漏。通过共聚焦显微镜和细胞组分的化学分析来评估从FDP-DOX解吸的DOX。结果:FDP-DOX的疗效具有剂量和时间依赖性，在肝癌细胞系和人结直肠癌类器官中均有表现。FDP-DOX迅速内化到癌细胞/类器官中，导致肿瘤生长抑制和细胞凋亡。FDP-DOX通过LDH释放和抑制线粒体代谢途径破坏细胞膜完整性(AlamarBlue测定)。通过直接紫外-可见荧光测定和DOX荧光共聚焦显微镜证实了游离DOX进入细胞核。结论:FDP-DOX在临床相关癌症模型中观察到的快速摄取和深刻的肿瘤抑制作用，突出了FDP-DOX在癌症化疗药物中的前景。我们还得出结论，体外数据证明进一步投资体内POC研究是合理的。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Nanotechnology, Science and Applications NANOSCIENCE & NANOTECHNOLOGY-

CiteScore

11.70

自引率

0.00%

发文量

审稿时长

16 weeks

期刊介绍： Nanotechnology, Science and Applications is an international, peer-reviewed, Open Access journal that focuses on the science of nanotechnology in a wide range of industrial and academic applications. The journal is characterized by the rapid reporting of reviews, original research, and application studies across all sectors, including engineering, optics, bio-medicine, cosmetics, textiles, resource sustainability and science. Applied research into nano-materials, particles, nano-structures and fabrication, diagnostics and analytics, drug delivery and toxicology constitute the primary direction of the journal.