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Targeting CD44 with nanoparticles in head and neck squamous cell carcinoma: A novel therapeutic strategy against cancer stem cells

机译：在头颈部鳞状细胞癌中以纳米粒子靶向CD44：针对癌症干细胞的新型治疗策略

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摘要

Head and neck squamous cell carcinoma (HNSCC) is the sixth most common type of cancer worldwide and is associated with significant morbidity and mortality. Advances in multi-modality treatments have only minimally improved survival rates in the past several years. Recent attention has been focused on the hypothesis that cancer stem cells (CSCs) may be responsible for the failure of current treatments. In HNSCC, a CSC population is contained within the cell fraction that expresses high levels of CD44. CD44 is a cell surface glycoprotein and was the first CSC marker to be described in solid malignancies. in this study, hyaluronan conjugated, dextran-coated super paramagnetic iron-oxide nanoparticles (HA-DESPIONs) were used to target the CD44 population in CD44-overexpressed HNSCC cell lines for treatment by establishing the interaction of HA-DESPIONs with radiation and hyperthermia therapy.;The first part of this dissertation studied the cytotoxic, radiosensitizing, and hyperthermic properties of the HA-DESPIONs using cell proliferation and clonogenic survival assays. Cells were grown, plated, treated with HA-DESPIONs, irradiated/exposed to local hyperthermia, and then analyzed for apoptosis. HA-DESPIONs proved to be relatively non-toxic and nonradiosensitizing. However, temperature-dependent cell survival reduction upon incubation with HA-DESPIONs was observed with evidence of apoptotic cell death. These results supported further development of an alternating magnetic field (AMF) approach to activate the HADESPIONs attached to CSCs.;In the second part of the dissertation, an AMF generator was constructed and its heat generating effect was tested via kinetic and dose-dependent bulk heating experiments by exposing magnetic nanoparticles to AMF. For elimination of the CD44 population, cells were treated with HA-DESPIONs/DESPIONs, exposed to AMF, and processed for flow cytometrybased apoptosis analysis. Magnetic nanoparticles caused concentration-dependent bulk heating in response to AMF resulting in a significant temperature rise. Following exposure to AMF, DESPIONs were unable to induce targeted hyperthermia and hence had no effect on CD44 cell death in HNSCC cells. However, there was significant cell death in the CD44 population treated with HA-DESPIONs and exposed to AMF. This effect was observed only when the AMF was turned on. These results demonstrated that HA-DESPIONs caused targeted cell-death in CD44overexpressing cells. This may be a promising strategy to specifically target CSCs for the treatment of HNSCC.
机译：头颈部鳞状细胞癌（HNSCC）是全球第六大最常见的癌症，与高发病率和高死亡率相关。在过去的几年中，多模式治疗的进展仅使生存率仅有极少的提高。最近的注意力集中在癌症干细胞（CSC）可能导致当前治疗失败的假说上。在HNSCC中，CSC群体包含在表达高水平CD44的细胞级分内。 CD44是一种细胞表面糖蛋白，是第一个在实体恶性肿瘤中描述的CSC标记。在这项研究中，透明质酸缀合的葡聚糖包被的超顺磁性氧化铁纳米粒子（HA-DESPIONs）被用于靶向CD44过表达的HNSCC细胞系中的CD44群体，通过建立HA-DESPIONs与放射线和高温疗法的相互作用来治疗本文的第一部分使用细胞增殖和克隆形成存活试验研究了HA-DESPIONs的细胞毒性，放射增敏和高温特性。细胞生长，铺板，用HA-DESPIONs处理，照射/暴露于局部高温，然后分析细胞凋亡。 HA-DESPIONs被证明是相对无毒且无放射敏感性的。但是，观察到与HA-DESPIONs孵育后温度依赖性细胞存活率降低，并有凋亡细胞死亡的迹象。这些结果支持了交流磁场（AMF）方法的进一步发展，以激活附着在CSC上的HADESPION。通过将磁性纳米颗粒暴露于AMF进行​​加热实验。为了消除CD44群体，将细胞用HA-DESPIONs / DESPIONs处理，暴露于AMF，并处理以用于基于流式细胞术的凋亡分析。磁性纳米颗粒响应AMF引起浓度依赖性整体加热，导致温度显着上升。暴露于AMF后，DESPIONs无法诱导靶向高温，因此对HNSCC细胞中CD44细胞死亡没有影响。但是，用HA-DESPIONs处理并暴露于AMF的CD44群体中存在明显的细胞死亡。仅在打开AMF时观察到此效果。这些结果表明，HA-DESPIONs在CD44过表达的细胞中引起了定向的细胞死亡。这可能是一个有前途的策略，专门针对CSCs治疗HNSCC。

著录项

  • 作者

    Thapa, Ranjeeta.;

  • 作者单位

    Oakland University.;

  • 授予单位 Oakland University.;
  • 学科 Oncology.;Biology.;Physics.
  • 学位 Ph.D.
  • 年度 2016
  • 页码 183 p.
  • 总页数 183
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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