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The Tumor Microenvironment02:17

The Tumor Microenvironment

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Every normal cell or tissue is embedded in a complex local environment called stroma, consisting of different cell types, a basal membrane, and blood vessels. As normal cells mutate and develop into cancer cells, their local environment also changes to allow cancer progression. The tumor microenvironment (TME) consists of a complex cellular matrix of stromal cells and the developing tumor. The cross-talk between cancer cells and surrounding stromal cells is critical to disrupt normal tissue...
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Analysis of Targeted Viral Protein Nanoparticles Delivered to HER2+ Tumors
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瘤微环境向的 PROTAC 纳米颗粒自组装被结构描述器广泛预测.

Kristen C Vogt1,2,3, Magdalini Panagiotakopoulou1, Mandana T Manzari Honu1

  • 1Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.

Science advances
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针对蛋白质分解的嵌合体 (PROTACs) 自组装成纳米粒子 (nanoPROTACs),改善药物输送和疗效. 在临床前模型中,这种策略增强了瘤向,药物吸收和生存.

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科学领域:

  • 生物化学 生物化学
  • 纳米技术 纳米技术
  • 药理学 药理学是指药理学的学科.

背景情况:

  • 针对蛋白质溶解的嵌合体 (PROTACs) 显示出临床前前景,但由于药理性质和毒性差,往往与大分子量有关,因此面临临临床翻译挑战.
  • PROTACs的非药物特性,包括高分子量,阻碍了它们的临床应用.

研究的目的:

  • 研究PROTACs自组装成纳米粒子 (纳米PROTACs),以克服药物动力学限制.
  • 识别能够预测纳米PROTAC形成的分子描述物,并评估它们的治疗潜力.

主要方法:

  • 利用基于结构的预测算法来识别驱动纳米PROTAC形成的分子描述符.
  • 开发了P-selectin向的纳米PROTACs,用于输送到瘤微环境中.
  • 评估瘤药物吸收,标降解,瘤生长抑制,以及固体瘤异种移植中的存活率.

主要成果:

  • 大多数PROTAC自组装成具有高药载荷能力的纳米粒子 (纳米PROTAC).
  • 确定了特定的分子描述器,以高精度 (96%的灵敏度,100%的特异性) 预测纳米PROTAC的形成.
  • 针对P-选择因的纳米PROTACs在临床前模型中显示显著增强瘤药物吸收,标降解,瘤生长抑制,并改善了生存率.

结论:

  • PROTACs可以自组装成纳米粒子,为改善其药理性质和治疗指数提供了一种策略.
  • 纳米PROTACs代表了一种有前途的方法,以提高PROTACs和其他非药物类似疗法的疗效.
  • 向的纳米PROTAC输送到瘤微环境显著改善了固体瘤模型中的治疗结果.