Nanoparticles for efficient delivery to solid tumors

描述(由申请人提供)： 癌症分子分析的新技术确定了在致癌细胞中发生的基因和蛋白质表达变化的模式。应用这些工具进行体内分析对于全面了解转移癌是至关重要的；遗憾的是，由于缺乏有效的转移方法，此类研究一直受到限制。这些药物的纳米制剂提供体内保护和集中的肿瘤递送，因此是很有前途的递送实体。然而，纳米粒子用于肿瘤递送的一个主要限制是限制了间质转运。在这里，我们建议利用肌动蛋白聚合产生的力，通过能量中介的细胞到细胞的转移来推动纳米颗粒在间隙中，从而导致更有效的纳米颗粒渗透。这一目标可以通过实现以下目标来实现：(I)用ActA修饰纳米颗粒，ActA是一种细菌蛋白质，可以引发肌动蛋白聚合，产生推进力，并优化细胞质提取液中的运动性配方，(Ii)在培养的单层细胞中实现纳米颗粒在细胞间的转移，以及(Iii)在三维球体培养中证明纳米颗粒的渗透性得到改善。高效的输送系统对研究和临床应用都至关重要；因此，该项目的成功完成将导致朝着实现癌症的分子分析、检测和治疗的全部潜力迈出重要的一步。

DESCRIPTION (provided by applicant): New technologies for molecular analysis of cancer identify patterns of genetic and protein expression changes that have occurred in tumorigenic cells. Application of these tools for in vivo analysis is critical for a complete understanding of metastatic cancer; sadly, such studies have been limited by the lack of effective methods for delivery to metastases. Nanoparticle formulations of these agents offer in vivo protection and concentrated tumor delivery and are therefore promising delivery entities. However, a major limitation of nanoparticles for tumor delivery is restricted interstitial transport. Here, we propose to harness forces generated by actin polymerization to propel nanoparticles within the interstitial space by energy-mediated, cell-to-cell transfer, thus resulting in more efficient nanoparticle penetration. This goal can be achieved by realizing the following aims: (i) modifying nanoparticles with ActA, a bacterial protein that initiates actin polymerization resulting in propulsive forces, and optimizing formulations for motility in cytoplasmic extract, (ii) achieving actin-mediated, cell-to-cell transfer of nanoparticles in cultured monolayer cells, and (iii) demonstrating improved nanoparticle penetration in three-dimensional spheroid cultures. Efficient delivery systems are crucial for both research and clinical applications; thus, successful completion of this project would result in a major step toward realizing the full potential of molecular analysis, detection, and treatment of cancer.