Nanoparticles for efficient delivery to solid tumors

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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.