Sub-TumorDistribution Of PRINT Nanoparticles And Its Application For Nucleic Acid Delivery Public Deposited

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  • March 19, 2019
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  • Roode, Luke
    • Affiliation: Eshelman School of Pharmacy, Division of Pharmacoengineering and Molecular Pharmaceutics
Abstract
  • Nanoparticle accumulation is typically measured at the organ level. However, much basic in vitro and in vivo research points to differences in nanoparticle internalization and interaction among cell types. This is a particularly significant point when considering solid tumor drug delivery with nanoparticles where there is a significant interplay between the pathophysiology and physical forces present within the tumor, the nanoparticle itself, and the mileu of cell types present. Unlike other nanoparticle fabrication systems, PRINT affords the exquisite ability to control size and shape of a given nanoparticle. Particles fabricated with this method are highly uniform, allowing for easy control and dissection of the interplay between nanoparticle properties and resulting effects. Herein we describe an approach to examining the distribution of particles within the tumor. This approach accounts for 98.6% of all live cells that were dissociated from the tumor. Analysis of the particle association of the sub-populations present reveals that the nanoparticle dose administered shows dose-independent cancer cell association at high doses using 80x320nm PRINT hydrogel nanoparticles. Moreover, this maximal association seen with this approach is roughly 7%. Notably, other immune cells like macrophages and neutrophils show significant association with particles. Quantification of the mean fluroesence intensity of particle-positive cells reveals that macrophages associate with significantly more particles per cell than any other cell type, perhaps suggesting that macrophages may be a significant target of nanoparticles within the tumor. Overall, however, the data shows that cancer cells are still the main cell type of accumulation due to the fact that in this model, macrophages make up roughly 1% of the tumor. Other nanoparticle factors like size and route of administration were similarly examined. Smaller nanoparticle size seemed to play a significant role in increasing cancer cell association as well as increasing the accumulation of particles to cancer cells. When administering particles intratumorally, cancer cell association was increased along with significant increases in the mean fluorescence intensity. Combined, these results suggest a need for analysis of particle distribution and association at the cellular level.
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  • In Copyright
Advisor
  • Huang, Leaf
  • DeSimone, Joseph M.
  • Davis, Ian
  • Wang, Andrew
  • Juliano, Rudolph
Degree
  • Doctor of Philosophy
Degree granting institution
  • University of North Carolina at Chapel Hill Graduate School
Graduation year
  • 2014
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  • Chapel Hill, NC
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  • This item is restricted from public view for 1 year after publication.
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