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Dynamic topography of nanoparticles enables their ultra-long blood circulation and highly efficient antitumor efficacy
Dissertation   Open access

Dynamic topography of nanoparticles enables their ultra-long blood circulation and highly efficient antitumor efficacy

Hao Zhou
Doctor of Philosophy (Ph.D.), Drexel University
Jun 2017
DOI:
https://doi.org/10.17918/exxp-zd79
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Abstract

Biomimetic materials Polymeric drug delivery systems Heterogeneous distributed computing systems Hyaluronic acid Extracellular Matrix Materials Science
Major challenges in applying nanomedicine in cancer therapy include the quick clearance of synthetic nanoparticles in the blood and their inefficient diffusion in solid tumors. Polyethylene glycol (PEG) coating is the most commonly used approach to reduce protein adsorption on nanoparticles and extend their circulation in the blood. Unlike the conventional PEG layer, we designed a two-layered hierarchical PEG structure as the topographical surface on nanoparticles. It was found that a primary PEG layer in a dense brush regime and a dynamic outer PEG layer in the mushroom-to-brush transition regime can dramatically prolong the circulation half-lives of conventional PEGylated nanoparticles. Further studies revealed that the outer PEG layer does not reduce the amount of proteins adsorbed on nanoparticles, but reduced their binding affinity with nanoparticles, leading to decreased nanoparticle clearance by non-kupffer cells in the liver and resulting in extended nanoparticle blood circulation. Further modification of nanoparticles with recombinant human hyaluronidase PH20 (rHuPH20) under the mushroom layer instead of exposing the enzyme to the outer most PEG layer quadruples the accumulation of conventional PEGylated nanoparticles in 4T1 breast tumors. This improvement stems from the enhanced nanoparticle blood circulation and tumor penetration by degrading hyaluronic acid in the tumor matrix. Our topographical design maintains the function of rHuPH20 and avoids its negative effect on nanocarrier blood circulation. We also showed that rHuPH20 conjugated on nanoparticles is more efficient than free rHuPH20 in facilitating nanoparticle diffusion. This functionalization approach was also applied to cell membrane-coated nanoparticles, which further expanded the potential of this emerging family of nanocarriers. Thus, our platform technology may be valuable to enhance the clinical efficacy of a broad range of drug nanocarriers by extending their blood circulation. It also provides a general functionalization strategy to decorate nanoparticle surfaces with enzymes that otherwise may reduce nanoparticle circulation or lose their function in the blood.

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