Controlled Synthesis of Gold Nanoparticle Aggregates as a Platform for Investigating Nanoparticle Uptake, Biodistribution, and Clearance
Başlık:
Controlled Synthesis of Gold Nanoparticle Aggregates as a Platform for Investigating Nanoparticle Uptake, Biodistribution, and Clearance
Yazar:
Liu, Alice T., author.
ISBN:
9780438055933
Yazar Ek Girişi:
Fiziksel Tanımlama:
1 electronic resource (212 pages)
Genel Not:
Source: Dissertation Abstracts International, Volume: 79-10(E), Section: B.
Advisors: Jacob M. Berlin; Tim Synold Committee members: John E. Shively; Konstantin Sokolov; John Termini.
Özet:
Liver accumulation and clearance is a primary concern for any nanoparticle-based delivery system because high liver accumulation decreases the effective dose that can be delivered to the target site. Despite the various nanoparticle design strategies used to decrease uptake by macrophages of the mononuclear phagocytic system, the majority of nanoparticles injected into the bloodstream still accumulate within the liver. In order to study both liver accumulation and clearance, we sought to design a nanomaterial that can meet the size parameters for each step---large enough to accumulate within the liver, yet small enough to potentially be excreted after initial accumulation.
Our lab has previously developed a unique method for the controlled assembly of smaller gold nanoparticles (AuNPs) into larger, uniform aggregates using a tetravalent small molecule crosslinker. In this work I expand the synthesis platform using trivalent and bivalent crosslinkers, and describe the impact of crosslinker valency on aggregate physicochemical properties. For all three crosslinkers, the final aggregate size can be by simply varying crosslinker concentration. Additionally, decreasing crosslinker valency increases the range of AuNP subunit sizes that can be assembled into aggregates. Therefore, by tuning linker valency and linker concentration, a variety of permutations of final aggregate size and AuNP subunit size can be synthesized and tailored for different applications.
In probing the biological interactions of these aggregates, we found that changing crosslinker valency significantly changed the degree of cellular uptake. This difference in uptake was not due to cytotoxicity, agglomeration in cell culture media, or any measurable differences in aggregate size, shape, surface charge, and surface chemistry. However, these aggregates did have differences in their surface coverage (as measured by cyanide stability), and aggregates with higher surface coverage had lower cell uptake. This relationship between surface coverage and cell uptake was further demonstrated using a model system of 50 nm solid particles (gold and silver) with a high surface coverage coating using the tetravalent and trivalent crosslinkers.
Despite these aggregates demonstrating extremely low cell uptake in vitro, in vivo biodistribution experiments showed that they still accumulated rapidly and to a great degree in the liver and spleen. Additionally, we found that after 1 month post-injection, aggregates did not show increased clearance from the liver compared to solid AuNPs. Therefore, although surface coverage can predict in vitro cell uptake, neither of these could predict in vivo biodistribution.
Although these aggregates did not exhibit decreased accumulation or enhanced clearance from the liver, they have allowed us to challenge long-standing paradigms about the mechanism of nanoparticle accumulation in the liver. Our nanomaterials have demonstrated that biodistribution and clearance more complex than can be predicted by current assays such as in vitro cell uptake. Future studies investigating other parameters, such as PEG coating stability and the spatial distribution of aggregates in the liver, will progress our understanding of how nanoparticles interact with the liver, with the hope of improving the clinical translation of nanoparticle-based therapies in the future.
Notlar:
School code: 0517
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Yer Numarası | Demirbaş Numarası | Shelf Location | Lokasyon / Statüsü / İade Tarihi |
---|---|---|---|
XX(680689.1) | 680689-1001 | Proquest E-Tez Koleksiyonu | Arıyor... |
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