IN VIVO BIODISTRIBUTION, LUNG TARGETING, AND PARAMETRIC MODULATION OF A DNA-BASED DRUG DELIVERY SYSTEM ADDRESSED TO ICAM-1
| dc.contributor.advisor | Muro, Silvia | en_US |
| dc.contributor.advisor | Bentley, William | en_US |
| dc.contributor.author | Roki, Niksa | en_US |
| dc.contributor.department | Bioengineering | en_US |
| dc.contributor.publisher | Digital Repository at the University of Maryland | en_US |
| dc.contributor.publisher | University of Maryland (College Park, Md.) | en_US |
| dc.date.accessioned | 2020-07-13T05:33:46Z | |
| dc.date.available | 2020-07-13T05:33:46Z | |
| dc.date.issued | 2020 | en_US |
| dc.description.abstract | The design goal of ligand-targeted nanoparticles (NPs) is to achieve site-specific targeting to specific biological targets, which can maximize therapeutic efficacy and safety. However, site-specific delivery remains suboptimal due to biological barriers, particularly non-specific interactions and sequestration of NPs by the immune system and anatomic structures of clearance organs in vivo. This formidable challenge prompted the exploration of novel ligand-based NP designs. Due to their exceptional precision, versatility, and biocompatibility, NPs composed of DNA (DNA-NPs) and targeted via ligands, have emerged as a promising strategy to deliver therapeutic effects with unique precision. One such formulation is anti-ICAM/3DNA, a multibranched DNA-made nanocarrier (3DNA®) functionalized with antibodies (Abs) against intercellular adhesion molecule-1 (ICAM-1), a cell surface glycoprotein accessible for targeting from the bloodstream and overexpressed in the lungs in many diseases. In particular, a prototype formulation of anti-ICAM/3DNA had demonstrated high cell-specific targeting and therapeutic potential in vitro. In this dissertation, we explored the kinetics, biodistribution, and lung-specific targeting in vivo of a new anti-ICAM/3DNA design that enabled precise surface functionalization with Abs to provide and modulate targeting. In Aim 1, we modified a radiotracing-based method to correct 125I-NP biodistribution results by separating the signal arising from the free 125I label, providing more accurate measurements of the NP biodistribution. In Aim 2, intravenous injection of anti-ICAM/3DNA in mice resulted in profuse and specific lung targeting, which had an unprecedently high specificity index over non-specific control. In Aim 3, we demonstrated that below the lung delivery saturation conditions and within the parametric range tested, anti-ICAM density on 3DNA played a key role in modulating lung specificity compared to the dose concentration and size of anti-ICAM/3DNA. Additionally, we estimated how this would impact targeting of drugs that can be intercalated into the DNA carrier core or linked to carrier outer arms. Overall, this study demonstrates that anti-ICAM/3DNA bio-physicochemical properties allow for efficient, specific, and tunable lung targeting. This new knowledge will help guide future DNA-NP designs for targeted therapeutic delivery and set the basis for investigational applications aimed at the treatment of pulmonary diseases. | en_US |
| dc.identifier | https://doi.org/10.13016/h4an-1y7j | |
| dc.identifier.uri | http://hdl.handle.net/1903/26249 | |
| dc.language.iso | en | en_US |
| dc.subject.pqcontrolled | Bioengineering | en_US |
| dc.subject.pqcontrolled | Nanotechnology | en_US |
| dc.subject.pqcontrolled | Biomedical engineering | en_US |
| dc.subject.pquncontrolled | DNA nanotechnology | en_US |
| dc.subject.pquncontrolled | ICAM-1 | en_US |
| dc.subject.pquncontrolled | nanoparticle dose concentration | en_US |
| dc.subject.pquncontrolled | nanoparticle size | en_US |
| dc.subject.pquncontrolled | targeted delivery in vivo | en_US |
| dc.subject.pquncontrolled | targeting ligand density and valency | en_US |
| dc.title | IN VIVO BIODISTRIBUTION, LUNG TARGETING, AND PARAMETRIC MODULATION OF A DNA-BASED DRUG DELIVERY SYSTEM ADDRESSED TO ICAM-1 | en_US |
| dc.type | Dissertation | en_US |
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