Dissertation/Thesis Abstract

In vivo Biodistribution, Lung Targeting, and Parametric Modulation of a DNA-Based Drug Delivery System Addressed to ICAM-1
by Roki, Nikša, Ph.D., University of Maryland, College Park, 2020, 255; 27836312
Abstract (Summary)

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.

Indexing (document details)
Advisor: Muro, Silvia, Bentley, William E.
Commitee: Getts, Robert, Kofinas, Peter, Chen, Yu
School: University of Maryland, College Park
Department: Bioengineering
School Location: United States -- Maryland
Source: DAI-B 82/1(E), Dissertation Abstracts International
Subjects: Bioengineering, Nanotechnology, Biomedical engineering
Keywords: DNA nanotechnology, ICAM-1, Nanoparticle dose concentration, Nanoparticle size, Targeted delivery in vivo, Targeting ligand density and valency
Publication Number: 27836312
ISBN: 9798662472808
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