Abstract/Details

Engineering nanoparticle adhesive properties for selective targeting of cardiovascular disease


2008 2008

Other formats: Order a copy

Abstract (summary)

Receptor-mediated targeting of nano-metric drug or contrast agent carriers holds great potential for treating cardiovascular and vascular-associated diseases. However, predicting the adhesive behavior of these vectors under dynamic conditions is complex due to the interplay of transport, hydrodynamic force and multivalent bond formation dynamics. To address this problem we first developing techniques to analyze multivalent particle adhesion using data that was generated using a model nanocarrier comprised of a 200 nm diameter polystyrene particle coated with monoclonal antibody (Chapter 3). These analytical techniques included a transport-reaction model to track particle species, account for transport phenomena and define kinetic parameters for attachment and detachment. In addition, since particles displayed history-dependent detachment behavior, we employed a Monte Carlo simulation to recreate binding data by stochastically sampling for detachment events based on a time-dependent detachment rate. Next we extended the model system to include 40 nm and 1 µm particles, and demonstrated that size can dramatically affect both carrier recruitment efficiency and bound-state stability (Chapter 4). This included influences from both fluid flow dependent factors as well as the size of the contact area. Furthermore, we demonstrated how particle size can be exploited to engineer delivery carriers with optimal binding characteristics for given therapeutic applications. Next we examined the dependence of receptor/ligand bond properties on nanoparticle adhesion using numerous molecular adhesion systems, including recombinant antibody fragment proteins engineered with specific kinetic and structural characteristics (Chapter 5). Using these systems we demonstrated a significant role for receptor size but observed limited influences from kinetics and mechanics. Finally, we developed a novel single-chain antibody that was specific for VCAM-1 and demonstrated that it can effectively mediate nanoparticle binding under flow, and thus could serve as a viable option to target nanocarriers to VCAM-1 related pathologies such as atherosclerosis and inflammation (Chapter 6). Taken together, these findings demonstrate that targeted nanocarrier adhesion can be engineered through appropriate selection of carrier size, molecular binding efficiency and valency tuning, which could hold important implications for optimizing the efficacy of targeted therapies.

Indexing (details)


Subject
Biomedical research
Classification
0541: Biomedical research
Identifier / keyword
Applied sciences; Cardiovascular drug delivery; Molecular adhesion; Molecular targeting; Multivalent adhesion; Nanoparticles; Selective targeting; Single-chain antibody
Title
Engineering nanoparticle adhesive properties for selective targeting of cardiovascular disease
Author
Haun, Jered Brackston
Number of pages
214
Publication year
2008
Degree date
2008
School code
0175
Source
DAI-B 69/04, Dissertation Abstracts International
Place of publication
Ann Arbor
Country of publication
United States
ISBN
9780549573142
University/institution
University of Pennsylvania
University location
United States -- Pennsylvania
Degree
Ph.D.
Source type
Dissertations & Theses
Language
English
Document type
Dissertation/Thesis
Dissertation/thesis number
3309441
ProQuest document ID
304504009
Copyright
Database copyright ProQuest LLC; ProQuest does not claim copyright in the individual underlying works.
Document URL
http://search.proquest.com/docview/304504009
Access the complete full text

You can get the full text of this document if it is part of your institution's ProQuest subscription.

Try one of the following:

  • Connect to ProQuest through your library network and search for the document from there.
  • Request the document from your library.
  • Go to the ProQuest login page and enter a ProQuest or My Research username / password.