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Biophysical Characterization of novel Amphiphilic Macromolecules: Modeling membrane interaction

by
Adriana A.T Martin
B.S., Bloomfield College- 2008

Thesis Advisors: William Welsh, Ph.D. and
Prabhas Moghe, Ph.D.
Graduate Program in Cellular & Molecular Pharmacology

Biomedical Engineering building,
Room 122
Piscataway

Friday, April 25, 2014
10:00 a.m.


Abstract

Nanomedicine, described as the concentrated focus on nanoscale events for therapeutic agents, is an emerging field in biotechnology. The physical interactions encountered by nano-scale molecular entities in a biorelevant environment must be characterized before harnessed as a molecular tool. As a case study, several methods were developed to classify molecular behavior of an evolving series of novel compounds referred to as amphiphilic macromolecules (AMs), synthesized from carbohydrate acid sugars, aliphatic chains and polyethylene glycol (PEG). The amphiphilicity afforded by PEG for improved solubility allows for spontaneous self-assembled micelle formation in aqueous solutions. Given these properties, investigators are exploring AMs for applications such as drug encapsulation in micelle or nanoparticle. To date no studies have been performed which examine in detail the relationship between AM structural characteristics and ‘binding readiness,’ i.e., the measurement of non-specific binding of a macromolecule in unimer or multimer form. The primary objective of my dissertation research was to expand our current understanding of AM structure-activity relationships (SARs) and to generate a quantitative SAR model (QSAR) to make predictions a priori of the solution properties of these complex structures. My central hypothesis is the rate and propensity for membrane retention and subsequent biological properties are largely dictated by the physicochemical structural properties of the AMs. Our studies are focused on: 1) assessing the prediction capabilities of a computational modeling approach for measuring the effects of structural changes to AMs on membrane interactions, and 2) using information acquired experimentally to validate the theoretical simulations. As a result of the so-developed screening protocol, we have determined that specific stereochemical conformations and charge presentations, as exemplified by 1cM and L-1cT, exhibit significantly enhanced binding association as compared with PEG as control. The specific aims are as follows: I) to characterize the physicochemical properties and interactions of AMs using molecular modeling; II) to experimentally assess both qualitatively and quantitatively the AM-bilayer interaction using quartz crystal microbalance with dissipation (QCM-D); and III) to assess formulation modifications for potential therapeutic indications. More broadly, my dissertation project has produced an integrated computational-experimental strategy for the rational and systematic design of AMs for therapeutic applications.


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