The long-term goal of this project is to facilitate rational design of polymer based gene delivery systems by providing microscopic understanding of the actions of polycations during the delivery process. The project will investigate a few critical issues raised by recent experimental developments that shed new understanding on the delivery process. These experimental studies suggest that polycations used in successful vector preparations may be divided into two different portions that play distinct roles during the delivery. First, as has been long established, a portion of the polycation interacts with the plasmid DNA, resulting in DNA condensation. Recent evidence has indicated that the amount of polycation needed for complete DNA condensation may be governed by simple charge neutralization principles and is independent of the molecular weight and branching structure of polycations. Second, successful vector preparations include an additional portion of polycations that remain free in solution. These 'excess'polycations may function to destabilize cell, endosome, and even nuclear membranes, aiding in release of the DNA from the endosome and importation into the nucleus. Although a complete clarification of the suggested delivery mechanism requires more experimental investigations, theoretical/computational investigations that examine these potential actions using multi-scale modeling techniques will be very helpful at this time. The current study will focus on polyethyleneimine (PEI), one of the most promising polymeric vectors that has recently made it to phase II clinical trials for treating HIV diseases and bladder carcinoma. PEI is commercially available in both linear and branched forms with a wide range of molecular weights. The proposed computational/theoretical studies will first develop coarse-grained models for PEI that reproduce their structures and properties in aqueous solution. Atomistic and derived coarse grained models will be used to investigate condensation of nucleic acids and destabilization of lipid membranes by PEI with different branching and molecular weights. The proposed computational studies will provide microscopic knowledge on the structures of the underlying systems and enable the establishment of the structure function relationship for PEI based gene delivery vectors.

Public Health Relevance

The long-term goal of this project is to facilitate rationale design of polymer-based non-viral gene delivery systems by providing critical information inaccessible in experiments with the use of computational approaches. Success in the project will impact gene therapy, a technique that holds great promise for the treatment of a variety of inherited or acquired diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Academic Research Enhancement Awards (AREA) (R15)
Project #
1R15GM106346-01A1
Application #
8495743
Study Section
Biochemistry and Biophysics of Membranes Study Section (BBM)
Program Officer
Preusch, Peter C
Project Start
2013-06-01
Project End
2016-05-31
Budget Start
2013-06-01
Budget End
2016-05-31
Support Year
1
Fiscal Year
2013
Total Cost
$314,493
Indirect Cost
$84,493
Name
University of Memphis
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
055688857
City
Memphis
State
TN
Country
United States
Zip Code
38152