Rapid Optimization of Gene Delivery by Parallel End-modification of Poly(β-amino ester)s.
Poly(β-amino ester)s are cationic degradable polymers that have significant potential as gene delivery vectors. Here we present a generalized method to modify poly(β-amino ester)s at the chain ends to improve their delivery performance. End-chain coupling reactions were developed so that polymers could be synthesized and tested in a high-throughput manner, without the need for purification. In this way, many structural variations at the polymer terminus could be rapidly evaluated. End-modification of the terminal amine structure of a previously optimized poly(β-amino ester), C32, significantly enhanced its in vitro transfection efficiency. In vivo, intraperitoneal (IP) gene delivery using end-modified C32 polymers resulted in expression levels over one order of magnitude higher than unmodified C32 and jet-polyethylenimine (jet-PEI) levels in several abdominal organs. The rapid end-modification strategy presented here has led to the discovery of many effective polymers for gene delivery and may be a useful method to develop and optimize cationic polymers for gene therapy.
Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
Gregory T
GT
Zugates
Lankenau Institute for Medical Research, Wynnewood, Pennsylvania, USA.
Weidan
W
Peng
Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
Andreas
A
Zumbuehl
Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA; Present address: Department of Bioengineering, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
Siddharth
S
Jhunjhunwala
Lankenau Institute for Medical Research, Wynnewood, Pennsylvania, USA.
Yu-Hung
YH
Huang
Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA; Center for Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
Robert
R
Langer
Lankenau Institute for Medical Research, Wynnewood, Pennsylvania, USA.
Janet A
JA
Sawicki
Center for Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA. Electronic address: dgander@mit.edu.
Daniel G
DG
Anderson