Rapid optimization of gene delivery by parallel end-modification of poly(beta-amino ester)s.
Poly(beta-amino ester)s are cationic degradable polymers that have significant potential as gene delivery vectors. Here we present a generalized method to modify poly(beta-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(beta-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.
Zugates
Gregory T
GT
Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
Peng
Weidan
W
Zumbuehl
Andreas
A
Jhunjhunwala
Siddharth
S
Huang
Yu-Hung
YH
Langer
Robert
R
Sawicki
Janet A
JA
Anderson
Daniel G
DG
D000588:Amines / Q000737:chemistry; D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D004952:Esters / Q000138:chemical synthesis / Q000737:chemistry; D015870:Gene Expression; D018014:Gene Transfer Techniques; D017930:Genes, Reporter / Q000235:genetics; D007274:Injections, Intraperitoneal; D007275:Injections, Intravenous; D008297:Male; D051379:Mice; D015394:Molecular Structure; D011108:Polymers / Q000138:chemical synthesis / Q000737:chemistry; D013997:Time Factors
D000588:Amines; D004952:Esters; D011108:Polymers; C507253:poly(beta-amino ester)