Biodegradable branched polycationic polymers with varying hydrophilic spacers for nonviral gene delivery.
Biodegradable branched polycationic polymers with varying hydrophilic spacer lengths were synthesized from different triacrylate monomers and the amine monomer 1-(2-aminoethyl)piperazine by Michael addition polymerization. The hydrophilic spacers were varied by the number of ethyleneoxy groups in the triacrylate monomer (E/M) that ranged from 0 to 14. The polymer degradation depended on the spacer length and pH; the amount of ester degraded as determined by (1)H NMR after 14 days was 43.4 +/- 2.1% (pH 5.0) and 89.7 +/- 1.3% (pH 7.4) for the polymer with 0 E/M compared to 55.7 +/- 2.6% (pH 5.0) and 98.5 +/- 1.6% (pH 7.4) for the polymer with 14 E/M. Cell viability of rat fibroblasts after exposure to polymer solutions of concentrations up to 1000 microg/mL remained high (above 66.9 +/- 12.1% compared to below 7.6 +/- 1.1% for polyethylenimine at a concentration of 50 microg/mL or higher) and increased with the spacer length. The polyplexes made with all the synthesized polymers showed higher transfection efficiency (4.5 +/- 1.7% to 9.4 +/- 2.0%, dependent on the polymer/pDNA weight ratio) with an enhanced green fluorescent protein reporter gene compared to naked pDNA (0.8 +/- 0.4%) as quantified by flow cytometry. This study demonstrates that hydrophilic spacers can be incorporated into polycationic polymers to reduce their cytotoxicity and enhance their degradability for nonviral gene delivery.
Chew
Sue Anne
SA
Department of Bioengineering, Rice University, MS-142, PO Box 1892, Houston, Texas 77251-1892, USA.
Hacker
Michael C
MC
Saraf
Anita
A
Raphael
Robert M
RM
Kasper
F Kurtis
FK
Mikos
Antonios G
AG
D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D005347:Fibroblasts / Q000166:cytology; D018014:Gene Transfer Techniques; D011073:Polyamines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000071228:Polyelectrolytes; D011108:Polymers / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D055672:Static Electricity
D011073:Polyamines; D000071228:Polyelectrolytes; D011108:Polymers
Gene Ther. 1996 Dec;3(12):1074-80
8986433
J Control Release. 2002 May 17;81(1-2):201-17
11992692
Nucleic Acids Res. 1997 Aug 1;25(15):3095-101
9224610
Chem Commun (Camb). 2003 Oct 21;(20):2630-1
14594315
Gene Ther. 2002 Feb;9(3):157-67
11859418
Int J Pharm. 2003 Feb 18;252(1-2):263-6
12550802
J Biomed Mater Res A. 2003 Dec 15;67(4):1148-54
14624500
Proc Natl Acad Sci U S A. 1999 Apr 27;96(9):5177-81
10220439
Biomacromolecules. 2008 Mar;9(3):818-27
18247565
Biomacromolecules. 2004 Sep-Oct;5(5):1926-32
15360307
Pharm Res. 1996 Jul;13(7):1038-42
8842041
Gene Ther. 1997 Jan;4(1):16-24
9068791
J Biomed Mater Res. 1997 Dec 15;37(4):517-24
9407300
Curr Drug Deliv. 2004 Apr;1(2):165-93
16305382
J Biomed Mater Res. 1999 Jun 5;45(3):268-75
10397985
Bioconjug Chem. 2005 May-Jun;16(3):694-9
15898739
J Control Release. 2008 Mar 3;126(2):97-110
18201788
Biomacromolecules. 2005 Nov-Dec;6(6):3166-73
16283742
Proc Natl Acad Sci U S A. 2007 Sep 4;104(36):14454-9
17726101
Methods Mol Med. 2004;90:139-60
14657563
Biomaterials. 2005 Nov;26(32):6343-56
15913769
J Gene Med. 2005 Oct;7(10):1287-98
15906395
Bioconjug Chem. 2005 Sep-Oct;16(5):1140-8
16173791
Gene Ther. 1998 Oct;5(10):1425-33
9930349
Bioconjug Chem. 1999 May-Jun;10(3):406-11
10346871
Bioconjug Chem. 2006 Sep-Oct;17(5):1339-45
16984145
J Control Release. 2005 Dec 5;109(1-3):317-29
16081184
Crit Rev Ther Drug Carrier Syst. 2003;20(4):249-93
14635981
Biomacromolecules. 2002 Sep-Oct;3(5):1030-7
12217050
Mol Pharm. 2005 May-Jun;2(3):224-32
15934783
Pharm Res. 2002 Oct;19(10):1471-9
12425464
Bioconjug Chem. 2003 Sep-Oct;14(5):934-40
13129396
J Control Release. 1999 Aug 5;60(2-3):149-60
10425321
J Control Release. 1998 Apr 30;53(1-3):289-99
9741937
Biomacromolecules. 2003 Jul-Aug;4(4):1026-33
12857088
J Biomed Mater Res. 2000 Jun 5;50(3):440-51
10737887
J Am Chem Soc. 2001 Aug 22;123(33):8155-6
11506588