TY - JOUR
T1 - Maximizing gene delivery efficiencies of cationic helical polypeptides via balanced membrane penetration and cellular targeting
AU - Zheng, Nan
AU - Yin, Lichen
AU - Song, Ziyuan
AU - Ma, Liang
AU - Tang, Haoyu
AU - Gabrielson, Nathan P.
AU - Lu, Hua
AU - Cheng, Jianjun
N1 - Funding Information:
J.C. acknowledges support from the NSF ( CHE-0809420 ), the NIH (NIH Director's New Innovator Award 1DP2OD007246, 1R21EB013379).
PY - 2014/1
Y1 - 2014/1
N2 - The application of non-viral gene delivery vectors is often accompanied with the poor correlation between transfection efficiency and the safety profiles of vectors. Vectors with high transfection efficiencies often suffer from high toxicities, making it unlikely to improve their efficiencies by increasing the DNA dosage. In the current study, we developed a ternary complex system which consisted of a highly membrane-active cationic helical polypeptide (PVBLG-8), a low-toxic, membrane-inactive cationic helical polypeptide (PVBLG-7) capable of mediating mannose receptor targeting, and DNA. The PVBLG-7 moiety notably enhanced the cellular uptake and transfection efficiency of PVBLG-8 in a variety of mannose receptor-expressing cell types (HeLa, COS-7, and Raw 264.7), while it did not compromise the membrane permeability of PVBLG-8 or bring additional cytotoxicities. Because of the simplicity and adjustability of the self-assembly approach, optimal formulations of the ternary complexes with a proper balance between membrane activity and targeting capability were easily identified in each specific cell type. The optimal ternary complexes displayed desired cell tolerability and markedly outperformed the PVBLG-8/DNA binary complexes as well as commercial reagent Lipofectamine™ 2000 in terms of transfection efficiency. This study therefore provides an effective and facile strategy to overcome the efficiency-toxicity poor correlation of non-viral vectors, which contributes insights into the design strategy of effective and safe non-viral gene delivery vectors.
AB - The application of non-viral gene delivery vectors is often accompanied with the poor correlation between transfection efficiency and the safety profiles of vectors. Vectors with high transfection efficiencies often suffer from high toxicities, making it unlikely to improve their efficiencies by increasing the DNA dosage. In the current study, we developed a ternary complex system which consisted of a highly membrane-active cationic helical polypeptide (PVBLG-8), a low-toxic, membrane-inactive cationic helical polypeptide (PVBLG-7) capable of mediating mannose receptor targeting, and DNA. The PVBLG-7 moiety notably enhanced the cellular uptake and transfection efficiency of PVBLG-8 in a variety of mannose receptor-expressing cell types (HeLa, COS-7, and Raw 264.7), while it did not compromise the membrane permeability of PVBLG-8 or bring additional cytotoxicities. Because of the simplicity and adjustability of the self-assembly approach, optimal formulations of the ternary complexes with a proper balance between membrane activity and targeting capability were easily identified in each specific cell type. The optimal ternary complexes displayed desired cell tolerability and markedly outperformed the PVBLG-8/DNA binary complexes as well as commercial reagent Lipofectamine™ 2000 in terms of transfection efficiency. This study therefore provides an effective and facile strategy to overcome the efficiency-toxicity poor correlation of non-viral vectors, which contributes insights into the design strategy of effective and safe non-viral gene delivery vectors.
KW - α-Helical polypeptide
KW - Cytotoxicity
KW - Mannose targeting
KW - Membrane penetration
KW - Non-viral gene delivery
KW - Self-assembly
UR - http://www.scopus.com/inward/record.url?scp=84888436693&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84888436693&partnerID=8YFLogxK
U2 - 10.1016/j.biomaterials.2013.09.090
DO - 10.1016/j.biomaterials.2013.09.090
M3 - Article
C2 - 24211080
AN - SCOPUS:84888436693
SN - 0142-9612
VL - 35
SP - 1302
EP - 1314
JO - Biomaterials
JF - Biomaterials
IS - 4
ER -