TY - JOUR
T1 - Highlighting the role of polymer length, carbohydrate size, and nucleic acid type in potency of glycopolycation agents for pDNA and siRNA delivery
AU - Xue, Lian
AU - Ingle, Nilesh P.
AU - Reineke, Theresa M.
PY - 2013/11/11
Y1 - 2013/11/11
N2 - While nucleic acids such as small interfering RNA (siRNA) and plasmid DNA (pDNA) are promising research tools and therapeutic modalities, their potential in medical applications is limited by a fundamental mechanistic understanding and inadequate efficiency. Herein, two series of carbohydrate-based polycations were synthesized and examined that varied in the degree of polymerization (n), one containing trehalose [Tr4(n) series: Tr4(23), Tr4(55), Tr4(77)] and the other containing β-cyclodextrin [CD4(n) series: CD4(10), CD4(26), CD4(39), CD4(143), CD4(239)]. In addition, two monosaccharide models were examined for comparison that contain tartaramidoamine (T4) and galactaramidoamine (G4 or Glycofect) repeats. Delivery profiles for pDNA were compared with those obtained for siRNA delivery and reveal that efficacy differs significantly as a function of carbohydrate type, nucleic acid type and dose, polymer length, and presence of excess polymer in the formulation. The Tr4 polymers yielded higher efficacy for pDNA delivery, yet the CD4 polymers achieved higher siRNA delivery and gene down-regulation. The T4 and Glycofect derivatives, while efficient for pDNA delivery, were completely ineffective for siRNA delivery. A strong polymer length and dose dependence on target gene knockdown was observed for all polymers tested. Also, free polymer in solution (uncomplexed) was demonstrated to be a key factor in promoting siRNA uptake and gene down-regulation.
AB - While nucleic acids such as small interfering RNA (siRNA) and plasmid DNA (pDNA) are promising research tools and therapeutic modalities, their potential in medical applications is limited by a fundamental mechanistic understanding and inadequate efficiency. Herein, two series of carbohydrate-based polycations were synthesized and examined that varied in the degree of polymerization (n), one containing trehalose [Tr4(n) series: Tr4(23), Tr4(55), Tr4(77)] and the other containing β-cyclodextrin [CD4(n) series: CD4(10), CD4(26), CD4(39), CD4(143), CD4(239)]. In addition, two monosaccharide models were examined for comparison that contain tartaramidoamine (T4) and galactaramidoamine (G4 or Glycofect) repeats. Delivery profiles for pDNA were compared with those obtained for siRNA delivery and reveal that efficacy differs significantly as a function of carbohydrate type, nucleic acid type and dose, polymer length, and presence of excess polymer in the formulation. The Tr4 polymers yielded higher efficacy for pDNA delivery, yet the CD4 polymers achieved higher siRNA delivery and gene down-regulation. The T4 and Glycofect derivatives, while efficient for pDNA delivery, were completely ineffective for siRNA delivery. A strong polymer length and dose dependence on target gene knockdown was observed for all polymers tested. Also, free polymer in solution (uncomplexed) was demonstrated to be a key factor in promoting siRNA uptake and gene down-regulation.
UR - http://www.scopus.com/inward/record.url?scp=84887583668&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84887583668&partnerID=8YFLogxK
U2 - 10.1021/bm401026n
DO - 10.1021/bm401026n
M3 - Article
C2 - 24028685
AN - SCOPUS:84887583668
SN - 1525-7797
VL - 14
SP - 3903
EP - 3915
JO - Biomacromolecules
JF - Biomacromolecules
IS - 11
ER -