Tags

Type your tag names separated by a space and hit enter

Biodegradable amphiphilic poly(ethylene oxide)-block-polyesters with grafted polyamines as supramolecular nanocarriers for efficient siRNA delivery.
Biomaterials 2009; 30(2):242-53B

Abstract

The RNA interference (RNAi) technology has been successfully used in elucidating mechanisms behind various biological events. However, in the absence of safe and effective carriers for in vivo delivery of small interfering RNAs (siRNAs), application of this technology for therapeutic purposes has lagged behind. The objective of this research was to develop promising carriers for siRNA delivery based on degradable poly(ethylene oxide)-block-polyesters containing polycationic side chains on their polyester block. Toward this goal, a novel family of biodegradable poly(ethylene oxide)-block-poly(epsilon-caprolactone) (PEO-b-PCL) based copolymers with polyamine side chains on the PCL block, i.e., PEO-b-PCL with grafted spermine (PEO-b-P(CL-g-SP)), tetraethylenepentamine (PEO-b-P(CL-g-TP)), or N,N-dimethyldipropylenetriamine (PEO-b-P(CL-g-DP)) were synthesized and evaluated for siRNA delivery. The polyamine-grafted PEO-b-PCL polymers, especially PEO-b-P(CL-g-SP), demonstrated comparable toxicity to PEO-b-PCL in vitro. The polymers were able to effectively bind siRNA, self-assemble into micelles, protect siRNA from degradation by nuclease and release complexed siRNA efficiently in the presence of low concentrations of polyanionic heparin. Based on flow cytometry and confocal microscopy, siRNA formulated in PEO-b-P(CL-g-SP) and PEO-b-P(CL-g-TP) micelles showed efficient cellular uptake through endocytosis by MDA435/LCC6 cells transfected with MDR-1, which encodes for the expression of P-glycoprotein (P-gp). The siRNA formulated in PEO-b-P(CL-g-SP) and PEO-b-P(CL-g-TP) micelles demonstrated effective endosomal escape after cellular uptake. Finally, MDR-1-targeted siRNA formulated in PEO-b-P(CL-g-SP) and PEO-b-P(CL-g-TP) micelles exhibited efficient gene silencing for P-gp expression. The results of this study demonstrated the promise of novel amphiphilic PEO-b-P(CL-g-polyamine) block copolymers for efficient siRNA delivery.

Authors+Show Affiliations

Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta, Canada T6G 2N8.No affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

18838158

Citation

Xiong, Xiao-Bing, et al. "Biodegradable Amphiphilic Poly(ethylene Oxide)-block-polyesters With Grafted Polyamines as Supramolecular Nanocarriers for Efficient siRNA Delivery." Biomaterials, vol. 30, no. 2, 2009, pp. 242-53.
Xiong XB, Uludağ H, Lavasanifar A. Biodegradable amphiphilic poly(ethylene oxide)-block-polyesters with grafted polyamines as supramolecular nanocarriers for efficient siRNA delivery. Biomaterials. 2009;30(2):242-53.
Xiong, X. B., Uludağ, H., & Lavasanifar, A. (2009). Biodegradable amphiphilic poly(ethylene oxide)-block-polyesters with grafted polyamines as supramolecular nanocarriers for efficient siRNA delivery. Biomaterials, 30(2), pp. 242-53. doi:10.1016/j.biomaterials.2008.09.025.
Xiong XB, Uludağ H, Lavasanifar A. Biodegradable Amphiphilic Poly(ethylene Oxide)-block-polyesters With Grafted Polyamines as Supramolecular Nanocarriers for Efficient siRNA Delivery. Biomaterials. 2009;30(2):242-53. PubMed PMID: 18838158.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Biodegradable amphiphilic poly(ethylene oxide)-block-polyesters with grafted polyamines as supramolecular nanocarriers for efficient siRNA delivery. AU - Xiong,Xiao-Bing, AU - Uludağ,Hasan, AU - Lavasanifar,Afsaneh, Y1 - 2008/10/05/ PY - 2008/06/30/received PY - 2008/09/02/accepted PY - 2008/10/8/pubmed PY - 2009/4/2/medline PY - 2008/10/8/entrez SP - 242 EP - 53 JF - Biomaterials JO - Biomaterials VL - 30 IS - 2 N2 - The RNA interference (RNAi) technology has been successfully used in elucidating mechanisms behind various biological events. However, in the absence of safe and effective carriers for in vivo delivery of small interfering RNAs (siRNAs), application of this technology for therapeutic purposes has lagged behind. The objective of this research was to develop promising carriers for siRNA delivery based on degradable poly(ethylene oxide)-block-polyesters containing polycationic side chains on their polyester block. Toward this goal, a novel family of biodegradable poly(ethylene oxide)-block-poly(epsilon-caprolactone) (PEO-b-PCL) based copolymers with polyamine side chains on the PCL block, i.e., PEO-b-PCL with grafted spermine (PEO-b-P(CL-g-SP)), tetraethylenepentamine (PEO-b-P(CL-g-TP)), or N,N-dimethyldipropylenetriamine (PEO-b-P(CL-g-DP)) were synthesized and evaluated for siRNA delivery. The polyamine-grafted PEO-b-PCL polymers, especially PEO-b-P(CL-g-SP), demonstrated comparable toxicity to PEO-b-PCL in vitro. The polymers were able to effectively bind siRNA, self-assemble into micelles, protect siRNA from degradation by nuclease and release complexed siRNA efficiently in the presence of low concentrations of polyanionic heparin. Based on flow cytometry and confocal microscopy, siRNA formulated in PEO-b-P(CL-g-SP) and PEO-b-P(CL-g-TP) micelles showed efficient cellular uptake through endocytosis by MDA435/LCC6 cells transfected with MDR-1, which encodes for the expression of P-glycoprotein (P-gp). The siRNA formulated in PEO-b-P(CL-g-SP) and PEO-b-P(CL-g-TP) micelles demonstrated effective endosomal escape after cellular uptake. Finally, MDR-1-targeted siRNA formulated in PEO-b-P(CL-g-SP) and PEO-b-P(CL-g-TP) micelles exhibited efficient gene silencing for P-gp expression. The results of this study demonstrated the promise of novel amphiphilic PEO-b-P(CL-g-polyamine) block copolymers for efficient siRNA delivery. SN - 1878-5905 UR - https://www.unboundmedicine.com/medline/citation/18838158/Biodegradable_amphiphilic_poly_ethylene_oxide__block_polyesters_with_grafted_polyamines_as_supramolecular_nanocarriers_for_efficient_siRNA_delivery_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0142-9612(08)00650-9 DB - PRIME DP - Unbound Medicine ER -