Well-defined block copolymers for gene delivery to dendritic cells: Probing the effect of polycation chain-length

Rupei Tang; R. Noelle Palumbo; Lakshmi Nagarajan; Emily Krogstad; Chun Wang

doi:10.1016/j.jconrel.2009.10.021

Well-defined block copolymers for gene delivery to dendritic cells: Probing the effect of polycation chain-length

Rupei Tang, R. Noelle Palumbo, Lakshmi Nagarajan, Emily Krogstad, Chun Wang

Research output: Contribution to journal › Article › peer-review

58 Scopus citations

Abstract

The development of safe and efficient polymer carriers for DNA vaccine delivery requires mechanistic understanding of structure-function relationship of the polymer carriers and their interaction with antigen-presenting cells. Here we have synthesized a series of diblock copolymers with well-defined chain-length using atom transfer radical polymerization and characterized the influence of polycation chain-length on the physico-chemical properties of the polymer/DNA complexes as well as the interaction with dendritic cells. The copolymers consist of a hydrophilic poly(ethylene glycol) block and a cationic poly(aminoethyl methacrylate) (PAEM) block. The average degree of polymerization (DP) of the PAEM block was varied among 19, 39, and 75, with nearly uniform distribution. With increasing PAEM chain-length, polyplexes formed by the diblock copolymers and plasmid DNA had smaller average particle size and showed higher stability against electrostatic destabilization by salt and heparin. The polymers were not toxic to mouse dendritic cells (DCs) and only displayed chain-length-dependent toxicity at a high concentration (1 mg/mL). In vitro gene transfection efficiency and polyplex uptake in DCs were also found to correlate with chain-length of the PAEM block with the longer polymer chain favoring transfection and cellular uptake. The polyplexes induced a modest up-regulation of surface markers for DC maturation that was not significantly dependent on PAEM chain-length. Finally, the polyplex prepared from the longest PAEM block (DP of 75) achieved an average of 20% enhancement over non-condensed anionic dextran in terms of uptake by DCs in the draining lymph nodes 24 h after subcutaneous injection into mice. Insights gained from studying such structurally well-defined polymer carriers and their interaction with dendritic cells may contribute to improved design of practically useful DNA vaccine delivery systems.

Original language	English (US)
Pages (from-to)	229-237
Number of pages	9
Journal	Journal of Controlled Release
Volume	142
Issue number	2
DOIs	https://doi.org/10.1016/j.jconrel.2009.10.021
State	Published - Mar 2010

Bibliographical note

Funding Information:
The GM-CSF secreting cell line (J558L) was kindly provided by Dr. Kristin Hogquist, Center for Immunology, University of Minnesota. The authors thank Dr. Robert Tranquillo for the use of fluorescence plate reader. Emily Krogstad thanks the University of Minnesota UROP Program for partial support. This work is partially funded by the NIH (grants R21CA121832 and R01CA129189 ), the Wallace H. Coulter Foundation (Early Career Translational Research Award), and the US Department of Defense .

Keywords

Block copolymers
DNA vaccine
Dendritic cells
Gene delivery

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10.1016/j.jconrel.2009.10.021

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title = "Well-defined block copolymers for gene delivery to dendritic cells: Probing the effect of polycation chain-length",

abstract = "The development of safe and efficient polymer carriers for DNA vaccine delivery requires mechanistic understanding of structure-function relationship of the polymer carriers and their interaction with antigen-presenting cells. Here we have synthesized a series of diblock copolymers with well-defined chain-length using atom transfer radical polymerization and characterized the influence of polycation chain-length on the physico-chemical properties of the polymer/DNA complexes as well as the interaction with dendritic cells. The copolymers consist of a hydrophilic poly(ethylene glycol) block and a cationic poly(aminoethyl methacrylate) (PAEM) block. The average degree of polymerization (DP) of the PAEM block was varied among 19, 39, and 75, with nearly uniform distribution. With increasing PAEM chain-length, polyplexes formed by the diblock copolymers and plasmid DNA had smaller average particle size and showed higher stability against electrostatic destabilization by salt and heparin. The polymers were not toxic to mouse dendritic cells (DCs) and only displayed chain-length-dependent toxicity at a high concentration (1 mg/mL). In vitro gene transfection efficiency and polyplex uptake in DCs were also found to correlate with chain-length of the PAEM block with the longer polymer chain favoring transfection and cellular uptake. The polyplexes induced a modest up-regulation of surface markers for DC maturation that was not significantly dependent on PAEM chain-length. Finally, the polyplex prepared from the longest PAEM block (DP of 75) achieved an average of 20% enhancement over non-condensed anionic dextran in terms of uptake by DCs in the draining lymph nodes 24 h after subcutaneous injection into mice. Insights gained from studying such structurally well-defined polymer carriers and their interaction with dendritic cells may contribute to improved design of practically useful DNA vaccine delivery systems.",

keywords = "Block copolymers, DNA vaccine, Dendritic cells, Gene delivery",

author = "Rupei Tang and Palumbo, {R. Noelle} and Lakshmi Nagarajan and Emily Krogstad and Chun Wang",

note = "Funding Information: The GM-CSF secreting cell line (J558L) was kindly provided by Dr. Kristin Hogquist, Center for Immunology, University of Minnesota. The authors thank Dr. Robert Tranquillo for the use of fluorescence plate reader. Emily Krogstad thanks the University of Minnesota UROP Program for partial support. This work is partially funded by the NIH (grants R21CA121832 and R01CA129189 ), the Wallace H. Coulter Foundation (Early Career Translational Research Award), and the US Department of Defense . ",

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AU - Krogstad, Emily

AU - Wang, Chun

N1 - Funding Information: The GM-CSF secreting cell line (J558L) was kindly provided by Dr. Kristin Hogquist, Center for Immunology, University of Minnesota. The authors thank Dr. Robert Tranquillo for the use of fluorescence plate reader. Emily Krogstad thanks the University of Minnesota UROP Program for partial support. This work is partially funded by the NIH (grants R21CA121832 and R01CA129189 ), the Wallace H. Coulter Foundation (Early Career Translational Research Award), and the US Department of Defense .

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N2 - The development of safe and efficient polymer carriers for DNA vaccine delivery requires mechanistic understanding of structure-function relationship of the polymer carriers and their interaction with antigen-presenting cells. Here we have synthesized a series of diblock copolymers with well-defined chain-length using atom transfer radical polymerization and characterized the influence of polycation chain-length on the physico-chemical properties of the polymer/DNA complexes as well as the interaction with dendritic cells. The copolymers consist of a hydrophilic poly(ethylene glycol) block and a cationic poly(aminoethyl methacrylate) (PAEM) block. The average degree of polymerization (DP) of the PAEM block was varied among 19, 39, and 75, with nearly uniform distribution. With increasing PAEM chain-length, polyplexes formed by the diblock copolymers and plasmid DNA had smaller average particle size and showed higher stability against electrostatic destabilization by salt and heparin. The polymers were not toxic to mouse dendritic cells (DCs) and only displayed chain-length-dependent toxicity at a high concentration (1 mg/mL). In vitro gene transfection efficiency and polyplex uptake in DCs were also found to correlate with chain-length of the PAEM block with the longer polymer chain favoring transfection and cellular uptake. The polyplexes induced a modest up-regulation of surface markers for DC maturation that was not significantly dependent on PAEM chain-length. Finally, the polyplex prepared from the longest PAEM block (DP of 75) achieved an average of 20% enhancement over non-condensed anionic dextran in terms of uptake by DCs in the draining lymph nodes 24 h after subcutaneous injection into mice. Insights gained from studying such structurally well-defined polymer carriers and their interaction with dendritic cells may contribute to improved design of practically useful DNA vaccine delivery systems.

AB - The development of safe and efficient polymer carriers for DNA vaccine delivery requires mechanistic understanding of structure-function relationship of the polymer carriers and their interaction with antigen-presenting cells. Here we have synthesized a series of diblock copolymers with well-defined chain-length using atom transfer radical polymerization and characterized the influence of polycation chain-length on the physico-chemical properties of the polymer/DNA complexes as well as the interaction with dendritic cells. The copolymers consist of a hydrophilic poly(ethylene glycol) block and a cationic poly(aminoethyl methacrylate) (PAEM) block. The average degree of polymerization (DP) of the PAEM block was varied among 19, 39, and 75, with nearly uniform distribution. With increasing PAEM chain-length, polyplexes formed by the diblock copolymers and plasmid DNA had smaller average particle size and showed higher stability against electrostatic destabilization by salt and heparin. The polymers were not toxic to mouse dendritic cells (DCs) and only displayed chain-length-dependent toxicity at a high concentration (1 mg/mL). In vitro gene transfection efficiency and polyplex uptake in DCs were also found to correlate with chain-length of the PAEM block with the longer polymer chain favoring transfection and cellular uptake. The polyplexes induced a modest up-regulation of surface markers for DC maturation that was not significantly dependent on PAEM chain-length. Finally, the polyplex prepared from the longest PAEM block (DP of 75) achieved an average of 20% enhancement over non-condensed anionic dextran in terms of uptake by DCs in the draining lymph nodes 24 h after subcutaneous injection into mice. Insights gained from studying such structurally well-defined polymer carriers and their interaction with dendritic cells may contribute to improved design of practically useful DNA vaccine delivery systems.

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Well-defined block copolymers for gene delivery to dendritic cells: Probing the effect of polycation chain-length

Abstract

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