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 chainlength 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 hours 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.

Diblock Glycopolymers Promote Colloidal Stability of Polyplexes and Effective pDNA and siRNA Delivery under Physiological Salt and Serum Conditions

“…In a similar study by Wang and coworkers, the colloidal stability of a related series of block copolymers composed of PEG and poly(N-(2-aminoethyl) methacrylate) (PAEM) in the presence of salt was studied. 31 Interestingly, the block lengths of the PEG (DP = 45) and the PAEM (DPs = 19, 39, and 75) are similar to the block lengths utilized in our current study, which allows for a direct comparison of the incorporation of PEG vs PMAG as a stabilizing block due to the similarity of the DPs and cationic block chemistry. In the presence of 150 mM NaCl, the polyplexes formed with the shortest two polymers, PEG-b-PAEM 19 and PEGb-PAEM 39 , doubled in size over a time period of 4 h, whereas PEG-b-PAEM 75 only slightly increased in size.…”

Mannosylated biodegradable polyethyleneimine for targeted DNA delivery to dendritic cells

“…The results, shown in Figure 9, show that the maturation abilities of complexes based on PEI derivates were not as strong as those of LPS. However, compared to other systems such as poly(lactic-co-glycolic acid) and polyethylene glycol-blockpoly(aminoethyl methacrylate), 36,37 which had been reported to only slightly alter the phenotypes of iBMDCs, the PEI system in the current study could significantly upregulate the expression of the costimulatory molecules. Given that CD40 and CD86 play an important role in the induction of adaptive immunity through activation of CD4+ T cells, this result would be beneficial for the application of DNA vaccines specifically targeting DCs.…”

Synergistic Anticancer Effects Achieved by Co‐Delivery of TRAIL and Paclitaxel Using Cationic Polymeric Micelles

“…[31,32] Moreover, the adsorption of TRAIL molecules on particle surface could also increase the probability of TRAIL molecules interacting with death/ TRAIL receptors present on cell surfaces.…”