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Biodegradable poly(amine-co-ester) terpolymers for targeted gene delivery

Nature Materials volume 11, pages 82–90 (2012)Cite this article

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Abstract

Many synthetic polycationic vectors for non-viral gene delivery show high efficiency in vitro, but their usually excessive charge density makes them toxic for in vivo applications. Here we describe the synthesis of a series of high molecular weight terpolymers with low charge density, and show that they exhibit efficient gene delivery, some surpassing the efficiency of the commercial transfection reagents Polyethylenimine and Lipofectamine 2000. The terpolymers were synthesized via enzyme-catalyzed copolymerization of lactone with dialkyl diester and amino diol, and their hydrophobicity adjusted by varying the lactone content and by selecting a lactone comonomer of specific ring size. Targeted delivery of the pro-apoptotic TRAIL gene to tumour xenografts by one of the terpolymers results in significant inhibition of tumour growth, with minimal toxicity both in vitro and in vivo. Our findings suggest that the gene delivery ability of the terpolymers stems from their high molecular weight and increased hydrophobicity, which compensates for their low charge density.

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Figure 1: Synthesis and characteristics of polymers and terpolymer/DNA complexes.
Figure 2: Gene delivery efficiency and toxicity of terpolymer.
Figure 3: Coating III-20% PDL/DNA polyplexes with peptide polyE–mRGD for improved stability in vitro and gene delivery in vivo.
Figure 4: Evaluation of coated III-20%PDL/TRAIL DNA polyplexes in vivo.

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Acknowledgements

We thank M. Graham in the EM Core Facility at the Yale School of Medicine for technical assistance and Nha Duong for editorial assistance. This work was supported by US National Institutes of Health (grant EB000487), Chicago Institute of Neurosurgery and Neuroresearch Foundation, the Voices Against Brain Cancer Foundation, and a pilot grant from the Yale Institute for Nanoscience and Quantum Engineering (YINQE).

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Author notes

  1. Jiangbing Zhou and Jie Liu: These authors contributed equally to this work

Authors and Affiliations

  1. Department of Biomedical Engineering, Yale University, New Haven, Connecticut 06511, USA

    Jiangbing Zhou, Christopher J. Cheng, Caroline E. Weller, Zhaozhong Jiang & W. Mark Saltzman

  2. Department of Neurosurgery, Yale University, New Haven, Connecticut 06511, USA

    Jiangbing Zhou, Toral R. Patel & Joseph M. Piepmeier

  3. School of Engineering, Sun Yat-sen University, Guangzhou, Guangdong 510275, China

    Jie Liu

  4. Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, Connecticut 06511, USA

    Christopher J. Cheng

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Contributions

J.Z., J.L., Z.J. and W.M.S. designed the experiments. J.Z., J.L., C.J.C., T.R.P., C.E.W. and Z.J. performed the experiments. All the authors were involved in the analyses and interpretation of data. J.Z., Z.J. and W.M.S. wrote the paper, with the help of the co-authors.

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Correspondence to Zhaozhong Jiang or W. Mark Saltzman.

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Zhou, J., Liu, J., Cheng, C. et al. Biodegradable poly(amine-co-ester) terpolymers for targeted gene delivery. Nature Mater 11, 82–90 (2012). https://doi.org/10.1038/nmat3187

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