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

• Published in: Nature materials Vol. 11; no. 1; pp. 82 - 90
• Main Authors: Zhou, Jiangbing, Liu, Jie, Cheng, Christopher J., Patel, Toral R., Weller, Caroline E., Piepmeier, Joseph M., Jiang, Zhaozhong, Saltzman, W. Mark
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01-01-2012; Nature Publishing Group
• Subjects: 631/61/2300; 639/301/54/990; 639/301/923/1028; Animals; Biocompatibility; Biodegradable materials; Biodegradation; Biomaterials; Biomedical materials; Cell Line, Tumor; Charge density; Chemistry and Materials Science; Condensed Matter Physics; Female; Flow Cytometry; Gene therapy; Gene Transfer Techniques; Genes; Genetic Therapy - methods; HEK293 Cells; Humans; Hydrophobicity; In Situ Nick-End Labeling; In vitro testing; Lactones; Materials Science; Mice; Mice, Nude; Nanoparticles - chemistry; Nanoparticles - toxicity; Nanotechnology; Neoplasms - therapy; Optical and Electronic Materials; Polyamines - chemistry; Polyamines - toxicity; Polymers; Polymers - chemistry; Polymers - toxicity; Reagents; Surgical implants; Terpolymers; Toxicity Tests; Tumors
• ISSN: 1476-1122; 1476-4660
• DOI: 10.1038/nmat3187

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.
Many synthetic polymer nanoparticles used for non-viral gene delivery contain excess cations on their surface, which makes the particles cytotoxic and the delivery of genes inefficient. Terpolymers with a low charge density, high molecular weight and increased hydrophobicity are now shown to have minimal toxicity, and to efficiently deliver the apoptosis-inducing TRAIL gene to transplanted tumours in mice.