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

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.

A nanoparticle formulation that selectively transfects metastatic tumors in mice

“…Given that the shell dose mediates both toxicity and transfection efficiency, we wondered whether replacing the LPEI88 in the shell with a less-toxic LPEI might reduce toxicity but preserve in vivo transfectability. Composite nanoparticles containing two types of cationic polymers described in the literature (37,38), along with the data presented in Tables S1 and S2, inspired us to synthesize composite LPEI-based nanoparticles that take advantage of both the high transfectability of LPEI88 and the low toxicity of LPEI2.5. Thus, a nanoparticle core was formed by incubating DNA with LPEI88, and a shell around this core was formed by incubating this core with excess LPEI2.5.…”

Decationized polyplexes for gene delivery

“…However, PEG shielding is only partial since PEGylated polyplexes are still rapidly cleared compared to other well-known delivery systems (e.g., PEGylated liposomes), resulting in short blood circulation half-lives [9,10]. Alternatives to this approach consist of masking the net positive charge of the pre-formed complexes, by modification of with polyanions [11,12]. This results in the formation of negatively charged ternary complexes, which have shown decreased toxicity, improved in vivo stability and therapeutic effects in vivo [11].…”

“…Alternatives to this approach consist of masking the net positive charge of the pre-formed complexes, by modification of with polyanions [11,12]. This results in the formation of negatively charged ternary complexes, which have shown decreased toxicity, improved in vivo stability and therapeutic effects in vivo [11]. Another interesting approach concerns polymer/calcium phosphate polymer (CaP) hybrid nanoparticles.…”

A fluorinated dendrimer achieves excellent gene transfection efficacy at extremely low nitrogen to phosphorus ratios

“…These materials are easy-to-manufacture and have superior safety compared with viral gene vectors; however, their commercial and clinical applications are limited by relatively low transfection efficacy and poor cell viability after transfection [8][9][10][11] . Functionalization of polymers with amino acids 12 , lipids 13 , cyclodextrins 14 , peptides 15 , other polymers 16 and inorganic nanoparticles 17 can improve their transfection efficacy and biocompatibility to some extent, but the resulting materials are still not efficient enough to justify clinical uses.…”