Abstract
Polyethylenimine (PEI) is a gold standard polymer with excellent transfection efficacy, yet its severe toxicity and nondegradability hinders its therapeutic application as a gene delivery vector. To tackle this problem, herein we incorporated the biodegradable polylactide (PLA) into the branched PEI by synthesizing a PEI-PLA copolymer via a facile synthetic route. PLA modification significantly improved the cytocompatibility of PEI, PEI-PLA copolymer showed much higher cell viability than PEI as verified in three different human cancer cell lines (HCT116, HepG2 and SKOV3). Interestingly, the PEI-PLA copolymer could effectively bind siRNA targeting PKM2, and the obtained polyplex displayed much higher stability in serum than naked siRNA as determined by agarose gel electrophoresis. Moreover, cellular uptake study demonstrated that PEI-PLA could efficiently deliver the Cy5-labled siRNA into the three tested cancer cell lines, and the transfection efficiency is equivalent to the commercial Lipofectamine® 2000. Finally, it is noteworthy that the polyplex is comparable to Lipo2000 in down-regulating the expression of PKM2 at both mRNA and protein level as measured by q-PCR and western blotting, respectively. Overall, the PEI-PLA copolymer developed in this study has the potential to be developed as a versatile carrier for safe and effective delivery of other nucleic acid-based agents.
Highlights
Cancer is still the leading cause of mortality worldwide, and conventional chemotherapy and radiotherapy suffer from the disadvantages of low efficacy and adverse systemic toxicity to normal tissues [1,2]
As a gold standard polymer with high transfection efficacy, polyethylenimine (PEI), especially branched PEI, is widely employed for in vitro and in vivo Small interfering RNAs (siRNAs) delivery due to its well-known proton sponge effect, which is responsible for efficient endosome escape [20,21,22]
PEI-PLA copolymer was synthesized by conjugation of acrylated PLA and the primary amine group of PEI via Michael addition
Summary
Cancer is still the leading cause of mortality worldwide, and conventional chemotherapy and radiotherapy suffer from the disadvantages of low efficacy and adverse systemic toxicity to normal tissues [1,2]. SiRNA-based RNA interference (RNAi) offers an invaluable technique for personalized cancer therapy, as it can selectively and effectively knockdown the expression of targeted genes [5,6]. In the past few decades, various delivery systems have been developed to improve the intracellular trafficking of siRNAs. viral vectors exhibit excellent efficiency in gene transfer, there are fundamental drawbacks, including serious safety concerns due to their undesirable off-target effects (immunogenicity, carcinogenesis, inflammatory response and toxicity) and the difficulty in large-scale production [9,10]. Among the above-mentioned siRNA delivery systems, studies on cationic polymers are gaining increasing attention due to their strong capability to condense large siRNAs and protect siRNAs against ribozyme degradation [19]. As a gold standard polymer with high transfection efficacy, polyethylenimine (PEI), especially branched PEI (bPEI), is widely employed for in vitro and in vivo siRNA delivery due to its well-known proton sponge effect, which is responsible for efficient endosome escape [20,21,22]
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