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Enabling Combinatorial siRNA Delivery against Apoptosis-Related Proteins with Linoleic Acid and α-Linoleic Acid Substituted Low Molecular Weight Polyethylenimines

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Abstract

Purpose

Short interfering RNA (siRNA) therapy promises a new era in treatment of breast cancers but effective delivery systems are needed for clinical use. Since silencing complementary targets may offer improved efficacy, this study was undertaken to identify non-viral carriers for combinatorial siRNA delivery for more effective therapy.

Methods

A library of lipid-substituted polymers from low molecular weight polyethyleneimine (PEI), linoleic acid (LA) and α-linoleic acid (αLA) with amide or thioester linkages was prepared and investigated for delivering Mcl-1, survivin and STAT5A siRNAs in breast cancer cells.

Results

The effective polymers formed 80–190 nm particles with similar zeta-potentials, but the serum stability was greater for complexes formed with amide-linked lipid conjugates. The LA and αLA substitutions, with the low molecular weight PEI (1.2 kDa and 2.0 kDa) were able to deliver siRNA effectively to cells and retarded the growth of breast cancer cells. The amide-linked lipid substituents showed higher cellular delivery of siRNA as compared to thioester linkages. Upon combinational delivery of siRNAs, growth of MCF-7 cells was inhibited to a greater extent with 2.0PEI-LA9 mediated delivery of Mcl-1 combined survivin siRNAs as compared to individual siRNAs. The qRT-PCR analysis confirmed the decrease in mRNA levels of target genes with specific siRNAs and 2.0PEI-LA9 was the most effective polymer for delivering siRNAs (either single or in combination).

Conclusions

This study yielded effective siRNA carriers for combinational delivery of siRNAs. Careful choice of siRNA combinations will be critical since targeting individual genes might alter the expression of other critical mediators.

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Authors and Affiliations

  1. Department of Chemical & Material Engineering, Faculty of Engineering, University of Alberta, Edmonton, Canada

    Samarwadee Plianwong, Remant Bahadur KC, Cezary Kucharski & Hasan Uludağ

  2. Faculty of Pharmacy, Silpakorn University, Bangkok, Thailand

    Samarwadee Plianwong & Theerasak Rojanarata

  3. Faculty of Pharmacy & Pharmaceutical Sciences, University of Alberta, Edmonton, Canada

    Bindu Thapa & Hasan Uludağ

  4. Department of Biomedical Engineering, Faculty of Medicine & Dentistry, University of Alberta, Edmonton, Alberta, Canada

    Hasan Uludağ

  5. Chemical & Materials Engineering Department, 2-021 RTF, University of Alberta, Edmonton, Alberta, Canada

    Hasan Uludağ

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  1. Samarwadee Plianwong
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  2. Bindu Thapa
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  3. Remant Bahadur KC
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Correspondence to Hasan Uludağ.

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Plianwong, S., Thapa, B., KC, R. et al. Enabling Combinatorial siRNA Delivery against Apoptosis-Related Proteins with Linoleic Acid and α-Linoleic Acid Substituted Low Molecular Weight Polyethylenimines. Pharm Res 37, 46 (2020). https://doi.org/10.1007/s11095-020-2770-9

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  • DOI: https://doi.org/10.1007/s11095-020-2770-9

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