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Synthesis, Functionalization, and Characterization of Fusogenic Porous Silicon Nanoparticles for Oligonucleotide Delivery
Published on: April 16, 2019
Targeted delivery and enhanced gene-silencing activity of centrally modified folic acid-siRNA conjugates
Lidya Salim1, Golam Islam1, Jean-Paul Desaulniers1
1Faculty of Science, University of Ontario Institute of Technology, Oshawa, Ontario L1G 0C5, Canada.
Abstract:
One of the major hurdles in RNAi research has been the development of safe and effective delivery systems for siRNAs. Although various chemical modifications have been proposed to improve their pharmacokinetic behaviour, their delivery to target cells and tissues presents many challenges. In this work, we implemented a receptor-targeting strategy to selectively deliver siRNAs to cancer cells using folic acid as a ligand. Folic acid is capable of binding to cell-surface folate receptors with high affinity. These receptors have become important molecular targets for cancer research as they are overexpressed in numerous cancers despite being expressed at low levels in normal tissues. Employing a post-column copper-catalyzed alkyne-azide cycloaddition (CuAAC), we report the synthesis of siRNAs bearing folic acid modifications at different positions within the sense strand. In the absence of a transfection carrier, these siRNAs were selectively taken up by cancer cells expressing folate receptors. We show that centrally modified folic acid-siRNAs display enhanced gene-silencing activity against an exogenous gene target (∼80% knockdown after 0.75 μM treatment) and low cytotoxicity. In addition, these siRNAs achieved potent dose-dependent knockdown of endogenous Bcl-2, an important anti-apoptotic gene.
Insights
Researchers developed folic acid-modified siRNAs for targeted cancer cell delivery, achieving significant gene knockdown without carriers. This strategy enhances RNAi therapy safety and efficacy.
Area of Science:
- Biochemistry
- Molecular Biology
- Nanotechnology
Background:
- RNA interference (RNAi) faces delivery challenges for safe and effective siRNA therapeutics.
- Targeted delivery to cancer cells is crucial for enhancing therapeutic efficacy and minimizing off-target effects.
Purpose of the Study:
- To develop a receptor-targeting strategy for selective siRNA delivery to cancer cells using folic acid.
- To synthesize and characterize folic acid-conjugated siRNAs (folic acid-siRNAs) for enhanced cancer cell uptake and gene silencing.
Main Methods:
- Synthesis of siRNAs with folic acid modifications at various positions using copper-catalyzed alkyne-azide cycloaddition (CuAAC).
- Evaluation of selective cellular uptake in folate receptor-expressing cancer cells without transfection carriers.
- Assessment of gene-silencing activity against exogenous and endogenous targets (Bcl-2).
Main Results:
- Folic acid-siRNAs demonstrated selective uptake by folate receptor-overexpressing cancer cells.
- Centrally modified folic acid-siRNAs achieved significant gene knockdown (∼80%) of an exogenous target with low cytotoxicity.
- Potent, dose-dependent knockdown of endogenous Bcl-2 was observed.
Conclusions:
- Receptor-targeting with folic acid enables efficient and selective siRNA delivery to cancer cells.
- Folic acid-siRNA conjugates represent a promising strategy for developing safer and more effective RNAi-based cancer therapies.
- This approach overcomes key delivery hurdles in RNAi research.
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