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Published on: June 17, 2022
Effective RNAi in leukemia cells is enhanced by spermine-modified pullulan combined with desloratadine
Tian Wang1, Boya Hao1, Shilin Xu1
1Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing 100005, China.
Abstract:
RNA interference is a very useful tool for clinical treatment as well as mechanistic studies of leukemia. However, leukemia cells are known as hard-to-transfected by non-virus carriers. The low capacity of endocytosis and lysosomal escape of synthetic carriers are two obstacles for successful RNAi in leukemia cells. In this work, we established a universal powerful strategy for mediating effective RNAi in different types of leukemia cells by sequentially using spermine-modified pullulan (PS) as siRNA carrier and desloratadine (DL) to promote the lysosomal escape. It was shown that the complex of PS and siRNA could be largely internalized by human T-cell acute lymphoblastic leukemia cells, acute myeloid leukemia cells and chronic myeloid leukemia cells in serum-containing media, and the internalized complex was able to escape from the lysosomes by the aid of DL, resulting in effective RNAi against the key genes for the different leukemia cells.
Insights
This study introduces a novel strategy for effective RNA interference (RNAi) in leukemia cells. It utilizes spermine-modified pullulan (PS) as a carrier and desloratadine (DL) to enhance siRNA delivery and lysosomal escape, overcoming transfection challenges.
Area of Science:
- Biochemistry
- Molecular Biology
- Oncology
Background:
- RNA interference (RNAi) is a valuable tool for leukemia research and treatment.
- Leukemia cells present significant challenges for non-viral gene delivery due to poor endocytosis and lysosomal escape.
- Overcoming these barriers is crucial for successful RNAi-based therapies in leukemia.
Purpose of the Study:
- To develop a universal and effective strategy for RNAi in various leukemia cell types.
- To address the limitations of synthetic carriers in delivering siRNA to leukemia cells.
- To enhance the efficiency of RNAi by improving cellular uptake and endosomal escape.
Main Methods:
- Sequential application of spermine-modified pullulan (PS) as a siRNA carrier.
- Utilizing desloratadine (DL) to promote lysosomal escape of the siRNA complex.
- Testing the strategy on human T-cell acute lymphoblastic leukemia, acute myeloid leukemia, and chronic myeloid leukemia cells.
Main Results:
- The PS-siRNA complex demonstrated significant internalization by multiple leukemia cell lines in serum-containing media.
- Desloratadine (DL) effectively facilitated the escape of the internalized complex from lysosomes.
- Successful RNAi was achieved against critical genes in different leukemia cell types.
Conclusions:
- The developed PS-siRNA and DL strategy offers a powerful and universal approach for effective RNAi in diverse leukemia cells.
- This method overcomes key obstacles in non-viral gene delivery to challenging leukemia cell types.
- The findings pave the way for improved RNAi-based therapeutic strategies for leukemia treatment.
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This process occurs naturally in cells, often through the activity of genomically-encoded microRNAs. Researchers can take advantage of this mechanism by introducing synthetic RNAs to deactivate specific genes for research or therapeutic purposes. For example, RNAi could be used...