Targeted delivery of SiRNA to CD33-positive tumor cells with liposomal carrier systems
Miriam Rothdiener1, Dafne Müller, Patricia Garrido Castro
1Institut für Zellbiologie und Immunologie, Universität Stuttgart, Allmandring 31, 70569 Stuttgart, Germany.
Abstract:
SiRNA molecules represent promising therapeutic molecules, e.g. for cancer therapy. However, efficient delivery into tumor cells remains a major obstacle for treatment. Here, we describe a liposomal siRNA carrier system for targeted delivery of siRNA to CD33-positive acute myeloid leukemia cells. The siRNA is directed against the t(8;21) translocation resulting in the AML1/MTG8 fusion protein. The siRNA was encapsulated in free or polyethylene imine (PEI)-complexed form into PEGylated liposomes endowed subsequently with an anti-CD33 single-chain Fv fragment (scFv) for targeted delivery. The resulting siRNA-loaded immunoliposomes (IL) and immunolipoplexes (ILP) showed specific binding and internalization by CD33-expressing myeloid leukemia cell lines (SKNO-1, Kasumi-1). Targeted delivery of AML1/MTG8 siRNA, but not of mismatch control siRNA, reduced AML1/MTG8 mRNA and protein levels and decreased leukemic clonogenicity, a hallmark of leukemic self-renewal. Although this study revealed that further modifications are necessary to increase efficacy of siRNA delivery and silencing, we were able to establish a targeted liposomal siRNA delivery system combining recombinant antibody fragments for targeted delivery with tumor cell-specific siRNA molecules as therapeutic agents.
Insights
Researchers developed a targeted liposomal system to deliver siRNA specifically to acute myeloid leukemia cells. This novel approach successfully reduced leukemia cell growth by targeting the AML1/MTG8 fusion protein.
Area of Science:
- Biotechnology
- Molecular Biology
- Cancer Therapy
Background:
- Small interfering RNA (siRNA) holds therapeutic potential but faces delivery challenges.
- Targeted delivery of siRNA to cancer cells is crucial for effective treatment.
- Acute myeloid leukemia (AML) cells often express CD33, a potential target for drug delivery.
Purpose of the Study:
- To develop a liposomal siRNA carrier system for targeted delivery to CD33-positive AML cells.
- To evaluate the efficacy of siRNA targeting the AML1/MTG8 fusion protein in AML.
- To establish a liposomal delivery platform combining antibody fragments and siRNA.
Main Methods:
- siRNA targeting the AML1/MTG8 fusion protein was encapsulated in PEGylated liposomes.
- Liposomes were functionalized with anti-CD33 single-chain Fv fragments for targeted delivery.
- Liposomes (immunoliposomes, IL) and lipoplexes (immunolipoplexes, ILP) were tested on CD33-expressing AML cell lines (SKNO-1, Kasumi-1).
Main Results:
- IL and ILP demonstrated specific binding and internalization by CD33-expressing AML cells.
- Targeted delivery of AML1/MTG8 siRNA reduced AML1/MTG8 mRNA and protein levels.
- Leukemic cell clonogenicity was decreased by the targeted siRNA, indicating reduced self-renewal.
Conclusions:
- A targeted liposomal siRNA delivery system for AML was successfully established.
- The system combines antibody fragments for targeting with tumor-specific siRNA for therapeutic effect.
- Further optimization is needed to enhance siRNA delivery and silencing efficacy.
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