Antibody-Targeted Cyclodextrin-Based Nanoparticles for siRNA Delivery

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In the laboratory of C. M. O’Driscoll (University College Cork), an antibody targeted cyclodextrin-based siRNA delivery vector (CD.DSPE-PEGFab) was developed using a self-assembling process.  The fragment antigen-binding (Fab) of a monoclonal antibody was coupled to CD through a PEGylated linker (1,2-distearoyl-sn-glycero-3-phosphoethanolamine conjugated to polyethyleneglycol and modified with maleimide, DSPE-PEG-Maleimide). The presence of the CD enables binding of siRNA, the application of PEG is designed to stabilize nanoparticles in physiological environments thereby prolonging the systemic circulation and reducing in vivo toxicity, and the incorporation of Fab is to target IL-3 receptor α-chain (IL-3Rα, highly expressed on acute myeloid leukemia stem cells) for selective targeting of these cells responsible for the relapse of the disease. The leukemia stem cells uptake these nanoparticles via receptor-mediated endocytosis resulting in downregulation of mRNA in leukemia stem cells and trigger leukemia apoptosis. A sinergetic therapeutic effect was detected when administered in combination with the chemotherapeutic cytarabine.

Using this technique the antibody-targeted cyclodextrin can be flexibly tuned to target other leukemia stem cell antigens (i.e., CD33, CD44, CD47, and CLL-1) for cell-specific delivery. In addition, as more genes are identified as causative factors for acute myeloid leukemia and relapse, this delivery system can be easily and readily modified to incorporate the appropriate siRNA, thereby facilitating the production of personalized medicines.


Guo J, Russell EG, Darcy R, Cotter TG, McKenna SL, Cahill MR, O’Driscoll CM
Antibody-targeted cyclodextrin-based nanoparticles for siRNA Delivery in the treatment of acute myeloid leukemia: physicochemical characteristics, in vitro mechanistic studies, and ex vivo patient derived therapeutic efficacy.
Mol Pharm. 2017;14(3):940-952.





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