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.
Acute myeloid leukemia (AML) is the most common type of acute leukemia in adults and is associated with high relapse rates. It is known that leukemia stem cells (LSCs), a very small subpopulation of the total number of leukemic cells, maintain the leukemia phenotype (∼80-90% of AML remain the same as at first diagnosis), display chemotherapy resistance, and contribute to disease regeneration. Therefore, targeting LSCs could control the relapse of AML. Small interfering RNA (siRNA), an effector of the RNA interference (RNAi) pathway, can selectively downregulate any gene implicated in the pathology of disease, presenting great potential for treatment of AML. In this study an antibody targeted cyclodextrin-based nanoparticle (NP) (CD.DSPE-PEG-Fab) was developed for siRNA delivery specifically to AML LSCs. The targeted CD.siRNA.DSPE-PEG-Fab formulation, where Fab specifically targets the IL-3 receptor α-chain (IL-3Rα, also known as CD123, a cell surface antigen for human AML LSCs), achieved antigen-mediated cellular uptake in KG1 cells (an AML leukemia stem and progenitor cell line). Efficient delivery of bromodomain-containing protein 4 (BRD4) siRNA using the targeted formulation resulted in downregulation of the corresponding mRNA and protein in KG1 cells and in ex vivo primary AML patient derived samples. The resulting silencing of BRD4 induced myeloid differentiation and triggered leukemia apoptosis. In addition, a synergistic therapeutic effect was detected when administered in combination with the chemotherapeutic, cytarabine (Ara-C). These results indicate the clinical potential of the antibody-tagged cyclodextrin NP for targeted delivery of therapeutic siRNA in the treatment of AML.
School of Pharmaceutical Sciences, Jilin University , Changchun 130021, China.|Pharmacodelivery Group, School of Pharmacy, University College Cork , Cork, Ireland.
Jianfeng
J
Guo
Tumour Biology Laboratory, School of Biochemistry and Cell Biology, University College Cork , Cork, Ireland.
Eileen G
EG
Russell
Pharmacodelivery Group, School of Pharmacy, University College Cork , Cork, Ireland.
Raphael
R
Darcy
Tumour Biology Laboratory, School of Biochemistry and Cell Biology, University College Cork , Cork, Ireland.
Thomas G
TG
Cotter
Cork Cancer Research Centre, University College Cork , Cork, Ireland.
Sharon L
SL
McKenna
Department of Haematology, Cork University Hospital , Cork, Ireland.
Mary R
MR
Cahill
Pharmacodelivery Group, School of Pharmacy, University College Cork , Cork, Ireland.
Caitriona M
CM
O'Driscoll
D000906:Antibodies / Q000008:administration & dosage*; D017209:Apoptosis / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D003505:Cyclodextrins / Q000008:administration & dosage*; D003561:Cytarabine / Q000494:pharmacology; D015536:Down-Regulation / Q000187:drug effects; D006801:Humans; D020014:K562 Cells; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000378:metabolism; D053758:Nanoparticles / Q000008:administration & dosage*; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism; D034741:RNA, Small Interfering / Q000008:administration & dosage*; D016185:Receptors, Interleukin-3 / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism
D000906:Antibodies; D003505:Cyclodextrins; D034741:RNA, Small Interfering; D016185:Receptors, Interleukin-3; D014157:Transcription Factors; D003561:Cytarabine
RNAi therapeutics; cancer epigenetic gene therapy; leukemia stem cells; nonviral nanoparticles; personalized medicine