title: CD33-Targeted Lipid Nanoparticles (aCD33LNs) for Therapeutic Delivery of GTI-2040 to Acute Myelogenous Leukemia.
abstract: CD33-targeted lipid nanoparticles (aCD33LNs) were synthesized for delivery of GTI-2040, an antisense oligonucleotide (ASO) against the R2 subunit of ribonucleotide reductase, to acute myelogenous leukemia (AML). These LNs incorporated a deoxycholate-polyethylenimine (DOC-PEI) conjugate, which has shown significant activity to facilitate oligonucleotide delivery. Anti-CD33 scFv (aCD33) was added as a targeting ligand. The delivery efficiency of this system was investigated both in vitro and in vivo. When cells were treated with aCD33LN/GTI-2040, significant uptake was observed in CD33 positive Kasumi-1 cells. aCD33LNs loaded with GTI-2040 induced significant down-regulation of R2 mRNA and protein levels in AML cells. Moreover, aCD33LN/GTI-2040 showed a 15-fold reduction in the IC50 of antileukemic drug Ara-C in Kasumi-1 cells. In Kasumi-1 xenograft model, aCD33LN/GTI-2040 showed significant R2 downregulation compared to LN/GTI-2040. Furthermore, aCD33LN/GTI-2040 coadministered with Ara-C was shown to be highly effective in tumor growth inhibition and to greatly increase survival time of mice bearing Kasumi-1 xenograft tumors. The conjugate DOC-PEI has shown an ability to include calcein release from lipid nanoparticles, suggesting a potential mechanism contributing to efficient endosome release by DOC-PEI2K. These results indicate that aCD33LNs are a highly effective vehicle for the therapeutic delivery of antisense agents to AML.
authors: †Division of Pharmaceutics, College of Pharmacy, ‡Division of Hematology-Oncology, §Molecular, Cellular and Developmental Biology Program, and ∥Department of Chemical and Biomolecular Engineering, The Ohio State University, Columbus, Ohio 43210, United States.
authors: Hong
authors: H
authors: Li
authors: †Division of Pharmaceutics, College of Pharmacy, ‡Division of Hematology-Oncology, §Molecular, Cellular and Developmental Biology Program, and ∥Department of Chemical and Biomolecular Engineering, The Ohio State University, Columbus, Ohio 43210, United States.
authors: Songlin
authors: S
authors: Xu
authors: †Division of Pharmaceutics, College of Pharmacy, ‡Division of Hematology-Oncology, §Molecular, Cellular and Developmental Biology Program, and ∥Department of Chemical and Biomolecular Engineering, The Ohio State University, Columbus, Ohio 43210, United States.|⊥Pharmacy College, Yanbian University, Yanji, Jilin 133002, China.
authors: Jishan
authors: J
authors: Quan
authors: †Division of Pharmaceutics, College of Pharmacy, ‡Division of Hematology-Oncology, §Molecular, Cellular and Developmental Biology Program, and ∥Department of Chemical and Biomolecular Engineering, The Ohio State University, Columbus, Ohio 43210, United States.
authors: Bryant C
authors: BC
authors: Yung
authors: Jiuxia
authors: J
authors: Pang
authors: †Division of Pharmaceutics, College of Pharmacy, ‡Division of Hematology-Oncology, §Molecular, Cellular and Developmental Biology Program, and ∥Department of Chemical and Biomolecular Engineering, The Ohio State University, Columbus, Ohio 43210, United States.
authors: Chenguang
authors: C
authors: Zhou
authors: †Division of Pharmaceutics, College of Pharmacy, ‡Division of Hematology-Oncology, §Molecular, Cellular and Developmental Biology Program, and ∥Department of Chemical and Biomolecular Engineering, The Ohio State University, Columbus, Ohio 43210, United States.
authors: Young-Ah
authors: YA
authors: Cho
authors: Mengzi
authors: M
authors: Zhang
authors: Shujun
authors: S
authors: Liu
authors: Natarajan
authors: N
authors: Muthusamy
authors: †Division of Pharmaceutics, College of Pharmacy, ‡Division of Hematology-Oncology, §Molecular, Cellular and Developmental Biology Program, and ∥Department of Chemical and Biomolecular Engineering, The Ohio State University, Columbus, Ohio 43210, United States.
authors: Kenneth K
authors: KK
authors: Chan
authors: John C
authors: JC
authors: Byrd
authors: L James
authors: LJ
authors: Lee
authors: Guido
authors: G
authors: Marcucci
authors: †Division of Pharmaceutics, College of Pharmacy, ‡Division of Hematology-Oncology, §Molecular, Cellular and Developmental Biology Program, and ∥Department of Chemical and Biomolecular Engineering, The Ohio State University, Columbus, Ohio 43210, United States.
authors: Robert J
authors: RJ
authors: Lee
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D005260:Female; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy*; D008055:Lipids / Q000737:chemistry*; D008081:Liposomes / Q000737:chemistry; D051379:Mice; D053758:Nanoparticles / Q000737:chemistry*; D009838:Oligodeoxyribonucleotides / Q000008:administration & dosage / Q000627:therapeutic use*; D016376:Oligonucleotides, Antisense / Q000737:chemistry*; D023041:Xenograft Model Antitumor Assays
chemical_list: D008055:Lipids; D008081:Liposomes; D009838:Oligodeoxyribonucleotides; D016376:Oligonucleotides, Antisense; C464617:GTI2040
keywords: CD33-targeting; GTI-2040; acute myelogenous leukemia; antisense oligonucleotide; deoxycholate-polyethylenimine conjugate; lipid nanoparticles