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: Hong Li, Songlin Xu, Jishan Quan, Bryant C Yung, Jiuxia Pang, Chenguang Zhou, Young-Ah Cho, Mengzi Zhang, Shujun Liu, Natarajan Muthusamy, Kenneth K Chan, John C Byrd, L James Lee, Guido Marcucci, Robert J Lee
• Journal: Molecular pharmaceutics (Mol Pharm) Vol. 12 Issue 6 Pg. 2010-8 (Jun 01 2015) ISSN: 1543-8392 [Electronic] United States
• PMID: 25871632 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Lipids
• Liposomes
• Oligodeoxyribonucleotides
• Oligonucleotides, Antisense
• GTI2040

Topics

• Animals
• Cell Line, Tumor
• Cell Survival (drug effects)
• Female
• Humans
• Leukemia, Myeloid, Acute (drug therapy)
• Lipids (chemistry)
• Liposomes (chemistry)
• Mice
• Nanoparticles (chemistry)
• Oligodeoxyribonucleotides (administration & dosage, therapeutic use)
• Oligonucleotides, Antisense (chemistry)
• Xenograft Model Antitumor Assays