Antisense Oligonucleotides (As ODNs) Based Leuckemia Therapy Using Therapeutic Antibody Conjugated Nano-Lipopolyplexes (NLPs)
Bo Yu, Department of Chemical and Biomolecular Engineering, The Ohio State University, 140 West 19th Avenue, Columbus, OH 43210, Yan Jin, NSF Center for Affordable Nanoengineering of Polymeric Biomedical Devices, The Ohio State University, 140 West 19th Avenue, Columbus, OH 43210, L. James Lee, Chemical and Biomolecular Engineering, The Ohio State University, 125 Koffolt Labs, 140 W 19th Ave, Columbus, OH 43210, and Robert J. Lee, College of Pharmacy, The Ohio State University, 542 Parks Hall, 500 West 12th Avenue, Columbus, OH 43210.
CD20 antibody is a FDA-approved therapeutic antibody that has been used in clinical treatment for leukemia. In this study, we conjugated antiCD20 on nano-lipopolyplexes (NLP) carrying Bcl-2 targeted antisense oligonucleotide (AS-ODN) for enhancing delivery to leukemia cells. In comparison to free ODN, the formulated ODN in antiCD20-NLP showed preferential uptake by B leukemia cells. The uptake of AS ODN correlated well with the CD20 expression levels on the cells. antiCD20-NLP mediated ODN delivery can enhance the intracellular Bcl-2 down-regulation in both B cell lines, such as Raji, and leukemia patient cells. The uptake and intracellular trafficking of ODN loaded antiCD20-NLP were characterized by confocal microscopy and Quantum Dot-FRET technology. We also found that the antiCD20 conjugated to NLPs can induce apoptosis on primary leukemia cells by the CD20 cross-linking mechanism. Our findings provide a new approach to improving the clinical efficacy of AS-ODNs therapy in treatment of B cell malignancies. The same approach can also be applied to therapeutic antibodies mediated small interfering RNA (siRNA) delivery for leukemia and other B cell related malignancies.