@article{13cf233b97714d4a834cf9b3bc47b2d9,
title = "A rationally designed nanoparticle for RNA interference therapy in B-lineage lymphoid malignancies",
abstract = "The purposes of the present study were to further evaluate the biologic significance of the CD22δE12 molecular lesion and determine if it could serve as a molecular target for RNA interference (RNAi) therapy. We show that both pediatric and adult B-lineage lymphoid malignancies are characterized by a very high incidence of the CD22δE12 genetic defect. We provide unprecedented experimental evidence for a previously unrecognized causal link between CD22δE12 and aggressive biology of BPL cells by demonstrating that siRNA-mediated knockdown of CD22δE12 in primary BPL cells is associatedwith amarked inhibition of their clonogenicity. These findings provide the preclinical proof-of-concept that siRNA-mediated depletion of CD22δE12 may help develop effective treatments for high-risk and relapsed BPL patients who are in urgent need for therapeutic innovations. We also describe a unique polypeptide-based nanoparticle formulation of CD22δE12-siRNA as an RNAi therapeutic candidate targeting CD22δE12 that is capable of delivering its siRNA cargo into the cytoplasmof leukemia cells causing effective CD22δE12 depletion andmarked inhibition of leukemic cell growth. Further development and optimization of this nanoparticle or other nanoformulation platforms for CD22δE12-siRNAmay facilitate the development of an effective therapeutic RNAi strategy against a paradigm shift in therapy of aggressive or chemotherapy-resistant B-lineage lymphoid malignancies.",
keywords = "Cationic polypeptides, Leukemia, Nanomedicine, Nanoparticles, Nanotechnology",
author = "Uckun, {Fatih M.} and Sanjive Qazi and Hong Ma and Lichen Yin and Jianjun Cheng",
note = "Funding Information: The project described was supported primarily by the USC Keck School of Medicine Regenerative Medicine Initiative Award (F.M.U.) and in part by DHHS grants P30CA014089 (F.M.U.), U01-CA-151837 (F.M.U.), and R01CA-154471 (F.M.U.) from the National Cancer Institute . J. C. acknowledges the support from NIH (Director's New Innovator Award 1DP2OD007246-01 ). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Cancer Institute or the National Institutes of Health. This work was also supported in part by Nautica Triathlon and its producer Michael Epstein (F.M.U.), Couples Against Leukemia Foundation (F.M.U.) and Saban Research Institute Merit Awards (F.M.U.). No pharmaceutical company or other agency has paid or encouraged the writing or submission of this article. We thank Mrs. Parvin Izadi of the CHLA Bone Marrow Laboratory, Mrs. Tsen-Yin Lin of the CHLA FACS Core as well as Ernesto Barron and Anthony Rodriguez of the USC Norris Comprehensive Cancer Center Cell and Tissue Imaging Core for their assistance. We thank Dr. Zanxian Xia (School of Biological Science and Technology, Central South University, Changsha, Hunan 410078, China) for the lentiviral vector pCL6-2AEGwo. We thank the technicians of the Uckun lab, including Anoush Shahidzadeh, Ingrid Cely and Martha Arellano for their assistance throughout the study. We also thank Drs. Amanda Termuhlen and Paul Gaynon from the USC Keck School of Medicine for providing primary BPL specimens. Publisher Copyright: {\textcopyright} 2014 The Authors.",
year = "2014",
doi = "10.1016/j.ebiom.2014.10.013",
language = "English (US)",
volume = "1",
pages = "141--155",
journal = "EBioMedicine",
issn = "2352-3964",
publisher = "Elsevier BV",
number = "2-3",
}