title: Viral/Nonviral Chimeric Nanoparticles To Synergistically Suppress Leukemia Proliferation via Simultaneous Gene Transduction and Silencing.
abstract: Single modal cancer therapy that targets one pathological pathway often turns out to be inefficient. For example, relapse of chronic myelogenous leukemia (CML) after inhibiting BCR-ABL fusion protein using tyrosine kinase inhibitors (TKI) (e.g., Imatinib) is of significant clinical concern. This study developed a dual modal gene therapy that simultaneously tackles two key BCR-ABL-linked pathways using viral/nonviral chimeric nanoparticles (ChNPs). Consisting of an adeno-associated virus (AAV) core and an acid-degradable polymeric shell, the ChNPs were designed to simultaneously induce pro-apoptotic BIM expression by the AAV core and silence pro-survival MCL-1 by the small interfering RNA (siRNA) encapsulated in the shell. The resulting BIM/MCL-1 ChNPs were able to efficiently suppress the proliferation of BCR-ABL+ K562 and FL5.12/p190 cells in vitro and in vivo via simultaneously expressing BIM and silencing MCL-1. Interestingly, the synergistic antileukemic effects generated by BIM/MCL-1 ChNPs were specific to BCR-ABL+ cells and independent of a proliferative cytokine, IL-3. The AAV core of ChNPs was efficiently shielded from inactivation by anti-AAV serum and avoided the generation of anti-AAV serum, without acute toxicity. This study demonstrates the development of a synergistically efficient, specific, and safe therapy for leukemia using gene carriers that simultaneously manipulate multiple and interlinked pathological pathways.
authors.affiliation: Department of Pharmaceutical Sciences, ‡Department of Chemical Engineering and Materials Science, §Department of Biological Sciences, ∥Division of Hematology/Oncology, ⊥Department of Molecular Biology and Biochemistry, and #Department of Biomedical Engineering, University of California , Irvine, California 92697, United States.
authors.forename: Cheol Am
authors.initials: CA
authors.lastname: Hong
authors.affiliation: Department of Pharmaceutical Sciences, ‡Department of Chemical Engineering and Materials Science, §Department of Biological Sciences, ∥Division of Hematology/Oncology, ⊥Department of Molecular Biology and Biochemistry, and #Department of Biomedical Engineering, University of California , Irvine, California 92697, United States.
authors.forename: Soo Kyung
authors.initials: SK
authors.lastname: Cho
authors.affiliation: Department of Pharmaceutical Sciences, ‡Department of Chemical Engineering and Materials Science, §Department of Biological Sciences, ∥Division of Hematology/Oncology, ⊥Department of Molecular Biology and Biochemistry, and #Department of Biomedical Engineering, University of California , Irvine, California 92697, United States.
authors.forename: Julius A
authors.initials: JA
authors.lastname: Edson
authors.affiliation: Department of Pharmaceutical Sciences, ‡Department of Chemical Engineering and Materials Science, §Department of Biological Sciences, ∥Division of Hematology/Oncology, ⊥Department of Molecular Biology and Biochemistry, and #Department of Biomedical Engineering, University of California , Irvine, California 92697, United States.
authors.forename: Jane
authors.initials: J
authors.lastname: Kim
authors.affiliation: Department of Pharmaceutical Sciences, ‡Department of Chemical Engineering and Materials Science, §Department of Biological Sciences, ∥Division of Hematology/Oncology, ⊥Department of Molecular Biology and Biochemistry, and #Department of Biomedical Engineering, University of California , Irvine, California 92697, United States.
authors.forename: Dominique
authors.initials: D
authors.lastname: Ingato
authors.affiliation: Department of Pharmaceutical Sciences, ‡Department of Chemical Engineering and Materials Science, §Department of Biological Sciences, ∥Division of Hematology/Oncology, ⊥Department of Molecular Biology and Biochemistry, and #Department of Biomedical Engineering, University of California , Irvine, California 92697, United States.
authors.forename: Bryan
authors.initials: B
authors.lastname: Pham
authors.affiliation: Department of Pharmaceutical Sciences, ‡Department of Chemical Engineering and Materials Science, §Department of Biological Sciences, ∥Division of Hematology/Oncology, ⊥Department of Molecular Biology and Biochemistry, and #Department of Biomedical Engineering, University of California , Irvine, California 92697, United States.
authors.forename: Anthony
authors.initials: A
authors.lastname: Chuang
authors.affiliation: Department of Pharmaceutical Sciences, ‡Department of Chemical Engineering and Materials Science, §Department of Biological Sciences, ∥Division of Hematology/Oncology, ⊥Department of Molecular Biology and Biochemistry, and #Department of Biomedical Engineering, University of California , Irvine, California 92697, United States.
authors.forename: David A
authors.initials: DA
authors.lastname: Fruman
authors.affiliation: Department of Pharmaceutical Sciences, ‡Department of Chemical Engineering and Materials Science, §Department of Biological Sciences, ∥Division of Hematology/Oncology, ⊥Department of Molecular Biology and Biochemistry, and #Department of Biomedical Engineering, University of California , Irvine, California 92697, United States.
authors.forename: Young Jik
authors.initials: YJ
authors.lastname: Kwon
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D001549:Benzamides; D049109:Cell Proliferation; D019008:Drug Resistance, Neoplasm; D016044:Fusion Proteins, bcr-abl; D020868:Gene Silencing; D015316:Genetic Therapy; D006801:Humans; D020014:K562 Cells; D007938:Leukemia / Q000188:drug therapy*; D053758:Nanoparticles; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D014161:Transduction, Genetic
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D016044:Fusion Proteins, bcr-abl
keywords: AAV transduction; BIM expression; MCL-1 silencing; RNA interference; core−shell nanoparticles; hybrid vector; synergistic leukemia gene therapy