title: Codelivery of Ponatinib and SAR302503 by Active Bone-Targeted Polymeric Micelles for the Treatment of Therapy-Resistant Chronic Myeloid Leukemia.
abstract: Point mutations in the BCR-ABL1 domain and primitive chronic myelogenous leukemia (CML) cells existing in the bone marrow environment insensitive to tyrosine kinase inhibitors (TKIs) have become two major challenges in the CML therapy. In this study, combined TKI ponatinib and JAK2 inhibitor SAR302503 short-term treatment effectively suppressed growth and promoted apoptosis of BaF3/T315I cells in cytokine-containing medium in vitro. SAR302503 prevented cytokine-dependent resistance to ponatinib via inhibition of JAK2/STAT5 phosphorylation. Codelivery of ponatinib and SAR302503 by active bone-targeted polymeric micellar formulation greatly increased the drug accumulation in medullary cavity. The therapeutic efficacy of bone-targeted formulation was demonstrated in BaF3/T315I cells inoculated murine model with no dose-limited toxicity detectable in health mice. Thus, the intravenous injectable bone-homing ponatinib and SAR302503 micellar formulation represents a promising strategy for the treatment of therapy-resistant CML.
authors.affiliation: Department of Pharmaceutics, College of Pharmacy, Zhejiang Chinese Medical University , Hangzhou, Zhejiang 310053, China.
authors.forename: Chao-Feng
authors.identifier: 0000-0002-0655-1626
authors.initials: CF
authors.lastname: Mu
authors.affiliation: Department of Pharmaceutics, College of Pharmacy, Zhejiang Chinese Medical University , Hangzhou, Zhejiang 310053, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Xiong
authors.affiliation: Department of Pharmaceutics, College of Pharmacy, Zhejiang Chinese Medical University , Hangzhou, Zhejiang 310053, China.
authors.forename: Xue
authors.initials: X
authors.lastname: Bai
authors.affiliation: Department of Pharmaceutics, College of Pharmacy, Zhejiang Chinese Medical University , Hangzhou, Zhejiang 310053, China.
authors.forename: Yun-Jie
authors.initials: YJ
authors.lastname: Sheng
authors.affiliation: Department of Biochemistry, College of Medicine, Yichun University , Yichun, Jiangxi 336000, China.
authors.forename: Jiajun
authors.initials: J
authors.lastname: Cui
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage; D001853:Bone Marrow / Q000187:drug effects / Q000378:metabolism; D001842:Bone and Bones / Q000187:drug effects* / Q000378:metabolism; D002460:Cell Line; D045744:Cell Line, Tumor; D002626:Chemistry, Pharmaceutical / Q000379:methods; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D005260:Female; D016044:Fusion Proteins, bcr-abl / Q000378:metabolism; D007093:Imidazoles / Q000008:administration & dosage*; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008823:Micelles; D011108:Polymers / Q000008:administration & dosage*; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage; D011724:Pyridazines / Q000008:administration & dosage*; D011759:Pyrrolidines / Q000008:administration & dosage*; D013449:Sulfonamides / Q000008:administration & dosage*; D000096926:Benzenesulfonamides
chemical_list: D000970:Antineoplastic Agents; D016044:Fusion Proteins, bcr-abl; D007093:Imidazoles; D008823:Micelles; D011108:Polymers; D047428:Protein Kinase Inhibitors; D011724:Pyridazines; D011759:Pyrrolidines; D013449:Sulfonamides; C545373:ponatinib; C528327:fedratinib; D000096926:Benzenesulfonamides
keywords: bone marrow microenvironment; combination treatment; targeted delivery; therapy resistance