title: Simultaneous inhibition of aberrant cancer kinome using rationally designed polymer-protein core-shell nanomedicine.
abstract: Simultaneous inhibition of deregulated cancer kinome using rationally designed nanomedicine is an advanced therapeutic approach. Herein, we have developed a polymer-protein core-shell nanomedicine to inhibit critically aberrant pro-survival kinases (mTOR, MAPK and STAT5) in primitive (CD34(+)/CD38(-)) Acute Myeloid Leukemia (AML) cells. The nanomedicine consists of poly-lactide-co-glycolide core (~250 nm) loaded with mTOR inhibitor, everolimus, and albumin shell (~25 nm thick) loaded with MAPK/STAT5 inhibitor, sorafenib and the whole construct was surface conjugated with monoclonal antibody against CD33 receptor overexpressed in AML. Electron microscopy confirmed formation of core-shell nanostructure (~290 nm) and flow cytometry and confocal studies showed enhanced cellular uptake of targeted nanomedicine. Simultaneous inhibition of critical kinases causing synergistic lethality against leukemic cells, without affecting healthy blood cells, was demonstrated using immunoblotting, cytotoxicity and apoptosis assays. This cell receptor plus multi-kinase targeted core-shell nanomedicine was found better specific and tolerable compared to current clinical regime of cytarabine and daunorubicin.
  
  
  BACKGROUND
  These authors demonstrate simultaneous inhibition of critical kinases causing synergistic lethality against leukemic cells, without affecting healthy blood cells by using rationally designed polymer-protein core-shell nanomedicine, provoding an advanced method to eliminate cancer cells, with the hope of future therapeutic use.
authors.affiliation: Amrita Centre for Nanosciences and Molecular Medicine, Amrita Institute of Medical Sciences and Research Centre, Kochi, Kerala, India.
authors.forename: Parwathy
authors.initials: P
authors.lastname: Chandran
authors.forename: Neha
authors.initials: N
authors.lastname: Gupta
authors.forename: Archana Payickattu
authors.initials: AP
authors.lastname: Retnakumari
authors.forename: Giridharan Loghanathan
authors.initials: GL
authors.lastname: Malarvizhi
authors.forename: Pavithran
authors.initials: P
authors.lastname: Keechilat
authors.forename: Shantikumar
authors.initials: S
authors.lastname: Nair
authors.forename: Manzoor
authors.initials: M
authors.lastname: Koyakutty
mesh_terms: D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D016503:Drug Delivery Systems; D000068338:Everolimus; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000201:enzymology / Q000276:immunology; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*; D008958:Models, Molecular; D050997:Nanomedicine; D009536:Niacinamide / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000627:therapeutic use; D010671:Phenylurea Compounds / Q000008:administration & dosage / Q000627:therapeutic use*; D011098:Polyglactin 910 / Q000737:chemistry; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use*; D050799:STAT5 Transcription Factor / Q000037:antagonists & inhibitors; D063268:Sialic Acid Binding Ig-like Lectin 3 / Q000276:immunology; D020123:Sirolimus / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000627:therapeutic use; D000077157:Sorafenib; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*
chemical_list: D000970:Antineoplastic Agents; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D050799:STAT5 Transcription Factor; D063268:Sialic Acid Binding Ig-like Lectin 3; D009536:Niacinamide; D011098:Polyglactin 910; D000068338:Everolimus; D000077157:Sorafenib; D058570:TOR Serine-Threonine Kinases; D020928:Mitogen-Activated Protein Kinases; D020123:Sirolimus
keywords: Cancer kinome; Core-shell nanomedicine; Kinase inhibitors; Leukemia; Targeting