title: Transferrin targeted core-shell nanomedicine for combinatorial delivery of doxorubicin and sorafenib against hepatocellular carcinoma.
abstract: Combinatorial drug delivery is an attractive, but challenging requirement of next generation cancer nanomedicines. Here, we report a transferrin-targeted core-shell nanomedicine formed by encapsulating two clinically used single-agent drugs, doxorubicin and sorafenib against liver cancer. Doxorubicin was loaded in poly(vinyl alcohol) nano-core and sorafenib in albumin nano-shell, both formed by a sequential freeze-thaw/coacervation method. While sorafenib from the nano-shell inhibited aberrant oncogenic signaling involved in cell proliferation, doxorubicin from the nano-core evoked DNA intercalation thereby killing >75% of cancer cells. Upon targeting using transferrin ligands, the nanoparticles showed enhanced cellular uptake and synergistic cytotoxicity in ~92% of cells, particularly in iron-deficient microenvironment. Studies using 3D spheroids of liver tumor indicated efficient penetration of targeted core-shell nanoparticles throughout the tissue causing uniform cell killing. Thus, we show that rationally designed core-shell nanoparticles can effectively combine clinically relevant single-agent drugs for exerting synergistic activity against liver cancer.
  
  
  BACKGROUND
  Transferrin-targeted core-shell nanomedicine encapsulating doxorubicin and sorafenib was studied as a drug delivery system against hepatocellular carcinoma, resulting in enhanced and synergistic therapeutic effects, paving the way towards potential future clinical applications of similar techniques.
authors.affiliation: Amrita center for Nanosciences and Molecular Medicine, Amrita Institute of Medical Sciences and Research Centre, Amrita Vishwa Vidyapeetham (Amrita University), Kochi, India.
authors.forename: Giridharan Loghanathan
authors.initials: GL
authors.lastname: Malarvizhi
authors.affiliation: Amrita center for Nanosciences and Molecular Medicine, Amrita Institute of Medical Sciences and Research Centre, Amrita Vishwa Vidyapeetham (Amrita University), Kochi, India.
authors.forename: Archana Payickattu
authors.initials: AP
authors.lastname: Retnakumari
authors.affiliation: Amrita center for Nanosciences and Molecular Medicine, Amrita Institute of Medical Sciences and Research Centre, Amrita Vishwa Vidyapeetham (Amrita University), Kochi, India. Electronic address: shantinair@aims.amrita.edu.
authors.forename: Shantikumar
authors.initials: S
authors.lastname: Nair
authors.affiliation: Amrita center for Nanosciences and Molecular Medicine, Amrita Institute of Medical Sciences and Research Centre, Amrita Vishwa Vidyapeetham (Amrita University), Kochi, India. Electronic address: manzoork@aims.amrita.edu.
authors.forename: Manzoor
authors.initials: M
authors.lastname: Koyakutty
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy*; D004317:Doxorubicin / Q000008:administration & dosage / Q000737:chemistry*; D004337:Drug Carriers / Q000737:chemistry; D016503:Drug Delivery Systems; D056945:Hep G2 Cells; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy*; D050997:Nanomedicine / Q000379:methods*; D009536:Niacinamide / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000737:chemistry; D010671:Phenylurea Compounds / Q000008:administration & dosage / Q000737:chemistry*; D000077157:Sorafenib; D014168:Transferrin / Q000737:chemistry*
chemical_list: D004337:Drug Carriers; D010671:Phenylurea Compounds; D014168:Transferrin; D009536:Niacinamide; D004317:Doxorubicin; D000077157:Sorafenib
keywords: Core-shell nanomedicine; Doxorubicin; Hepatocellular carcinoma; Poly(vinyl alcohol); Sorafenib; Transferrin