title: PEG-PE/clay composite carriers for doxorubicin: Effect of composite structure on release, cell interaction and cytotoxicity.
abstract: A novel drug delivery system for doxorubicin (DOX), based on organic-inorganic composites was developed. DOX was incorporated in micelles (M-DOX) of polyethylene glycol-phosphatidylethanolamine (PEG-PE) which in turn were adsorbed by the clay, montmorillonite (MMT). The nano-structures of the PEG-PE/MMT composites of LOW and HIGH polymer loadings were characterized by XRD, TGA, FTIR, size (DLS) and zeta measurements. These measurements suggest that for the LOW composite a single layer of polymer intercalates in the clay platelets and the polymer only partially covers the external surface, while for the HIGH composite two layers of polymer intercalate and a bilayer may form on the external surface. These nanostructures have a direct effect on formulation stability and on the rate of DOX release. The release rate was reversely correlated with the degree of DOX interaction with the clay and followed the sequence: M-DOX>HIGH formulation>LOW formulation>DOX/MMT. Despite the slower release from the HIGH formulation, its cytotoxicity effect on sensitive cells was as high as the "free" DOX. Surprisingly, the LOW formulation, with the slowest release, demonstrated the highest cytotoxicity in the case of Adriamycin (ADR) resistant cells. Confocal microscopy images and association tests provided an insight into the contribution of formulation-cell interactions vs. the contribution of DOX release rate. Internalization of the formulations was suggested as a mechanism that increases DOX efficiency, particularly in the ADR resistant cell line. The employment of organic-inorganic hybrid materials as drug delivery systems, has not reached its full potential, however, its functionality as an efficient tunable release system was demonstrated.
  
  
  
  DOX PEG-PE/clay formulations were design as an efficient drug delivery system. The main aim was to develop PEG-PE/clay formulations of different structures based on various PEG-PE/clay ratios in order to achieve tunable release rates, to control the external surface characteristics and formulation stability. The formulations showed significantly higher toxicity in comparison to "free" DOX, explained by formulation internalization. For each cell line tested, sensitive and ADR resistant, a different formulation structure was found most efficient. The potential of PEG-PE/clay-DOX formulations to improve DOX administration efficacy was demonstrated and should be further explored and implemented for other cancer drugs and cells.
authors.affiliation: Department of Soil and Water Science, The Robert H. Smith Faculty of Agriculture, Food and Environment, The Hebrew University of Jerusalem, Rehovot 76100, Israel. Electronic address: Hagay.Kohay@mail.huji.ac.il.
authors.forename: Hagay
authors.initials: H
authors.lastname: Kohay
authors.affiliation: Center for Pharmaceutical Biotechnology and Nanomedicine, Northeastern University, Boston, MA, USA. Electronic address: c.sarisozen@neu.edu.
authors.forename: Can
authors.initials: C
authors.lastname: Sarisozen
authors.affiliation: Center for Pharmaceutical Biotechnology and Nanomedicine, Northeastern University, Boston, MA, USA.
authors.forename: Rupa
authors.initials: R
authors.lastname: Sawant
authors.affiliation: Center for Pharmaceutical Biotechnology and Nanomedicine, Northeastern University, Boston, MA, USA. Electronic address: jhaveri.ad@husky.neu.edu.
authors.forename: Aditi
authors.initials: A
authors.lastname: Jhaveri
authors.affiliation: Center for Pharmaceutical Biotechnology and Nanomedicine, Northeastern University, Boston, MA, USA; Department of Biochemistry, Faculty of Science, King Abdulaziz University, Jeddah, Saudi Arabia. Electronic address: v.torchilin@neu.edu.
authors.forename: Vladimir P
authors.initials: VP
authors.lastname: Torchilin
authors.affiliation: Department of Soil and Water Science, The Robert H. Smith Faculty of Agriculture, Food and Environment, The Hebrew University of Jerusalem, Rehovot 76100, Israel. Electronic address: yael.mishael@mail.huji.ac.il.
authors.forename: Yael G
authors.initials: YG
authors.lastname: Mishael
mesh_terms: D000538:Aluminum Silicates / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D001546:Bentonite / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D045744:Cell Line, Tumor; D000077215:Clay; D003603:Cytotoxins / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D004317:Doxorubicin / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D004337:Drug Carriers / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D011092:Polyethylene Glycols / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology
chemical_list: D000538:Aluminum Silicates; D003603:Cytotoxins; D004337:Drug Carriers; D001546:Bentonite; D011092:Polyethylene Glycols; D004317:Doxorubicin; D000077215:Clay
keywords: Clay-montmorillonite; Composites; Control released; DOX; PEG-PE