title: Anticancer and antiangiogenic activity of surfactant-free nanoparticles based on self-assembled polymeric derivatives of vitamin E: structure-activity relationship.
abstract: α-Tocopheryl succinate (α-TOS) is a well-known mitochondrially targeted anticancer compound, however, it is highly hydrophobic and toxic. In order to improve its activity and reduce its toxicity, new surfactant-free biologically active nanoparticles (NP) were synthesized. A methacrylic derivative of α-TOS (MTOS) was prepared and incorporated in amphiphilic pseudoblock copolymers when copolymerized with N-vinylpyrrolidone (VP) by free radical polymerization (poly(VP-co-MTOS)). The selected poly(VP-co-MTOS) copolymers formed surfactant-free NP by nanoprecipitation with sizes between 96 and 220 nm and narrow size distribution, and the in vitro biological activity was tested. In order to understand the structure-activity relationship three other methacrylic monomers were synthesized and characterized: MVE did not have the succinate group, SPHY did not have the chromanol ring, and MPHY did not have both the succinate group and the chromanol ring. The corresponding families of copolymers (poly(VP-co-MVE), poly(VP-co-SPHY), and poly(VP-co-MPHY)) were synthesized and characterized, and their biological activity was compared to poly(VP-co-MTOS). Both poly(VP-co-MTOS) and poly(VP-co-MVE) presented triple action: reduced cell viability of cancer cells with little or no harm to normal cells (anticancer), reduced viability of proliferating endothelial cells with little or no harm to quiescent endothelial cells (antiangiogenic), and efficiently encapsulated hydrophobic molecules (nanocarrier). The anticancer and antiangiogenic activity of the synthesized copolymers is demonstrated as the active compound (vitamin E or α-tocopheryl succinate) do not need to be cleaved to trigger the biological action targeting ubiquinone binding sites of complex II. Poly(VP-co-SPHY) and poly(VP-co-MPHY) also formed surfactant-free NP that were also endocyted by the assayed cells; however, these NP did not selectively reduce cell viability of cancer cells. Therefore, the chromanol ring of the vitamin E analogues has an important role in the biological activity of the copolymers. Moreover, when succinate moiety is substituted and vitamin E is directly linked to the macromolecular chain through an ester bond, the biological activity is maintained.
authors.affiliation: †Group of Biomaterials, Department of Polymeric Nanomaterials and Biomaterials, Institute of Polymer Science and Technology, CSIC, C/Juan de la Cierva, 3, 28006 Madrid, Spain.|‡Networking Biomedical Research Centre in Bioengineering, Biomaterials and Nanomedicine, CIBER-BBN, Zaragoza, Spain.
authors.forename: Raquel
authors.initials: R
authors.lastname: Palao-Suay
authors.affiliation: †Group of Biomaterials, Department of Polymeric Nanomaterials and Biomaterials, Institute of Polymer Science and Technology, CSIC, C/Juan de la Cierva, 3, 28006 Madrid, Spain.|‡Networking Biomedical Research Centre in Bioengineering, Biomaterials and Nanomedicine, CIBER-BBN, Zaragoza, Spain.
authors.forename: María Rosa
authors.initials: MR
authors.lastname: Aguilar
authors.affiliation: †Group of Biomaterials, Department of Polymeric Nanomaterials and Biomaterials, Institute of Polymer Science and Technology, CSIC, C/Juan de la Cierva, 3, 28006 Madrid, Spain.
authors.forename: Francisco J
authors.initials: FJ
authors.lastname: Parra-Ruiz
authors.affiliation: †Group of Biomaterials, Department of Polymeric Nanomaterials and Biomaterials, Institute of Polymer Science and Technology, CSIC, C/Juan de la Cierva, 3, 28006 Madrid, Spain.|‡Networking Biomedical Research Centre in Bioengineering, Biomaterials and Nanomedicine, CIBER-BBN, Zaragoza, Spain.
authors.forename: Mar
authors.initials: M
authors.lastname: Fernández-Gutiérrez
authors.affiliation: ‡Networking Biomedical Research Centre in Bioengineering, Biomaterials and Nanomedicine, CIBER-BBN, Zaragoza, Spain.|§Clinical Research and Experimental Biopathology Unit, Healthcare Complex of Ávila, SACYL, C/Jesús del Gran Poder 42, 05003 Ávila, Spain.
authors.forename: Juan
authors.initials: J
authors.lastname: Parra
authors.affiliation: ∥Foundation for Biomedical Research, University Hospital of Getafe, Carretera de Toledo, km 12,500, 28905, Getafe, Madrid, Spain.|#European University of Madrid, C/ Tajo s/n. 28670, Villaviciosa de Odón (Madrid), Spain.
authors.forename: Carolina
authors.initials: C
authors.lastname: Sánchez-Rodríguez
authors.affiliation: ∥Foundation for Biomedical Research, University Hospital of Getafe, Carretera de Toledo, km 12,500, 28905, Getafe, Madrid, Spain.|#European University of Madrid, C/ Tajo s/n. 28670, Villaviciosa de Odón (Madrid), Spain.
authors.forename: Ricardo
authors.initials: R
authors.lastname: Sanz-Fernández
authors.affiliation: ∥Foundation for Biomedical Research, University Hospital of Getafe, Carretera de Toledo, km 12,500, 28905, Getafe, Madrid, Spain.
authors.forename: Laura
authors.initials: L
authors.lastname: Rodrigáñez
authors.affiliation: †Group of Biomaterials, Department of Polymeric Nanomaterials and Biomaterials, Institute of Polymer Science and Technology, CSIC, C/Juan de la Cierva, 3, 28006 Madrid, Spain.|‡Networking Biomedical Research Centre in Bioengineering, Biomaterials and Nanomedicine, CIBER-BBN, Zaragoza, Spain.
authors.forename: Julio San
authors.initials: JS
authors.lastname: Román
mesh_terms: D020533:Angiogenesis Inhibitors / Q000138:chemical synthesis / Q000737:chemistry; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry; D049109:Cell Proliferation / Q000187:drug effects; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D061986:MCF-7 Cells; D008689:Methacrylates / Q000138:chemical synthesis / Q000737:chemistry; D053758:Nanoparticles / Q000737:chemistry* / Q000627:therapeutic use; D009369:Neoplasms / Q000188:drug therapy; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D011108:Polymers / Q000138:chemical synthesis / Q000737:chemistry; D013329:Structure-Activity Relationship; D013501:Surface-Active Agents / Q000737:chemistry; D014810:Vitamin E / Q000031:analogs & derivatives / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D024502:alpha-Tocopherol / Q000031:analogs & derivatives / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D008689:Methacrylates; D011108:Polymers; D013501:Surface-Active Agents; D014810:Vitamin E; C008384:methacrylic acid; D024502:alpha-Tocopherol