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Title: Project title: "Interdisciplinary research on multifunctional hybrid particles for biorequirements


1
Project title "Interdisciplinary research on
multifunctional hybrid particles for
biorequirements acronim INTERBIORES
  • Contract no. 211/2012
  • Project Cod PN-II-PT-PCCA-
  • 2011-3.2-0428 Programme PN II
  • Partnerships Priority Areas -
  • Applied Research Projects
  • Type 2

2
Contracting Authority Executive Unit for
Financing Higher Education, Research Development
and Innovation (UEFISCDI) Contractor "Petru
Poni" Institute of Macromolecular Chemistry,Iasi
  • Duration of project 02.07.2012 02.07.2015
  • The total value of the contract 3.323.334 lei
  • From the source of funding
  • Source 1 - The state budget 2.950.000 lei
  • Source 2 - from other sources
  • (Net financing) 373.334 lei
  • Project Director CS I Dr. Aurica P. Chiriac

3
Members
  • Petru Poni Institute for Macromolecular
    Chemistry Iasi
  • - Project Coordinator
  • Project Director Dr. Chiriac P. Aurica
  • Gr. T. Popa Medicine and Pharmacy University
    Iasi
  • UMF - Partner 1
  • Team leader Dr. Verestiuc Liliana
  • Research and Development National Institute of
    Technical
  • Physics Iasi Iasi - Partner 2
  • Team leader Dr. Chiriac Horia
  • SC REZISTOTERM SRL Partner 3
  • Team leader Dr. Chiriac Mihai

4
Abstract
  • The project with multi-disciplinary character is
    focused on analysis and solving from the
    physical, chemical and biochemical viewpoint the
    design and technology of novel systems, based on
    antioxidants-loaded core-shell magnetic
    nanocomposites deposited onto the stent surface.
    Novel formulation methods based on the use of
    biocompatible polymers will be developed and
    applied to create a family of magnetic
    nanoparticles (MNPs) further characterized as a
    platform for magnetically guided delivery of
    therapeutics. The selected polymers will undergo
    physical (forming of interpolymer complexes by
    physical interactions) and chemical
    (functionalization, derivatization, crosslinking,
    reactive mixing) modifications in order to obtain
    stable multifunctional nanosystems. The key
    features of the new target delivery systems will
    be investigated, including in vitro bioactive
    compounds activity, capacity to protect the
    antioxidants from proteolysis, as well as the
    capacity of the magnetic guidance and retrieval.
    The project includes aspects like toxicology,
    biocompatibility of the nanodevices, and also
    efficacy and biodistribution of the system. The
    studies are doing to the facts that a major
    problem associated with target delivery is the
    inability to deliver pharmaceuticals to a
    specific site of the body without causing
    nonspecific toxicity. The bioproducts loaded
    magnetic nanoparticles have several
    advantages such as small particle size, large
    surface area, magnetic response, biocompatibility
    and non-toxicity and are directed with external
    magnets to the right site, and requires smaller
    dosage because of targeting, with no side
    effects.
  • One of the most innovative aspects of this
    proposal is the use of functionalized magnetic
    nanoparticles with antioxidative biomolecules
    deposited onto the stent surface to realize a
    drug-eluting-stent type for bio-requirements. The
    new stent device will functioning as a delivery
    platform. At the same time, the prepared MNPs
    will represent a particularly appropriate tool
    based on their ability to be simultaneously
    functionalized and guided by an external
    magnetic field, the presence of the antioxidative
    biomolecules would be an additional benefit.
  • To conclude, the purpose of the
    multi-disciplinary character project is to
    realize target delivery systems based on hybrid
    bio-nano-composites with improved magnetic
    performance of the nanoparticles and maximized
    therapeutic potential of the drug
    eluting/retrieval stents by the loaded
    antioxidative biomolecules layered on the stent
    surface. In addition, the design of the
    nanoparticles will include the improvement of the
    monodispersity, colloidal stability and
    functionality. Also, further engineering of these
    nanoparticles and of their formulation as hybrid
    systems for target delivery will allow improving
    their bioselectivity and bioefficiency.

5
Concept and objectives
  • The project with multi-disciplinary character is
    focused on analysis and solving from the
    physical, chemical and biochemical viewpoint the
    design and technology for the stents achievement
    with drug delivery possibilities, based on
    antioxidants-loaded core-shell magnetic
    nanocomposites deposited onto the stent surface.
  • The market for stents is, in many ways, still
    emerging. While coronary stents have been on the
    commercial market in one form or another for
    several years, the technologies and materials
    used to create the devices are improving every
    day. In addition, innovative technology is
    bringing new classes of devices (e.g., fully
    degradable stents) to market, technologies that
    grow the market and even expand means of
    diagnosis and therapy stent to new patient
    populations in some cases.
  • One of the most innovative aspects of this
    proposal is the use of functionalized magnetic
    nanoparticles with antioxidative biomolecules
    deposited onto the stent surface to realize stent
    devices type for bio-requirements. Thus the new
    stent device will function as a delivery
    platform. At the same time, the prepared MNPs
    will represent a particularly appropriate tool
    based on their ability to be simultaneously
    functionalized and guided and/or removed by an
    external magnetic field owing to the magnetic NPs
    inclusion, meanwhile the presence of the
    antioxidative biomolecules would be the
    additional benefit. As it is well known stents
    are scaffoldings, usually cylindrical or tubular
    in shape, which function to physically hold open
    and, if desired, to expand the wall of the
    vessel. Typically stents are capable of being
    compressed, so that they may be inserted through
    small cavities via catheters, and then expanded
    to a larger diameter once they are at the desired
    location. Although stents are significant
    innovations in the treatment of occluded vessels,
    there remains a need for administering
    therapeutic substances to the treatment site.
    Systemic administration of the therapeutic
    substance often produces adverse or toxic side
    effects for the patient. Local delivery of
    therapeutic substances, by contrast, provides a
    smaller overall dosage that is concentrated at a
    specific treatment site. Local delivery can
    produce fewer side effects and achieve more
    effective results. In this context novel
    formulation based on biocompatible polymers will
    be developed and applied to create a family of
    antioxidant magnetic nanoparticles (MNPs) for
    covering the stent surfaces further characterized
    as a platform for magnetically guided and
    delivery of therapeutics. The selected polymers
    will undergo physical (forming of interpolymer
    complexes by physical interactions) and chemical
    (functionalization, derivatization, crosslinking,
    reactive mixing) modifications in order to obtain
    stable multifunctional nanosystems. The key
    features of the new target delivery systems will
    be investigated, including in vitro bioactive
    compounds activity, capacity to protect the
    antioxidants from proteolysis, as well as the
    capacity of the magnetic guidance, retrieval and
    remove. The project includes aspects like
    toxicology, biocompatibility of the nanodevices,
    and also efficacy and biodistribution of the
    system. In addition, the design of the
    nanoparticles will include the improvement of the
    monodispersity, colloidal stability and
    functionality. Also, further engineering of these
    nanoparticles and of their formulation as hybrid
    systems for target delivery will allow improving
    their bioselectivity and bioefficiency.

6
Stage I/2012 the obtained results
  • In accordance with the plan of the project
    "Interdisciplinary research on multi-functional
    hybrid particles for bio-requirements", the stage
    I/2012 has the objectives
  • (I) magnetic composites preparation and (II)
    their physical chemical evaluation, which were
    fulfilled by specific activities - the
    obtaining of magnetic nanoparticles (NPs) with
    linking capacity and antioxidant enzymes
    transport - the surface modification of magnetic
    NPs with polymeric structures, as basis for
    antioxidant hybrid materials - the
    characterization of the magnetic composites with
    the aim of association with antioxidant enzymes
    and the estimation of the physical-chemical
    theoretical and experimental conditions necessary
    for their realization, and the dissemination of
    the results by national and international
    symposia communications, publications in the ISI
    quoted journals or indexed in international
    databases.
  • The conducted studies have resulted in
  • (I) Synthesis and characterization of polymeric
    matrices, respectively (1) poly(2-hidroxyethyl
    methacrilate-co-3,9-divinyl-2,4,8,10-tetraoxaspiro
    5.5undecan-co-glicidil methacrylate) ternar
    copolymer (synthesized by radical
    copolymerization in aqueous dispersion)
  • 2) poly(dimethyl acrylamide-co-3,9-divinyl-2,4,8,1
    0-tetraoxaspiro 5.5undecan-co-itaconic acid)
    ternar copolymer (synthesized by radical
    copolymerization in dimethyl acetamide solution)
  • (3) poly(2-hydroxyethyl methacylate-co-3,9-divinyl
    -2,4,8,10-tetraoxaspiro 5.5undecan
    coacrylamide)(synthesized by radical
    copolymerization in dimethyl acetamide solution)
  • (4) 6 variants of bloc copolymers based on
    poly(succinimide)-b-poly(ethylene glycol)(PEG)
    (synthesized by copolycondensation in dimethyl
    formamide in the presence of Mn(CH3COO)2.2H2O as
    catalyst ), PEG having different molecular
    weights, such as 2000, 3000, 4000, 10000, 20000
    and 35000
  • (5) one grafted polymeric structure based on
    carboxymethyl starch-g-poly(lactic acid) (II)
    The preparation of hybrid structures with
    magnetic characteristics by using the realized
    polymeric matrices (III) Testing activities of
    the polymeric matrices and hybrid structures for
    coupling of the antioxidant enzymes, in course.
  • In the context of the dissemination activity of
    the results by communications at national and
    international symposia, by publications in the
    ISI quoted journals or indexed in international
    databases, there were presented
  • (a) Three communications at 5th International
    Conference Biomaterials. Tissue Engineering and
    Medical Devices BiomMedD2012, Constanta, 29
    August 1 September 2012, respectively

7
  • Streptavidin-Biofunctionalized Magnetic Particles
    for Blood Contacting Applications V. Balan, M.I.
    Popa, A.P. Chiriac, I. Neamtu, L.E. Nita, M.T.
    Nistor, M. Butnaru, L. Verestiuc
  • Bioactive Hybrid Scaffolds in Regenerative
    Medicine and Tissue Engineering M.T. Nistor, C.
    Zgardan, C. Vasile, L.E. Nita, A. Chiriac
  • Assembly Design and Characterization of an
    Innovative Modulated Drug Delivery System L.
    Nita, M. Nistor, N. Tudorachi, I. Neamtu, A.
    Chiriac
  • (b) One communication Determination of the
    kinetic parameters and analysis of gases released
    by thermal decomposition of CMS-g-PLA copolymer
    at XXXII National Chemical Conference Rm Valcea,
    October 2012, and
  • ( c ) One paper accepted for publication in
    Industrial Engineering Chemistry Research (IF
    2.237) Thermal degradation of carboxymethyl
    starch-g-poly(lactic acid) copolymer by
    TG-FTIR-MS analysis, authors Nita Tudorachi,
    Rodica Lipsa, Fanica Mustata.

8
Stage II/2013
  • In accordance with the plan of the project
    Interdisciplinary research on multi-functional
    hybrid particles for bio-requirements, the phase
    II/2013 had as objectives (I) Magnetic composites
    synthesis and (II) Physical-chemical evaluation
    (phase I/2012 continuation). The objectives were
    carried out through and finalized by specific
    activities, such as
  • the obtaining of magnetic nanoparticles (NPs)
    with linking capacity and antioxidant enzymes
    transport
  • experimental development for magnetic NPs surface
    modification with the aim of obtaining molecular
    adapted bio-structures, as basis for new hybrid
    materials
  • the evaluation of antioxidant enzymes,
    significant for biological structures
  • magnetic NPs bio-functionalization with
    biological structures for the nanometric level
    control of the biological and biochemical
    processes
  • experimental development for the obtaining of
    bio-functionalized magnetic NPs
  • magnetic composites characterization in
    association with antioxidant enzymes for the
    estimation of the experimental and theoretical
    physical-chemical conditions necessary for their
    preparation
  • elucidation and characterization of the surface
    properties of the particles, associated with
    antioxidant enzymes coupling reactions and
    results interpretation for subsequent studies of
    targeted delivery and controlled release
  • dissemination of the results by communications at
    national and international symposia, by
    publications in the ISI quoted journals or
    indexed in international databases.
  • The dissemination of the results by
    communications at national and international
    symposia, by publications in the ISI quoted
    journals or indexed in international databases,
    materialized as it follows
  •  

9
The obtained results
  • Published papers
  • Characterization of the semi-interpenetrated
    network based on collagen and poly(N-isopropyl
    acrylamide-co-diethylene glycoldiacrylate).
    Authors MT Nistor, A.P. Chiriac, LE Nita, C
    Vasile. Int J Pharmaceutics 452 (2013) 92 101
    IF3.458.
  • Multilayered structure based on
    poly(N,N-dimethyl-acrylamide-co-3,9-divinyl-2,4,8,
    10-tetraoxaspiro (5.5) undecane) prepared in a
    multiphase gelation process. Authors AP Chiriac,
    LE Nita, MT Nistor, L Tartau. Int J Pharmaceutics
    456 (2013) 21 30 IF3.458.
  • Obtaining of new magnetic nanocomposites based on
    modified polysaccharide. Authors NTudorachi, AP
    Chiriac, Carbohydrate Polymers 98 (2013) 451
    459 IF3.479.
  • Upon the Delivery Properties of a Polymeric
    System Based on Poly(2-Hydroxyethyl Methacrylate)
    Prepared with Protective Colloids. Authors LE
    Nita, AP Chiriac, M Nistor, TBudtova. J Biom
    Nanobiotechnol 4(2013), 357-364 ISSN Online
    2158-7043.
  • Upon the Developments of Drug-Eluting Stents in
    the Treatment of Coronary Lesions. Authors
    A.Diaconu, V Balan, AP Chiriac. Recent Patents on
    Materials Science 6(2013) 229-237
    ISSN1874-4648.
  • Semi-interpenetrated Network with Improved
    Sensitivity Based on Poly(N-Isopropylacrylamide)
    and Poly(aspartic acid). Authors MT Nistor, AP
    Chiriac, LE Nita, INeamtu, CVasile. Polym Eng Sci
    53(2013) 2345-2352 IF1.243.
  • Poly(N,N-dimethylacrylamide-co-3,9-divinyl-2,4,8,1
    0-tetraoxaspiro(5.5)undecane) synthesis as matrix
    ensuring intramolecular strategies for further
    coupling applications. Authors AP Chiriac, MT
    Nistor, LE Nita, I Neamtu. Rev. Roum. Chim.
    58(2013)(2-3), 129-136 IF-0.331.
  •  

10
The obtained results
  • Hydrogel based on poly(N,N-dimethylacrylamide-co-3
    ,9-divinyl-2,4,8,10-tetraoxaspiro(5.5)undecane)
    with dual sensitive behavior. Synthesis and
    characterization. Authors LE Nita, AP Chiriac,
    MT Nistor, I Neamtu. Rev. Roum. Chim., 2013,
    58(2-3), 137-143 IF-0.331.
  • Poly(acrylic acid)/ poly(ethylene glycol)
    nanoparticles designed for ophthalmic drug
    delivery. Authors A.M. Vasi, M.I.Popa,
    E.C.Tanase, M. Butnaru, L. Verestiuc, agreed to
    be published in J. Pharm. Sci. IF3.13.
  • Book Chapters
  • Chapter 3. Hybrid Sensitive Hydrogels for Medical
    Applications. MT Nistor, C Vasile, AP Chiriac, A
    Rusu, C Zgardan, LE Nita, I Neamtu. In Polymer
    materials with smart properties. Ed. M Bercea.
    Nova Science Publ. New York 2013, 67 89.
  • Chapter 8. Sol-Gel Technique Implemented for
    Biomedical Applications. LENita, AP Chiriac, I
    Neamtu. 189-204. In Polymer materials with smart
    properties. Ed. M Bercea. Nova Science Publ. New
    York 2013, 189 204.
  • Published papers in Proceedings
  • Functionalized superparamagnetic nanoparticles as
    versatile carriers for targeted antioxidant
    enzyme therapy. Authors V.Balan, M. Butnaru, O.
    Bredetean, L. Profire, G. Lupascu, A.P.Chiriac,
    L.E. Nita I. Neamtu, L.Verestiuc Proceedings of
    the 4th ed. of E-Health and Bioengineering
    Conference-EHB 2013, Iasi, Romania.
  • Biomimetic composites based on calcium phosphates
    and chitosan - hyaluronic acid with potential
    application in bone tissue engineering. Authors
    F.D.Ivan, A.Marian, C. E. Tanase, M. Butnaru, L.
    Verestiuc, Bioceramics 25, Key Engineering
    Materials, 587, 191-196.

11
The obtained results
  • Communications at scientific meetings
  • Functionalized superparamagnetic nanoparticles as
    versatile carriers for targeted antioxidant
    enzyme therapy. V. Balan, M. Butnaru, O.
    Bredetean, L. Profire, G. Lupascu, A.P.Chiriac,
    L.E. Nita I. Neamtu, L.Verestiuc, 4th IEEE
    International Conference on E-Health And
    Bioengineering - EHB 2013, Iasi, Romania,
    November 21st-23rd, 2013.
  • Biomimetic composites based on calcium phosphates
    and chitosan - hyaluronic acid with potential
    application in bone tissue engineering. 25th
    Symposium and Annual Meeting of the International
    Society for Ceramics in Medicine Bucharest,
    Romania November 07-10th 2013 Autori F.D.Ivan,
    A.Marian, C. E. Tanase, M. Butnaru, L. Verestiuc,
    Bioceramics 25, Key Engineering Materials, 587,
    191-196.
  •  
  • Poster at scientific meetings
  • Process for magnetic composites synthesis.
    Authors AP Chiriac, LE Nita, INeamtu, MT Nistor.
    The 17th International Salon of Research,
    Innovation and Technological Transfer Inventica
    2013 19 21st June 2013 Iasi Romania.
  • Hybrid Structures for Bioapplications. Authors
    AP Chiriac, LE Nita, INeamtu, MT Nistor.
    National Innovation Salon CHIM-INVENT, 3 5 July
    2013, Iasi Romania.
  • Registered patent application
  • Magnetic composite synthesis process. Authors
    A.P. Chiriac, L.E. Nita, I. Neamtu, N.Tudorachi,
    A. Diaconu, V. Balan, C. Munteanu. Patent
    application No. A 00833/13.11.2013.

12
Stage III/2014 Plan and activities
  • Physico-chemical evaluation (continuation from
    2013)
  • Bio-chemical evaluation Methods for
    toxicological evaluation of NPs for providing
    fundamental knowledge on their design and testing
    as targeted delivery systems.
  • Integration of bio-magnetic systems
  • - Activity 2.7
  • Characterization of magnetic composites in
    combination with antioxidant enzymes to determine
    the
  • experimental conditions to achieve them -
    continuing in 2012 and 2013
  • - Activity 2.8
  • The elucidation and characterization of surface
    properties of the particles associated with the
    coupling reaction
  • of the antioxidant enzyme for further studies
    of release (activity continuation from 2012 and
    2013)
  • - Activity 2.9
  • Determination of the initiation reactions of
    self-assembling mechanisms for hybrid materials
    preparation - Part
  • - Activity 2.10
  • Conceptual design of coupling system between the
    magnetic composite and the antioxidant enzyme
    -Part I
  • - Activity 2.11
  • Dissemination of results through communications
    at national and international symposia,
    publications in
  • journals

13
Stage III/2014 Plan and activities
  • - Activity 3.1
  • Establish procedures for the preparation and
    characterization of new materials
  • - Activity 3.2
  • Dissemination of results through communications
    at national and international symposia,
    publications in
  • journals ISI or indexed in international
    databases
  • - Activity 3.3
  • Testing biomagnetic self-assembled hybrid
    materials with antioxidant characteristics -
    Part I
  • - Activity 3.4
  • Testing and evaluation of hybrid systems - Part I

14
The obtained results
  • Published papers
  • Current concepts on cardiovascular stent devices
    I. Neamtu, A. P. Chiriac, A. Diaconu, L. E. Nita,
    V. Balan, M. T. Nistor Mini-Reviews in Medicinal
    Chemistry, 14, 505-536 (2014). If3.186
  • Semi-imprinting quercetin into polyN,N-dimethylac
    rylamide-co-3,9-divinyl-2,4,8,10-tetraoxaspiro
    (5,5) undecane network Evaluation of the
    antioxidant character A. P. Chiriac, L. E. Nita,
    L. Tartau, I. Neamtu, M. T. Nistor Journal of
    Pharmaceutical Sciences, 103, 2338-2346 (2014).
    IF3.007
  • Upon some multi-membrane hydrogels based on poly
    (N,N-dimethyl-acrylamide-co-3,9-divinyl-2,4,8,10-t
    etraoxaspiro (5.5) Undecane) preparation,
    characterization and in vivo tests, L. E. Nita,
    A. P. Chiriac, M. T. Nistor, L. Tartau J. Mat.
    Sci. Mat. in Med., 25 (7), (2014) 1757-1768,
    IF2.379.
  • Upon Synthesis of Poly(N-isopropylacrylamide-co-2-
    dimethyl-aminoethyl methacrylate-co-itaconic
    acid) Copolymers as Matrix Ensuring
    Intramolecular Strategies for Further Coupling
    Applications A. P. Chiriac, L. E. Nita, I.
    Neamtu, V. Balan, A. Diaconu Journal of Research
    Updates in Polymer Science, 3 (1), 48-56 (2014).
    IF-0.0

15
The obtained results
  • Communications at scientific meetings
  • A. Diaconu, A. P. Chiriac, L. E. Nita, N.
    Tudorachi, I. Neamtu, V. Balan Upon synthesis of
    poly(maleic anhydride-co-3, 9-divinyl-2, 4, 8,
    10-tetraoxaspiro (5.5) undecane) copolymer with
    antioxidant character and possibilities for
    bioconjugation communicated at 2nd International
    Conference on Chemical Engineering, Iasi ,
    November 5-8 2014.
  • A. Diaconu, I. Neamtu, L. E. Nita, A. P. Chiriac,
    V. Balan, Poly(maleic anhydride-co-3,
    9-divinyl-2, 4, 8, 10-tetraoxaspiro (5.5)
    undecane) copolymer-based magnetic composites
    Potential vectors for remote-controlled bioactive
    substance release, 2nd International Conference
    on Chemical Engineering, Iasi , November 5-8
    2014.
  • Tudorachi, A. P. Chiriac, G. Lisa, V. Balan, L.
    Nita, Magnetic nanocomposites PLGA/magnetite,
    Alexandru Ioan Cuza University Days, Faculty of
    Chemistry Conference, Iasi, 31 octombrie 01
    noiembrie 2014,
  • R. Lipsa, N. Tudorachi, A. Grigoras, C. Vasile,
    P. Gradinariu, A. P. Chiriac, F. Mustata,
    Poly(vinyl alcohol) copolymers biodegradation
    with Trichotecium roseum fungi Alexandru Ioan
    Cuza University Days, Faculty of Chemistry
    Conference, Iasi, 31 octombrie 01 noiembrie
    2014.
  • Registered patent application Process for the
    synthesis of a magnetic composite A.P. Chiriac,
    L.E. Nita, I. Neamtu, N. Tudorachi, A. Diaconu,
    V. Balan, A00808 from 29.10.2014.

16
Stage IV/2015 Project objectives
  • Physical Chemical evaluation continued 2014
    Stage
  • Biochemical evaluation Methods for toxicological
    evaluation of new NPs to provide fundamental
    knowledge on design and testing as targeted
    delivery systems
  • Integration of bio-magnetic system continued
    2014 Stage
  • Activity 2.9 . Determination of the initiation
    mechanism of the self-assembling reaction of
    hybrid materials Part III
  • Activity 2.10. Conceptual approach and the design
    of the coupling system between antioxidant
    magnetic composite and stent Part III
  • Activity 3.3. Testing of self-assembled
    biomagnetic hybrid materials with antioxidant
    characteristics. Part II.
  • Activity 3.4. Hybrid systems testing and
    evaluation Part III
  • Activity 4.1. Working methods and protocols for
    new therapeutic strategies, applications and
    techniques for testing of the obtained hybrid
    systems. Toxicological evaluation methods of the
    new synthesized nanoparticles for testing them as
    targeted delivery systems.
  • Activity 4.2. Developing the capacity of
    knowledge of particle / stent systems and
    transport through different specific environments
  • Activity 4.3. Optimization and synthesis studies.
  • Activity 4.5.1. Dissemination of the results
    through publications in ISI journals or indexed
    in international databases.
  • Activity 4.6. Correlation and optimization of the
    interdependent functions for optimal conditions
    of hybrid magnetic antioxidant structures / stent
    realization. Developing of the laboratory
    technology for the integration of new hybrid
    materials as biomagnetic composites with
    antioxidant characteristics. Part I

17
Activity 2.9. Determination of the initiation
mechanism of the self-assembling reaction of
hybrid materials
  • Making of the polymer coating on the surface of
    magnetite is based on several physical
    interactions that lead to a process of
    assemblying between the two components and
    creating of a stable complex hybrid system with
    magnetic characteristics.
  • The formation of the hybrid type "core
    (magnetite) - shell (synthetic polymer)" is based
    on the occurrence of dipole electrostatic
    interactions, hydrogen bonding, hydrophobic
    interactions and van der Waals forces that
    determine the self-assembling process and the
    system stability.
  • Meanwhile, the hybrid system has free functional
    groups for subsequent attachment of new active
    structures, for example enzymes, which is the
    generic objective of the project.
  • Illustrating the initiation of the reaction
    mechanism of self-assembling hybrid materials

18
Illustration of the coupling procedure of
antioxidant enzyme (catalase) with the magnetic
composite
  • For the antioxidant magnetic composite
    realization by coupling antioxidant enzyme
    catalase with the magnetic composite, it is
    proceeded to two coupling methods, as shown
  • by physical links (reversible)
  • and
  • by chemical links (irreversible) via
    water-soluble carbodiimides1-ethyl
    -3-(3-dimethylaminopropyl) carbo-diimide (EDAC)

19
Evaluation of the magnetic composite
functionalization with antioxidant enzyme
Dimensional distribution (a) and zeta potential
distribution (b) of the magnetic composites
before and after the functionalization
  • Dimensional distribution (a) and zeta potential
    evaluation (b) of the magnetic composite before
    and after the functionalization with catalase
    confirm the immobilization of the enzyme on the
    surface of the magnetic composite.

20
Activity 2.10. Conceptual approach and the design
of the coupling system between antioxidant
magnetic composite and stent
  • The coating procedure of MC nanoparticles to the
    stent surface is done in an alternating magnetic
    field (AMF). In designing the system to achieve
    the conceptual approach of the new process is
    used the fact that magnetic hybrid nanocomposites
    as stable dispersed colloidal suspensions in a
    suitable solvent, can generate heat in AMF and
    also they show affinity for metal stent. Thus,
    there are created the right conditions for a
    uniform deposit on the surface of the stent. It
    is used an AMF with intensity H 200 Oe,
    obtained from a solenoid with the following
    characteristics L 700 µH, V 125 kHz, I 2.5
    A, U 1.3 Kv, P 3 Kvar.
  • After 10 minutes of maintaining the stent and the
    magnetic nanoparticles dispersion in AMF, the
    ambient temperature does not exceed 52 ?C, that
    certifies a relatively low Curie temperature for
    magnetic nanoparticles. It can be concluded that
    nanoparticles avoid the overheating of the
    tissue, when they are excited by AMF. Thus, these
    magnetic nanoparticles can be used for treatments
    including hyperthermia (when the AMF action is
    reduced to 2-3 min).

21
Magnetic susceptibility evaluation and the film
morphology deposited on metallic stent device
Deposition cycle Stent weight, g Stent weight, g Stent magnetic susceptibility, e4 V Stent magnetic susceptibility, e4 V
Deposition cycle Before deposition After deposition Before deposition After deposition
- 0.0120 - 0.023 -
I - 0.0140 - 0.052
II - 0.0142 - 0.054
III - 0.0146 - 0.058
IV - 0.0150 - 0.069
- After 5 repeated washings After 5 repeated washings After 5 repeated washings After 5 repeated washings
- - 0.0130 - 0.036
  • Optical microscopy imaging of the magnetic
    composite coated stent
  • Magnetic susceptibility values confirm the
    presence of magnetic composite nanopar-ticles on
    the stent surface.

22
Activity 3.3. Testing of self-assembled
biomagnetic hybrid materials with antioxidant
characteristics
  • The new polymer synthesized structures are
    evaluated in terms of antioxidant character by
    radical reactions in the presence of 2,
    2-diphenyl-1-picrylhydrazyl (DPPH) radical.
  • 28 inhibition of DPPH radicals in case of
    functionalized PMAU copolymer with
    meso-erythritol PMAU_E (1/5 ratio PMAU /
    erythritol) is recorded, meanwhile erythritol
    witness exhibited 29 inhibition and the PMAU
    copolymer just 14.75 reduction.
  • It can be concluded that the antioxidant ability
    of the functionalized copolymer is conferred by
    erythritol, but at the same time the PMAU
    copolymer has antioxidant character. It is
    noticeable that the antioxidant character is
    manifested by the system PMAU_E 1/5 even after 72
    hours testing period.

23
Activity 4.1. Working methods and protocols for
new therapeutic strategies, applications and
techniques of testing for the obtained hybrid
systems
The results of investigation of acute toxicity
and biocompatibility of the magnetic composites
  • According to Hodge Sterner toxicity scale is
    observed that the value LD50 is in the range of
    500 - 5000 mg / kbw, allowing the placement of MC
    in the group of low toxic substances.
  • There are no significant variations between the
    values of the elements of blood leukocyte formula
    for mice in the treated group with MC compared to
    the control group treated with distilled water,
    for 24 hours and 14 days. The laboratory analysis
    present no significant differences for glutamic
    pyruvic transaminase (GPT), glutamic oxalacetic
    transaminase (GOT) and lactic dehydrogenase (LDH)
    activities between the control and the treated MC
    groups, after 24 hours and after 14 days from the
    i.p. administration. In terms of serum opsonic
    capacity (OC), the phagocytic capacity (FC) and
    bactericidal capacity (BC) of peritoneal
    macrophages for the control group treated with
    distilled water and the treated group with MC,
    there are no major variations in the results.

24
Toxicological evaluation methods of the new
synthesized nanoparticles for testing them as
targeted delivery systems
  • Acute toxicity investigation shows that MC
    particles are relatively harmless from the
    toxicological point of view when i.p.
    administered to mice. They exert similar changes
    on leukocyte formula items and in enzymatic
    activity like the distilled water administered by
    i.p. injection in control group.
  • MC administration does not alter the animal's
    immune defense capability compared with the
    control group. The major histopathological
    changes do not occur in the liver structure. The
    results suggest good biocompatibility by in vivo
    tests in mice after administration of MC.

Microscopic image of liver structure a - normal
control group b - with diffuse liver stasis and
liver regeneration in the group treated with MC
(Van Gieson staining, x 40)
25
Optimization and synthesis studies
  • In the attempts to synthesize a polymer matrix
    having the best features for obtaining a magnetic
    composite, but with functional versatility for
    further coupling of biologically active
    substances (enzymes), the synthesis, properties
    and sensitive behavior of a set of random
    copolymers based on itaconic anhydride (IA) with
    various molar ratios of 3,9-divinyl-2,4,8,10-tetra
    oxaspiro 5.5 undecane (U) in the structure, are
    followed.
  • These new polymer structures, because of their
    ability to form networks, to possess excellent
    biodegradability and biocompatibility,
    amphiphilicity, oxidative properties and good
    thermal stability, they are good film formers,
    sensitive to acidic pH, but also with binding
    opportunities required by further investigations.
    This behavior can be explained by random
    spiral-type conformation of these copolymers,
    with folded and packaged macromolecules by
    physical interactions occurring between chains.
  • The spiroacetal segment with acidic pH
    sensitivity is capable of interaction from the
    ether oxygen with other functional groups by
    coordinative or hydrogen bonding, and thus to
    induce the dynamic change of macromolecular
    chains stereochemistry through anomerically
    effect, interfered with temperature increasing in
    the thermal agitation conditions.
  • Poly(itaconic anhydride-co-3,9-divinil-
  • -2,4,8,10-tetraoxaspiro 5,5 undecan)
  • schematic structure-

26
Dissemination of the results
  • Published papers
  • Design and synthesis of a new polymer network
    containing pendant spiroacetal moieties authors
    A. Diaconu, A. P. Chiriac , L. E. Nita, N.
    Tudorachi, I. Neamtu, C. Vasile, M. Pinteala
    Designed Monomers and Polymers, 2015, 18(8),
    780-788, IF2.78
  • New nanocomposite based on poly(lactic-co-glycolic
    acid) copolymer and magnetite. Synthesis and
    characterization authors N. Tudorachi, A. P.
    Chiriac, F. Mustata Composites Part
    B-Engineering, 2015, 72, 150-159, IF2.983.
  • Synthesis and thermal investigation by TG-FTIR-MS
    analysis of some functionalized acrylic
    copolymers and magnetic composites with Fe3O4
    authors N. Tudorachi, I. Bunia J. Anal. Appl.
    Pyrolysis, 2015, http//dx.doi.org/doi10.1016/j.j
    aap.2015.09.010, IF3.56.
  • Degradation of poly(vinyl alcohol)-graft-lactic
    acid copolymers by Trichotecium roseum fungus
    authors R. Lipsa, N. Tudorachi, V. C. Grigoras,
    C. Vasile J. Appl. Polym. Sci. 2015, 132, 14.
    (DOI 10.1002/APP), IF1.77.
  • Static and dynamic investigations of
    poly(aspartic acid) and Pluronic F127 complex
    prepared by self-assembling in aqueous solution
    authors L.E. Nita, A. P. Chiriac, M. Bercea,
    MT. Nistor Applied Surface Science, 2015, 359,
    486495, IF2.711.
  • Possibilities of quercetin insertion into poly(N,
    N-dimethylacrylamide-co-3, 9-divinyl-2, 4, 8,
    10-tetraoxaspiro (5.5) undecane) network
    authors A. P. Chiriac, L.E. Nita, I. Neamtu
    Materials Science and Engineering C, 2015,47,
    1725, IF3.088.
  • In situ preparation of a magnetic composite
    during functionalization of polymaleic
    anhydride-co-3,9- divinyl-2,4,8,10-tetraoxaspiro(5
    .5)undecane with erythritol authors I. Neamtu,
    A. P. Chiriac, L.E. Nita, N. Tudorachi, A
    Diaconu J Nanopart Res, 2015, 17254, IF2.184.
  • An investigation on multi-layered hydrogels based
    on poly(N, N-dimethylacrylamide co 3,
    9-divinyl-2, 4, 8, 10-tetraoxaspiro (5.5)
    undecane) authors A.P. Chiriac, M. T. Nistor,
    L.E. Nita Rev. Roum. Chim., 2014, 59(11-12),
    1059-1068, IF0.311
  • Patterning poly(maleic anhydride-1 co-3,
    9-divinyl-2, 4, 8, 10- tetraoxaspiro (5.5)
    undecane) copolymer bioconjugates for controlled
    release of drugs authors L.E. Nita, A.P.
    Chiriac, L. Mititelu-Tartaua, E. Stoleru, F.
    Doroftei, A. Diaconu International Journal of
    Pharmaceutics, 2015, 493, 328-40, IF3.65.
  • Upon synthesis of a polymeric matrix with pH and
    temperature responsiveness and antioxidant
    bioactivity based on poly(maleic
    anhydride-co-3,9-divinyl-2,4,8,10-tetraoxaspiro5.
    5 undecane) derivatives authors A. P.
    Chiriac, L. E. Nita, N. Tudorachi, I. Neamtu , V.
    Balan, L. Tartau Materials Science and
    Engineering C 2015, 50, 348357, IF3.088.

27
Dissemination of the results
  • Published paper in Proceedings
  • Study on poly(vinyl alcohol) copolymers
    biodegradation authors R. Lipsa, N. Tudorachi,
    A. Grigoras, C. Vasile, P. Gradinariu Memoirs of
    the Scientific Sections of the Romanian Academy,
    Tome XXXVIII, 2015, 1-22.
  • Communication at scientific meeting
  • Biocompatible magnetic nanoparticles with
    antioxidant enzymes for cardiovascular
    applications authors L. Lungoci, V. Balan, M.
    Butnaru, C. Dimitriu, L. Verestiuc 6th
    International Seminar on Biomaterials
    Regenerative Medicine, Oradea, România, 17-19th
    September 2015.
  • Registered patent application
  • Process for synthesis of a copolymer
    matrix for biomedical applications authors AP
    Chiriac, LE Nita, A Diaconu, I Neamtu, N
    Tudorachi, V Balan, Patent Application No.
    A/00341/15.05.2015

28
Dissemination of the results
  • Posters at scientific meetings
  • Upon synthesis of a comprehensive copolymer
    network based on itaconic anhydride and 3,
    9-divinyl-2, 4, 8, 10-tetraoxaspiro (5.5)
    undecane for bioconjugation authors A. Diaconu,
    L. Ni?a, A. Chiriac, E. Butnaru, N. Tudorachi, C.
    Vasile, M. Pinteala Frontiers in Macromolecular
    and Supramolecular Science, Simpozionul
    International Cristofor I. Simionescu , VII-th
    Edition.
  • Smart polymeric systems based on n,n
    dimethylacrylamide and 3, 9-divinyl-2, 4, 8,
    10-tetraoxaspiro (5.5) undecane, V. Balan
    authors A. Diaconu, M. Asandulesa, E. Butnaru,
    L. E. Nita, I. Neamtu, N. Tudorachi, A. P.
    Chiriac. Zilele Academiei iesene, ed. XXV, 24-26
    sept. 2015
  • SOD and catalase immobilization onto
    superparamagnetic nanoparticles for
    cardiovascular applications authors L. Lungoci,
    V.Balan, M. Butnaru, O.Bredetean L.Verestiuc
    12th International Conference on Nanosciences
    Nanotechnologies (NN15), 7-10 July 2015,
    Thessaloniki, Greece.
  • Antioxidant enzymes immobilized on biocompatible
    SPIONS for cardiovascular applications authors
    L. Verestiuc, L. Lungoci, V. Balan, M. Butnaru,
    O. Bredetean 27th European Conference on
    Biomaterials, 30 august-3 sept. 2015, Kracovia,
    Poland.
  • Investigation upon a novel poly(maleic anhydride
    co - 3, 9 divinyl - 2,4,8,10-tetraoxaspiro
    (5.5) undecane) / magnetite hybrid nanocomposite
    preparation authors I. Neamtu, A. P. Chiriac,
    L. E. Nita Fourth International Conference on
    Multifunctional, Hybrid and Nanomaterials 9-13
    March 2015, Sitges, Spain.
  • Possibilities for Quercetin insertion into
    poly(N,N-dimethylacrylamide-co-3,9- divinyl -
    2,4,8,10-tetraoxaspiro (5.5) undecane) network
    authors A. P. Chiriac, L. E. Nita, I. Neamtu
    Fourth International Conference on
    Multifunctional, Hybrid and Nanomaterials 9-13
    March 2015, Sitges, Spain.

29
Stage V/2016 - Project objectives
  • Bio-magnetic system integration continuation of
    2015 stage
  • Activity 5.1. Diversification of the procedures
    used for obtaining and characterization of
    functionalized hybrid stents
  • Activity 5.2. Correlation and optimization of
    the interdependent functions for developing
    optimal conditions for antioxidant / stent hybrid
    magnetic structures achievement. Elaboration of
    the laboratory technology for the integration of
    new hybrid materials as bio-magnetic composites
    with antioxidant characteristics. Part II
  • Activity 5.3. Elaboration of the laboratory
    technology for the antioxidant magnetic hybrid
    structures obtaining
  • Activity 5.4. Elaboration of a technique of
    using the prepared antioxidant magnetic hybrid
    structures
  • Activity 5.5. Dissemination of the results
    through communications at national and
    international symposia, publications in ISI
    journals or indexed in international databases.
  • Activity 5.5. 2. Organization of a workshop
    News in the domain of magnetic NPs obtaining,
    properties, applications of the hybrid magnetic
    NPs

30
Diversification of the used procedures for the
obtaining and characterization of the
functionalized hybrid stents
  • The comparative evaluation of the polymer
    matrices based on poly(maleic anhydride co - 3,
    9 divinyl - 2,4,8,10-tetraoxaspiro 5.5
    undecane) P(U-MA) and respectively poly(itaconic
    anhydride-co-3, 9-divinyl-2, 4, 8,
    10-tetraoxaspiro 5.5 undecane)(PU-ITA),
    utilized for the obtaining of the magnetic NPs,
    subsequent deposition on stents and
    functionalization with antioxidant enzymes,
    referring the hydrodynamic diameter, thermal
    stability, viscoelastic behavior and dielectric
    spectroscopy analysis, characteristics that
    recommend them in the deposition process on
    stent, it is realized.

Thermal analysis some differences in the heating
behavior of P(U-MA) and P(U-ITA) are observed,
referring to the degradation stages and weight
losses for every stage. P(U-MA) system has a
greater thermal stability. But, taking into
account the final destination of the two polymers
as matrices for magnetic nanocomposites with
biomedical applications, the both structures are
suitable for the purpose.
31
Dimension evaluation of P(U-MA) and P(U-ITA)
  • Dimension analysis of P(U-MA) and P(U-ITA) first
    evidences the nanosized character of the polymer
    matrices (see Table). The temperature sensitive
    character is evidenced by the evolution of the
    hydrodynamic diameter with temperature change in
    the range of 22 - 40?C.

P(U-ITA) presents greater diameters until 28?C
with an inflection at 34?C, while P(U-MA) shows
changes at 28?C and in the range of 34 - 37C.
Temperature sensitivity is attributed to the
spiroacetalic cycle that assures specific
conformations to the macromolecular chains, and
the hydrophilic-hydrophobic balance of the
copolymer generated by both comonomers.
32
Viscoelastic evaluation of P(U-MA) and P(U-ITA)
polymer structures
  • In the shear rate range of 0.01 - 100 s-1 the
    viscosity values of the polymer matrices
    decrease, which certifies the non-Newtonian
    (pseudoplastic) behavior, respective their shear
    thinning solutions with viscosity from 206,000
    Pa.s to 0.506 Pa.s in the case of P(U-MA) and
    from 0.327 Pa.s to 0.071 Pa.s in the case of
    P(U-ITA). However P(U-MA) shows a more pronounced
    pseudoplastic character.
  • In the shear rate range of 0.01 - 100 s-1 the
    complex viscosity values h decrease with
    frequency increase thus, ? P (U-MA) gt ? P
    (U-ITA) which certifies a greater crosslinking
    degree in the case of P (U-MA), because of a
    reduced flexibility of the anhydridic cycle of
    maleic anhydride compared to the itaconic
    anhydride. Crosslinked polymer network meshes
    further ensure the possibility to link bioactive
    compounds.
  • On the full-range angular frequency used in
    testing, in the case of P(U-MA) solution, elastic
    modulus is greater than viscous modulus G' gt G"
    the graphical representation of G' and G" show
    two parallel curves with no meeting point,
    confirming the strong gel character.
  • P(U-ITA) solution presents a gel behavior at low
    angular frequency, with G 'gt G''. At high angular
    frequency, P(U-ITA) shows G "gt G' corresponding
    to a fluid-like behavior, with a weaker
    crosslinked polymer network and with poor
    structural strength under stationally condition.

33
Dielectric spectroscopy analysis of P(U-MA) and
P(U-ITA) polymer structures
  • Regarding P(U-MA) copolymer, the activation
    energy for b relaxation is 34.5 kJ/mol while the
    relaxation transition is registered in the
    temperature range of - 65?C until 35o C.
  • Regarding P(U-ITA) copolymer, the activation
    energy for b relaxation is 38.4 kJ/mol in the
    temperature range of 20?C until 50o C in this
    case is evidenced too, g relaxation with
    activation energy of 28.8 kJ/mol, in the
    temperature range of - 140?C until -5oC.
  • P(U-MA) From broadband dielectric spectroscopy
    data it results a b relaxation process associated
    to the rotation of the rigid side groups of
    spiroacetalic cycle present in the macromolecular
    chain.
  • P(U-ITA) has a b relaxation process associated
    to greater spiroacetalic groups and g relaxation
    process due to smaller polar groups in the side
    chains, by localized and non-cooperative
    movements.

34
Conclusions
  • From the comparative evaluation study carried out
    on the polymer matrices based on poly(maleic
    anhydride-co-3,9-divinil-2,4,8,10-tetraoxaspiro
    5.5 undecane) and poly(itaconic
    anhydride-co-3,9- divinil-2,4,8,10-tetraoxaspiro
    5.5 undecane), were drown some conclusions
    about the two formulations with new structures
    and outstanding performances in terms of the
    possibility to use them for preparing magnetic
    nanocomposites, as well as the additional
    capabilities in increasing their functionalities
    for subsequent coupling of bioactive compounds,
    namely antioxidant enzymes and deposition on
    stents for biomedical uses. Thermal analysis
    evidenced a relative similar behavior for the
    both variants of copolymers. The temperature
    sensitivity is attributed to the hydrophobic-
    hydrophilic balance generated by the comonomers
    and to the spiroacetal groups presence this is
    evidenced by the hydrodynamic diameters values
    that change in the temperature range of 22 -
    40C. Rheological investigation in the shear rate
    range between 0.01 and 100 s -1 shows a fluid
    like non-Newtonian behavior for the two copolymer
    solutions. Also, the oscillatory testing proves a
    gel-like or a fluid-like behavior as a function
    of angular frequency. We decided after testing
    the use of P(U-MA) for subsequent applications
    according to the projects objectives.
  • For the structure of poly(maleic
    anhydride-co-3,9-divinyl-2,4,8,10-tetraoxaspiro
    5.5 undecane) was conducted further
    investigation and developed a laboratory
    technology for synthesis.

35
Correlation and optimization of the
interdependent functions for developing of the
optimal conditions in the antioxidant hybrid
magnetic structures / stent achievement -
optimizing of the conditions for magnetic
nanocomposites deposition on stent
  • In accordance with the optimized results of the
    synthesis, polymer matrices characterization (
    thermal stability, dimension, rheological
    behavior), development and transport of the
    magnetic NPs/stent through various specific
    environments, the polymer matrix constituted by
    poly(maleic anhydride-co-3,9-divinil-2,4,8,10-tetr
    aoxaspiro 5.5 undecane) was chosen and the
    laboratory technology of synthesis was detailed.
    On this basis it was subsequently developed the
    technology of in situ preparation of the magnetic
    composite NPs by the splitting of the anhydride
    cycle with erythritol and including of the
    magnetite core in the polymeric film. To optimize
    conditions for making antioxidant magnetic hybrid
    structures / stent, the conditions of the
    magnetic nanocomposite NPs deposition in an
    alternating magnetic field, as a function of the
    dispersion medium, deposition time and the cycles
    number of deposition, were researched.
  • Magnetic nanocomposites NPs in situ prepared
    during functionalization with erythritol of the
    copolymer poly(maleic anhydride-co-3,9-divinil-2,4
    ,8,10-tetraoxaspiro 5.5 undecane) were
    deposited on stent in an alternating magnetic
    field and the deposition dependence on the
    dispersion medium (dielectric constant, dipole
    moment, electrostatic factor, density, viscosity,
    surface tension, molecular polarization, magnetic
    susceptibility) was followed.
  • Study of the dependence of magnetic composite NPs
    deposition on stent, the deposition yield, stent
    magnetic susceptibility, correlated with the
    deposition conditions (such as the dispersion
    medium characteristics, time and number of
    deposition cycles) allowed to optimize the
    technological process of obtaining functionalized
    magnetic stent.

36
The characteristics of the dispersion medium used
in deposition
Solvent Dielectric constant, ? Dipole moment, 10 e-18emu Electrostatic factor, EF ? x ? Density, g/cm3 Viscosity, ? cP Surface tension, ? dyn/cm Molar polarization P Magnetic Susceptibility, ? x 10-6 cm3/mol Yield ,
Chloroform 4.806 1.15 5.527 1.48 0.514 26.53 44.96 -59.93 27.78
Ethyl acetate 6.02 1.88 11.32 0.89 0.426 22.55 61.20 -49.11 10
Tetrahydrofuran 7.58 1.75 13.27 0.89 0.426 26.40 55.57 -39.85 10
Cyclohexanol 15.00 1.86 27.90 0.97 41.06 33.91 84.90 -70.61 20
Methyl ethyl ketone 18.51 2.76 51.07 0.79 0.36 23.97 77.81 -45.72 19.60
Acetone 20.70 2.69 55.68 0.78 0.30 22.01 64.53 -33.86 14.29
Ethanol 24.55 1.66 40.75 0.79 0.99 21.40 51.65 -34.19 32.55
Dimethylformamide 36.71 3.86 141.70 0.94 0.802 35.20 71.64 -43.41 33.33
Dimethylsulfoxide 46.68 3.90 182.05 1.09 1.99 42.86 67.15 -42.86 66.67
Water with surfactant 78.39 1.85 145.38 0.99 0.89 71.81 17.41 -12.97 15.79
37
Deposition evolution of the magnetic
nanocomposite NPs on stent depending on the
dispersion medium
  Solvent Deposition (mg/min)x102 Deposition (mg/min)x102 Deposition (mg/min)x102 Deposition (mg/min)x102 Deposition (mg/min)x102 Deposition (mg/min)x102 Deposition Deposition Stent Susceptibility Stent Susceptibility
  Solvent 3 3 3 3 3 3 Deposition Deposition Stent Susceptibility Stent Susceptibility
  Solvent 3 3 3 3 3 3 mg x 100 Volume, e-4 V Masa, e-4 M
Etanol 0.43 0.43 0.48 0.52 0.56 0.57 0.14 32.55 0.012 0.429
DMSO 0.45 0.56 0.56 0.57 0.60 0.60 0.24 66.67 0.006 0.371
Acetone 0.45 0.46 0.48 0.48 0.49 0.50 0.06 14.29 0.014 0.495
DMF 0.53 0.58 0.58 0.59 0.60 0.62 0.15 33.33 0.016 0.519
Ethyl acetate 0.50 0.55 0.55 0.56 0.56 0.56 0.05 10 0.016 0.470
THF 0.42 0.42 0.43 0.43 0.44 0.44 0.04 10 0.016 0.519
MEC 0.54 0.59 0.59 0.59 0.60 0.61 0.10 19.60 0.025 0.668
Cloroform 0.43 0.43 0.43 0.45 0.45 0.46 0.8 27.78 0.007 0.453
Cyclohexanol 0.39 0.39 0.40 0.41 0.41 0.42 0.05 20 0.005 0.317
Water 0.41 0.42 0.42 0.42 0.43 0.44 0.04 15.79 0.017 0.453
38
Deposition evolvement of the magnetic composite
NPs on stent according to the dispersion medium
of NPs, time and number of deposition cycles (I)
  • Correlation of the magnetic composite NPs
    deposition on stent (mg x 100) and the magnetic
    susceptibility values of stent (mass x 104) with
    the density of the dispersing solvent for NPs and
    their deposition on the stent in alternating
    magnetic field conditions at the highest density
    of 1.48 g / cm3 for chloroform as dispersion and
    deposition medium, it is obtained the yield of
    28 and the mass susceptibility of stent 0.453
    e-4M.
  • Correlation of the deposition yield of the
    magnetic composite NPs on stent (mg x 100) and
    the magnetic susceptibility of stent (mass value
    x 104) with the viscosity of the dispersing
    solvent for NPs and their deposition on stent in
    alternating magnetic field conditions at the
    highest viscosity of 41.06 cP for cyclohexanol as
    dispersion and deposition medium it is obtained
    the yield 20 and mass susceptibility of stent
    0.317 e-4 M.
  • Correlation of the deposition yield of the
    magnetic composite NPs on stent (mg x 100) and
    the magnetic susceptibility of stent (mass value
    x 104) with the dielectric constant of the
    dispersing solvent for NPs and their deposition
    on stent in alternating magnetic field
    conditionsat the highest dielectric constant of
    78.39 for water with tensioactive as dispersion
    and deposition medium it is obtained the yield
    16 and mass susceptibility of stent 0.453 e-4
    M.
  • Correlation of the deposition yield of the
    magnetic composite NPs on stent (mg x 100) and
    the magnetic susceptibility of stent (mass value
    x 104) with the dipole moment of the dispersing
    solvent for NPs and their deposition on stent in
    alternating magnetic field conditionsat highest
    dipole moment of 3.90 for dimethyl sulfoxide it
    is obtained the yield 67 and mass
    susceptibility of stent 0.371 e-4 M.

39
Deposition evolvement of the magnetic composite
NPs on stent according to the dispersion medium
of NPs, time and number deposition cycles (II)
  • Correlation of the magnetic composite NPs
    deposition on stent (mg x 100) and the magnetic
    susceptibility values of stent (mass x 104) with
    the electrostatic factor of the dispersing
    solvent for NPs and their deposition on the stent
    in alternating magnetic field conditions at the
    highest electrostatic factor of 182 for dimethyl
    sulfoxide as dispersion and deposition medium, it
    is obtained the yield of 67 and the mass
    susceptibility of stent 0.371 e-4M.
  • Correlation of the magnetic composite NPs
    deposition on stent (mg x 100) and the magnetic
    susceptibility values of stent (mass x 104) with
    the surface tension of the dispersing solvent for
    NPs and their deposition on the stent in
    alternating magnetic field conditions at the
    highest surface tension of 71.81 dyne/cm for
    water with tensioactive as dispersion and
    deposition medium, it is obtained the yield of
    16 and the mass susceptibility of stent 0.453
    e-4M.
  • Correlation of the magnetic composite NPs
    deposition on stent (mg x 100) and the magnetic
    susceptibility values of stent (mass x 104) with
    the molecular polarization of the dispersing
    solvent for NPs and their deposition on the stent
    in alternating magnetic field conditions at the
    highest molecular polarization of 84.90 for
    cyclohexanol as dispersion and deposition medium,
    it is obtained the yield of 20 and the mass
    susceptibility of stent 0.317 e-4M.
  • Correlation of the magnetic composite NPs
    deposition on stent (mg x 100) and the magnetic
    susceptibility values of stent (mass x 104) with
    the magnetic susceptibility of the dispersing
    solvent for NPs and their deposition on the stent
    in alternating magnetic field conditions at the
    highest magnetic susceptibility of -70.61 for
    cyclohexanol as dispersion and deposition medium,
    it is obtained the yield of 20 and the mass
    susceptibility of stent 0.317 e-4M.

40
Conclusions
  • The resulted data show that the efficient
    deposition of the magnetic composite Nps on stent
    are dependent on the solvent characteristics in
    the following order density gt viscosity gt
    electrostatic factor gt magnetic susceptibility gt
    molecular polarization gt dielectric constant gt
    dipole moment gt surface tension.
  • One can obtain deposition yields up to 67 and
    magnetic susceptibility of 0.668 e-4 M for a
    stent with initial weight of 0.0051mg.
  • Optical microscopy images for magnetic composite
    NPs deposited on stent from (a) dimethyl
    sulfoxide (b) dimethylformamide (c) water with
    tensioactive

(a) Dimethyl sulfoxide
(b) dimethylformamide
(c) water with tensioactive
  • Based on the obtained information, the
    technological process for the deposition of the
    magnetic composite NPs on stent was carried out.

41
Stents biofunctionalization
  • The functionalized stents with magnetic
    nanocomposite NPs including functional groups
    able to couple bioactive structures have been
    used to bind antioxidant enzymes. Subsequently,
    in organ bath the enzymatic activity was tested.
  • The biofunctionalized magnetic stents were
    characterized by SEM. Functionalization with
    enzymes does not modify the stent surface
    morphology, while the magnetic particles after
    repeated washings still remain immobilized on the
    metallic surface.
  • It finds a decrease in the enzyme activity,
    proper to the decomposition of the substrates by
    the immobilized enzyme on stent, this being due
    to lower concentrations of the enzyme relative to
    the unit area of the surface and to the
    conformational changes undergone by the enzyme.
    Values of the enzyme activity can ensure the
    proper functioning of the stent with antioxidant
    activity.

42
Conclusions
  • Correlation and optimizing of the interdependent
    functions in the synthesis of the polymer matrix
    with the preparation of the magnetic
    nanocomposite and the creation of the conditions
    for functionalization with antioxidant enzymes
    superoxide dismutase and catalase allowed the
    elaboration of optimal conditions for the
    achievement of the antioxidant hybrid magnetic
    structures / stent and also developing the
    laboratory technology for the integration of the
    new hybrid materials and biomagnetic composites
    with antioxidant characteristics. By developing
    laboratory technology for obtaining antioxidant
    hybrid magnetic structures was insured the
    conception of the techniques for use.

43
Workshop - News in the domain of
magnetic NPs obtaining, properties, applications
of the hybrid magnetic NPs
  • According to the project objectives in 2016 was
    organized the workshop News in the domain of
    magnetic NPs obtaining, properties, applications
    of the hybrid magnetic NPs, held on 1st of July
    2016 at Petru Poni Institute of Macromolecular
    Chemistry in Iasi. The workshop included the
    following activities
  • Conferences
  • H. Chiriac. Low curie temperature glassy magnetic
    alloys for medical applications.
  • Communications
  • V. Balan, L. Verestiuc. Biofunctionalized
    magnetic nanoparticles for biomedical
    applications.
  • N. Tudorachi, A. Chiriac, L. E. Nita, I. Neamtu,
    V. Balan, A. Diaconu. Studies on magnetic
    nanocomposites based on carboxymethyl
    starchg-poly(lactic acid-co-glycolic acid)
    copolymer and magnetite.
  • Posters
  • D.D. Herea, H. Chiriac, E. Radu, N. Lupu,
    Magnetic nanoparticles for mechanically induced
    necrosis of cancerous cells.
  • E. Radu, H. Chiriac, C.M.Dnceanu, D.D. Herea, G.
    Stoian, N. Lupu, A ferrofluid based on low curie
    Fe67.2Cr12.5Nb0.3B20 nanoparticles with potential
    biomedical applications.
  • I. Neamtu, L. E. Nita, N. Tudorachi, A. Diaconu,
    A. P. Chiriac. Synthesis and properties of new
    magnetic hybrid composites.
  • A. Diaconu, L. E. Nita, L.Tartau, I. Neamtu, N.
    Tudorachi, A. P. Chiriac. Experimental researches
    on hybrid magnetic composites with applicability
    in the achievement of cardiovascular stents.
  • M. Bercea, L. E. Nita, I. Neamtu, A.P. Chiriac.
    Magnetic field effect on the rheological
    properties of composite materials.
  • N. Tudorachi, R. Lipsa, L. Matrical, G. L.
    Ailiesei, A.P. Chiriac. Carboxymethyl
    starchg-poly(lactic acid-co-glycolic acid)
    copolymer for biomedical applications. Synthesis
    and characterization.
  • T. Mereuta , L. Lungoci , O. Bredetean , C.
    Dimitriu , V. Balan , M.Butnaru , L. Verestiuc.
    Antioxidant enzymes immobilized on magnetic
    nanoparticles with potential cardiovascular
    applications.
  • F. D. Ivan, V. Balan, M. Butnaru , L. Verestiuc.
    Magnetic composite supports based on biopolymers,
    calcium phosphate and magnetic particles for
    bone tissue regeneration.
  • V. Redinciuc, V. Balan, L. Verestiuc.
    Nanoparticles based on N-palmitoyl chitosan
    biotinylated for breast cancer therapy.

44
Dissemination of the results (I)
  • Published papers
  • A. P. Chiriac, V. Balan, M. Asandulesa, E.
    Butnaru, N. Tudorachi, E. Stoleru, L. E. Nita, I.
    Neamtu, A. Diaconu, Investigation on thermal,
    rheological, dielectric and spectroscopic
    properties of a polymer containing pendant
    spiroacetal moieties, Materials Chemistry and
    Physics 180 (2016) 291-300, IF2.101.
  • R. Lipsa, N. Tudorachi, R. N. Darie-Nita, L.
    Oprica, C. Vasile, A. Chiriac, Biodegradation of
    poly(lactic acid) and some of its based systems
    with Trichoderma viride, International Journal of
    Biological Macromolecules 88 (2016) 515526,
    IF3.138.
  • A. P. Chiriac, L. E. Nita, L. Mititelu-Tartau, I.
    Neamtu, N. Tudorachi, A. Diaconu, Using an
    alternating magnetic field for covering a
    metallic stent with a new magnetic composite Rev.
    Roum. Chim., 61(4-5), (2016), 347-355, IF0.311.
  • V. Balan, M. Butnaru, L. Verestiuc, Preparation,
    characterization and preliminary evaluation of
    magnetic nanoparticles based on biotinylated
    N-palmitoyl chitosan, Proceedings of 5th
    International Conference on Advancements of
    Medicine and Health Care through Technology
    MediTech2016, 12 15 October 2016 (ISI
    Proceeding
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