Project tytle: "Interdisciplinary research on multifunctional hybrid particles for biorequirements

1
Project tytle"Interdisciplinary research on
multifunctionalhybrid particles for
biorequirementsacronim INTERBIORES

• Contract no. 211/2012
• Project Cod PN-II-PT-PCCA-
• 2011-3.2-0428 Program PN II
• Partnerships Priority Areas -
• Applied Research Projects
• Type 2

2
Contracting Authority Executive Unit for
Financing HigherEducation, 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.