Transcript Denumirea proiectului: 'Cercetare interdisciplinară

Project tytle:
"Interdisciplinary research on multifunctional
hybrid particles for biorequirements”
acronim: INTERBIORES
Contract no. 211/2012
Project Cod: PN-II-PT-PCCA2011-3.2-0428 – Program PN II –
Partnerships Priority Areas Applied Research Projects –
Type 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
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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 Iaşi - Partner 2
Team leader: Dr. Chiriac Horia
 SC REZISTOTERM SRL Partner 3
Team leader: Dr. Chiriac Mihai
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Abstract:
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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-nanocomposites 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.
Concept and objectives:
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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.
Stage I/2012 – the obtained results:
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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-2,4,8,10tetraoxaspiro[5.5]undecan-co-glicidil methacrylate) ternar copolymer (synthesized by radical copolymerization in aqueous dispersion);
2) poly(dimethyl acrylamide-co-3,9-divinyl-2,4,8,10-tetraoxaspiro [5.5]undecan-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 [5.5]undecan –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” BiomMedD’2012,
Constanta, 29 August – 1 September 2012, respectively:
Streptavidin-Biofunctionalized Magnetic Particles for Blood Contacting Applications; V.
Bălan, M.I. Popa, A.P. Chiriac, I. Neamtu, L.E. Nita, M.T. Nistor, M. Butnaru, L. Verestiuc
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Bioactive Hybrid Scaffolds in Regenerative Medicine and Tissue Engineering; M.T. Nistor,
C. Zgardan, C. Vasile, L.E. Nita, A. Chiriac
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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 TGFTIR-MS analysis”, authors Nita Tudorachi, Rodica Lipsa, Fanica Mustata.
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Stage II/2013:
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In accordance with the plan of the project „Interdisciplinary research on multi-functional hybrid particles for biorequirements”, the phase II/2013 had as objectives (I) Magnetic composites synthesis and (II) Physicalchemical evaluation (phase I/2012 continuation). The objectives were carried out through and finalized by
specific activities, such as:
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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:
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The obtained results:
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Published papers:
Characterization of the semi-interpenetrated network based on collagen and poly(N-isopropyl acrylamide-codiethylene glycoldiacrylate). Authors: MT Nistor, A.P. Chiriac, LE Nita, C Vasile. Int J Pharmaceutics 452 (2013)
92– 101; IF=3.458.
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; IF=3.458.
Obtaining of new magnetic nanocomposites based on modified polysaccharide. Authors: NTudorachi, AP
Chiriac, Carbohydrate Polymers 98 (2013) 451– 459; IF=3.479.
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), 357364; 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; ISSN:1874-4648.
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) 23452352; IF=1.243.
Poly(N,N-dimethylacrylamide-co-3,9-divinyl-2,4,8,10-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.
The obtained results:
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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.; IF=3.13.
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. Vereştiuc, Bioceramics 25,
Key Engineering Materials, 587, 191-196.
The obtained results:
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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, Iaşi, Romania, November 21st23rd, 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. Vereştiuc, 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.