Polymers for biomedical applications

1
Polymers for biomedical applications recent
results
Petru Poni Institute of Macromolecular
Chemistry Romanian Academy Aleea Grigore Ghica
Voda 41A, 700487, Iasi, Romania

• Gabrielle Charlotte Chitanu
• Green Chemistry of Polymers chita_at_icmpp.ro

2
Polymer nanoscience Nanotechnologies based on
polymers
Polymers and Nanoworld
Nanointeractions between polymers or polymers and
other entities
Nanomaterials from polymers
Organo-inorganic hybrid materials Polymers
metals, oxydes (TiO2, Fe2O3, ZrO2, silica),
salts , clays
nanolayers monolayers (LB), bilayers, multilayers
(LBL P-P, P-Prot, P-Dye, P-Tens, P-Inorg.)
Nanoobjects particles, spheres, capsules,
plaquets, discs, tubes, etc.
3
Results of the Petru Poni Institute teams in
nano/bio-topics
LBL deposition using poly- electrolytes and
dyes
Thin films of conjugated polymers
Micro/ nanoparticles from natural polymers
Hybrid supramolecular architectures
Photopolymers - organoclay composites for
optical applications
Thin films based on fluorinated polyimides
Maleic polymers for nanoapplications
4
POLYMERIC MICRO- and NANOPARTICLES Gh. Fundueanu,
M. Constantin, G. Mocanu, D. Mihai, A.
Carpov E-mail ghefun_at_icmpp.ro
Microparticles for liquid chromatography Micropar
ticles for drug delivery systems
Effect of temperature cycling on indomethacin
release from poly(NIPAAm-co-AAm-co-HEA)
intelligent microspheres
B
A
Optical photomicrographs of poly(NIPAAm-co-AAm-co-
HEA) microspheres taken in the swollen state in
phosphate buffer, pH7.4, under LCST (Panel A),
and above LCST (Panel B)
5
Hybrid supramolecular structures Valeria
Harabagiu (hvaleria_at_icmpp.tuiasi.ro), Bogdan C.
Simionescu, Mariana Pinteala, Virginia Epure,..

SEM surface (left) and cross (right) sections
Polysiloxanes/cyclodextrine rotaxanes
Nanoparticles based on organic-inorganic
copolymers
J. Polym. Sci. 2004 Carbohydrate Res. 2004
6

• Prospects
• MP for preparation of microspheres
• loaded with bioactive substances
• tailored MP bearing chromophores,
• fullerenes, LC moities for electro-optical
• applications, sensors, etc.

MALEIC POLYMERS (MP) FOR NANOAPPLICATIONS Gabriell
e Ch. Chitanu (chita_at_icmpp.ro), Gabriela Aldea,
Irina Popescu, Dana M. Suflet, Irina Pelin, Adina
G. Anghelescu-Dogaru, Adrian Carpov

7
(No Transcript)
8
Photopolymers - organoclay composites for optical
applications E.C. Buruiana, T. Buruiana, V.
Melinte, M. Olaru e-mail emilbur_at_icmpp.tuiasi.ro
Activities Study and development of new
photopolymers with photochromic, fluorescence and
UV/laser ablative properties. A tentative to
produce a photosensible liquid crystal (LC)
polymer is presented as follows
PA PA-Az
PA / PA-Az
LC texture for alkylammonium polyacrylates by
polarizing microscopy
References
1. Synthesis and characterization of liquid
crystalline alkylammonium polyacrylates, E.C.
Buruiana, T. Buruiana, Macromol. Rapid Commun.
2002, 23, 130 2. Design and using of new mesogens
to achieve ionic polyacrylates with possible
liquid crystalline properties, Grant of Roumanian
Academy, 2003-2004 3. Synthesis and properties
of new polyurethane ionomers. Photosensitive
cationomers with triazene units, E.C. Buruiana,
V. Niculescu, T. Buruiana, J. Appl. Polym. Sci.
2003, 88, 1203
9
LBL deposition using polyelectrolytes and
dyes Stela Dragan, Luminita Ghimici, Simona
Schwarz e.mail sdragan_at_icmpp.tuiasi.ro
10
Chemical structure of maleic anhydride (MA)
copolymers
Synthesis radical copolymerization of MA in
organic solvents
Characterization 1) composition electrochemical
methods IR, 1H or 13NMR spectroscopy 2) MW and
MWD SEC viscometry, light scattering
11
esterification
amidation
12
Advantages of maleic acid copolymers

• are obtained by a convenient technique, from
  cheap and available monomers
• have regular, reproducible chemical structure
• are capable to link a wide variety of low
  molecular compounds by mild reactions at low
  temperature, without catalysts
• are biocompatible
• have pH-dependent solubility
• have variable hydrophobic character depending on
  the comonomer

13
Applications of MA copolymers (most as
polyelectrolytes)

• Layer-by-layer deposition from maleic
  polyelectrolytes and dyes (Rhodamine G)
• Synthesis of new maleic copolymers derivatives
  containing dyes or chromophores for optical
  applications
• Organo-inorganic composites or hybrids based on
  maleic acid copolymers and phosphates
  (hydroxyapatite)
• Supports for controlled delivery of bioactive
  substances - (antibiotics, anesthesics and
  analgesics, growth factor,anticancer drugs, model
  proteins, if possess NH2 or OH groups)

• Antiscale agents
• Additives for tanning of hides with chromium
  basic salts
• Soil conditioners
• Phosphate substitutes in detergents
• Flocculants and coagulating aids
• Additives for drilling muds

14
A. Literature data biomedical uses of MA
copolymers

• Three main investigation ways could be evidenced
  from the literature
• i) MA copolymers possessing per se bioactivity
• ii) conjugates of MA copolymers with various
  drugs/bioactive agents
• iii) drug formulations as solid dispersions based
  on MA copolymers.
• another promising application seems to be the use
  in the dentistry
• Current applications
• SMANCS (neocarzinostatin conjugate with n-butyl
  monoester of MAstyrene copolymer)
• DIVEMA (MAdivinyl ether copolymer), promoted
  after laborious and long time lasted research
  efforts.

15
B. Selected results B.1. Conjugates of maleic
copolymers with pendant disinfectant molecules

16
B.2. Reaction of MA copolymers with piperazine

• 1. Reaction with piperazine and its derivatives
  2-amino-etylpiperazine, 2-hydroxyethylpiperazine,
  4-methylpiperazine, was carried out in organic
  solvents such as DMF, NMP, DMSO, at low
  temperature, without catalysts
• Soluble or insoluble derivatives were obtained,
  depending on the number of reactive groups in the
  molecule
• Soluble derivatives were characterized by
  elemental analysis, conductometric titration in
  acetone/water, IR spectra, potentiometric
  titration
• Insoluble derivatives were characterized by
  elemental analysis and IR spectra
• They are potential antihelmintic drugs with
  reduced toxicity

17
Soluble derivatives 4-methylpiperazine
Characterization
Conversion gt 50, depending on the comonomer
18

• Soluble derivatives
• 2-hydroxyethylpiperazine

Potential application sensors for CO
Conductometric curves in Ac/H2O. Conversion 90
19
Other promising uses in the bio topic

• The effect of maleic polyelectrolytes on the
  hydroxyapatite separation
• R.M. Piticescu, G.C. Chitanu. M.L.
  Popescu, W. Lojkowski, A. Opalinska, T.
  Strachowski, New hydroxyapatite based
  nanomaterials for potential use in medical
  field, Annals of Transpalntation, 9 (1A), 20-25
  (2004)
• The inhibition of crystal growth of COM - model
  for understanding and treatment of the renal
  calculi
• P. G. Koutsoukos, G.C. Chitanu, A.G.
  Anghelescu-Dogaru, A. Carpov, Inhibition of
  calcium oxalate monohydrate crystal growth by
  maleic acid copolymers, J. Urology,
  159,1755-1761, (1998)

20
Water soluble derivative of a maleic anhydride
copolymer with functionalized fullerene
40 C60
G. Aldea, G.C. Chitanu, J. Delaunay, J.-M. Nunzi,
J. Cousseau, B.C. Simionescu, Multi-functional
water soluble C60 - pendant maleic anhydride
copolymer, J. Polym. Sci. Part A Polym. Chem.
43(23), 5814-5822, 2005.
21
4. Crystallization of drugs nystatin
Nys is a polyene-macrolide antifungal antibiotic
produced by Streptomyces noursei
There are three different crystal forms of
Nystatin, referred as Types A, B and C. They can
be identified by X-ray powder diffraction
patterns, infrared spectra and thermal behaviour
22
Experiment

• Nystatin was crystallized from aqueous solution
  in which a maleic acid copolymer (MP) at low and
  high concentration was added. The samples were
  examined by FTIR spectroscopy, thermal analysis
  and X-ray diffraction.

Sample
D1 without MP
D2 with low MP concentration
D3 with high MP concentration
23
FTIR spectra quite similar no polymer
D1
D2
D3
24
X-ray diffraction pattern
25
Interplanar distances and relative intensities
26
DSC the sample D2 seems to have the most
crystalline organization
27
Conclusion Maleic acid copolymers
were demonstrated as efficient in

• the inhibition of crystal growth of COM (model
  for understanding and treatment of the renal
  calculi)
• the control of synthesis of HAP and HAP
  composites
• the control of the crystalline form of Nystatin
• In the future controlled synthesis of the
  nanocrystals, nanopowders..

28

• Thanks
• Prof. P. G. Koutsoukos, University of Patras,
  Greece
• Prof. Jean-Michel Nunzi, dr. Gabriela Aldea,
  University of Angers, France and Egide Agency
• Romanian Agency for Research and Development, for
  the financial support, project no. 16 and
  42/2005-2008
• My young co-workers Dana Suflet, Adina
  Anghelescu-Dogaru, Irina Popescu, Carmen Rosca,
  Elena Cadu, Irina Pelin
• Prof. dr. Antonia Poiata, UMF Iasi
• cpI Adrian Carpov, ICMPP Iasi
• and you all, for your kind attention!