“Petru Poni” Institute of Macromolecular Chemistry
Romanian Academy
Aleea Grigore Ghica Voda 41A, 700487, Iasi, Romania
Polymers for biomedical
applications – recent results
Gabrielle Charlotte Chitanu
Green Chemistry of Polymers
chita@icmpp.ro
Polymer nanoscience
Polymers and
“Nanoworld”
Nanotechnologies based
on polymers
Nanomaterials from polymers
Nanoobjects:
particles, spheres,
capsules, plaquets,
discs, tubes, etc.
nanolayers
monolayers (LB),
bilayers,
multilayers (LBL:
P-P, P-Prot,
P-Dye, P-Tens,
P-Inorg.)
Nanointeractions
between polymers or
polymers and other
entities
Organo-inorganic
hybrid materials
Polymers+ metals,
oxydes (TiO2, Fe2O3,
ZrO2, silica), salts ,
clays
Results of the “Petru Poni” Institute
teams in nano/bio-topics
Thin films
of conjugated
polymers
LBL
deposition
using polyelectrolytes
and dyes
Hybrid
supramolecular
architectures
Maleic
polymers for
nanoapplications
Thin films
based on
fluorinated
polyimides
Micro/
nanoparticles
from natural
polymers
Photopolymers
- organoclay
composites
for optical
applications
POLYMERIC MICRO- and NANOPARTICLES
Microparticles for drug
delivery systems
100
100
80
80
60
60
40
40
20
20
0
A
0
10
20
30
40
50
60
Time (min)
70
80
0
90 100
Temperature (°C)
Microparticles for
liquid chromatography
% drug released
Gh. Fundueanu, M. Constantin, G. Mocanu,
D. Mihai, A. Carpov
E-mail: ghefun@icmpp.ro
Effect of temperature cycling
on indomethacin release
from
poly(NIPAAm-co-AAm-coHEA) intelligent
microspheres
B
Optical photomicrographs of poly(NIPAAm-co-AAm-co-HEA)
microspheres taken in the swollen state in phosphate buffer, pH=7.4,
under LCST (Panel A), and above LCST (Panel B)
Hybrid supramolecular structures
Valeria Harabagiu (hvaleria@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
Nanosphere
Polymer
matrix
Nanocapsule
Active
principle
J. Polym. Sci. 2004
Carbohydrate Res. 2004
Nanoparticle
Galactose
OC
O
active
CH )
p
CH ) ( CH2
n
CH ) ( CH2
m
CO
( CH
Prospects:
• MP for
hydrophilic
preparation of microspheres
loaded with bioactive substances
hydrophobic
• tailored
maleic anhydride copolymers
MP bearing chromophores,
fullerenes, LC moities for electro-optical
supports for delivery systems (antibiotics, anaesthesics
and analgesics, growth factor, anticancer drugs, model
proteins, disinfectants, odorants, pesticides, etc.) if
possess NH2 or OH groups
applications, sensors, etc.
MALEIC POLYMERS (MP) FOR NANOAPPLICATIONS
Gabrielle Ch. Chitanu (chita@icmpp.ro), Gabriela Aldea, Irina Popescu, Dana M. Suflet, Irina Pelin,
Adina G. Anghelescu-Dogaru, Adrian Carpov
Calcium
Chemical Structure of The Partners Used for LBL
CH2
CH2
CH
CH2
+ NH3 Cl
N
+
CH3
Poly(ally lamine
hydrochloride)
H5C2HN
Cl
Salts
CH3
+
N C2H5
COOC2H5
and other
Calcium phosphates
Rhodamine
6G
H3C
Hydroxyapatite
Barium
+
CH
Na OO C
CH2
CO O Na +
CH
CH3
CH
OCOCH3
Poly(maleic acid
sodium salt - vinyl
acetate)
CH
+
Na OO C
CH
CH2
CO O Na +
Calcium
sulfate
_
Poly(dially ldimethylammoniumc h
loride)
O
carbonate
oxalate
CH2
CH2
Calcium
CH2
CH
CH
C
Barium titanate
TiO2, ZrO2
Fe oxides
Manganites
sulfate
COOCH3
Poly(maleic acid sodium salt – methyl
Crystallization modulators
FUNCTIONAL MICRO- AND NANOPARTICLES
BASED ON POLY[(N-ACYLIMINO)ETHYLENE]
Bogdan C. Simionescu (bcsimion@icmpp.ro), Geta David
O ( CH2 CH2 N )m
C O
CH3
(N
CH2 CH2 ) m
C O
CH3
CH3
O C ( CH2) 2 C N N C (CH 2)2 C
O
CH3
O
CH3
x
CH3
Macroazoinitiator for soapless emulsion polymerisation
block copolymer
TEM: micron sized block
copolymer
particles
J. Appl. Polym. Sci., 2001
Eur. Polym. J., 2001, 2002
J. Macromol. Sci. – Pure Appl. Chem., 2003
Mol. Cryst. Liq. Cryst., 2004
Photopolymers - organoclay composites for optical applications
E.C. Buruiana*, T. Buruiana, V. Melinte, M. Olaru
*e-mail: emilbur@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:
O
p
O
( )
H3C
( )
11 N+
11 CH3
- CH3 I ( O3S
N N
R)
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
LBL deposition using polyelectrolytes and dyes
Stela Dragan, Luminita Ghimici, Simona Schwarz
e.mail: sdragan@icmpp.tuiasi.ro
Spectral changes of DR80 by the interaction
with PCA5 in the multilayers
CHEMICAL STRUCTURES OF POLYCATION AND AZO DYES USED IN THE
MULTILAYER CONSTRUCTION
OH
(N
CH2
0.95
( CH2 )
-
3
Cl
N CH2
+
H3C
SO3Na
NaO3S
N= N
CH3
PCA5
OH
CH CH2
)
0.05
OH
0.5
CH CH2
OH
SO3Na
OH
NH CO NH
SO3Na
N= N
N= N
N=N
NaO3S
SO3Na
Direct Red 80 (DR80)
NH2
OH
OH
N= N
NaO3S
H3CO
N
N
N
SO3Na
N= N
OH
N N
N
400
N
0.2
4
6
8
10
12
14
450
500
550
600
650
n, dl
 (n m )
SO3Na
1 M NaCl, PCA5 10 mM,
Ra = 2.31 nm
0.3
SO3Na
NaO3S
Water, PCA5 10 mM,
Ra = 2.02 nm
0.2
0.4
2
Direct Blue 1 (DB1)
Crocein Scarlet MOO (CSMOO)
558.8
0.5
0.1
SO3Na
N
0.3
558.8
0.1
OCH3
SO3Na
OH
NH2
0.4
15 d l
12 d l
10 d l
8 dl
6 dl
4 dl
2 dl
intensity
CH CH2 )
CH3
intensity
(
CH3
+ Cl
N CH2
Ponceau SS (PSS)
SO3Na
1 M NaCl, PCA5 10 mM,
Ra = 3.44 nm
1M Na2SO4, PCA5 10 mM,
1
Ra = 2.72
M
1. Electrostatic self-assembled nanoarchitectures between
polycations of integral type and azo dyes
Stela Dragan, Simona Schwarz, Klaus-Jochen Eichhorn,
Klaus Lunkwitz
Colloid and Surfaces, A: Physicochem. Eng. Aspects
195, 243-251 (2001).
2. Surface Modification by Self-Assembled Polycation/Azo
Dye Multilayers
Stela Dragan, Simona Schwarz
Macromol. Symp. 181, 55-166 (2002).
3. Aggregation Mode of Two Bidentate Azo Dyes in the
Polycation/Dye Multilayers in Dependence on the Dye
Structure and the Polycation Conformation
Stela Dragan, Simona Schwarz
Prog. Colloid Polym. Sci. 122, 8-15 (2003).
Chemical structure of maleic anhydride (MA) copolymers
( CH
OC
CH ) ( CH2
m
CO
O
active
CH ) ( CH2
n
hydrophilic
CH )
p
hydrophobic
maleic anhydride 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
CH ) ( CH2
m
( CH
CH ) ( CH2
n
CH )
p
COOH COOH
maleic acid containing polyelectrolytes
CH
CH
CO
OC
CH2 CH
+ ROH
( CH
HOOC
R
CH
CO
OC
O
CH 2 CH
+ RNH
2
( CH
HOOC
R
CH )x ( CH
CO OC
1
NHR
amidation
1-x
O
OR
esterification
CH )
CO
CO OC
1
O
CH
CH )x ( CH
O
CH2 CH
R
1
CH )
CH 2 CH
CO
R1
1-x
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
Applications of MA copolymers
(most as polyelectrolytes)
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
• 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)
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 MA–
styrene copolymer)
DIVEMA (MA–divinyl ether copolymer), promoted after laborious and
long time lasted research efforts.
B. Selected results
B.1. Conjugates of maleic copolymers with pendant
disinfectant molecules
CH3
( CH
CH
CH2
CO
OC
R
+
CH )
OH
A
CH CH 3
3
thymol
O
(CH
HOOC
CH
CH2
CO
CH )x
A
( CH
CH
CH2
CO
OC
CH )1-x
A
O
OR
OCH3
where: A =
;
OCOCH ;
3
N(CO)(CH2)3
CH
2
CH
eugenol
CH2
B.2. Reaction of MA copolymers with
piperazine
1. Reaction with piperazine and its derivatives: 2-aminoetylpiperazine, 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
Soluble derivatives
4-methylpiperazine
( CH
CH
CH2
CH )x ( CH
NH
( CH
CH
CH2
CO
OC
CH )
COOH CO
+
O
OC
CO
O
N
N
A
A
CH3
N
CH3
Characterization
Sample
Parent
copolymer
Ia (g NaOH/
g)
N
(%)
VM
MA - VA
0.189
8.27
Conversion
(%)
Xcond
XN
76,48 76,75
SM
MA - St
0.157
8.28
86,47
86,57
MM
MA - MMA
0.141
4.44
56,83
58,89
PM
MA - NVP
0.169
10.74
78,25
51,97
Conversion > 50%, depending
on the comonomer
CH
CH2
CH ) -x
1
A
Soluble derivatives
2-hydroxyethylpiperazine
( CH
( CH
CH
C
CH2
N
C
O
CH )
O
O
NH
O
C
+
CH
C
OH
H2C
CO
N
H2C
CH2
CH2CH OH
2
N
CH2
CH )
N
O
H2C
CO
H2C
CH2
N
CH CH OH
2
2
600
C, S
copolimer P
500
SE1
400
300
200
Potential application:
sensors for CO
100
0
0
2
4
6
8
10
12
VNaOH, mL
Conductometric curves in Ac/H2O.
Conversion ~ 90%
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)
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.
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
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
FTIR spectra: quite similar; no polymer
D1
D2
D3
529.44
847.68
1175.57
1002.95
1070.45
1321.19
1400.27
1437.88
1572.89
1629.79
1711.76
2928.8
3409.06
1000
2000
Wavenumber (cm-1)
3000
4000
CH4
X-ray diffraction pattern
800
700
600
Lin (Counts)
500
400
300
200
100
0
2
10
20
2-Theta - Scale
File: ND1.raw - Type: 2Th/Th locked - Start: 2.000 ° - End: 30.000 ° - Step: 0.010 ° - Step time: 0.5 s - Temp.: 25 °C (Room) - Time Started: 12 s - 2-Theta: 2.000 ° - Theta: 1.000 ° - Chi: 0.00 ° - Phi: 0.00 ° - X: 0.0 mm Operations: Import
30
Interplanar distances and relative intensities
ND_1
d value
Angstrom
d=32.10122
d=29.25844
d=14.78677
d=11.88604
d=10.73653
d=10.22700
d=9.86338
d=8.85228
d=8.54942
d=7.91442
d=7.14479
d=6.41809
d=6.31279
d=5.99443
d=5.37534
d=4.80759
d=4.46802
d=4.33900
d=4.06457
d=3.24546
ND_2
Intensity
%
%
35,4
100
8,3
6,1
23,6
7,8
6,3
12,4
6,8
7,9
16,5
32,8
25,8
14
18,5
12,1
31,3
23,3
19,1
8
d value
Angstrom
d=32.95295
d=29.98935
d=14.96195
d=11.99545
d=10.82716
d=10.33122
d=9.95708
d=8.92893
d=8.62429
d=7.96450
d=7.17287
d=6.44544
d=6.32520
d=6.01733
d=5.40193
d=4.95878
d=4.81410
d=4.47833
d=4.38384
d=4.31115
d=4.06724
d=2.40118
ND_3
Intensity
%
%
39,4
100
9,9
8,1
33,6
10,2
7,5
14,3
9,3
9,3
21,8
34,1
26,9
19,2
23,4
12,5
12,3
33,3
27,1
27,6
16,6
8,6
d value
Angstrom
32,21835
29,50632
14,85592
11,88097
10,74424
10,25376
9,91608
8,86908
7,89977
7,13975
6,41194
6,3207
6,00771
5,37862
4,94679
4,79347
4,46486
4,34765
4,31817
4,06937
3,62781
Intensity
%
%
39,6
100
8,2
8,6
25,1
9,6
7,7
15,2
7,7
18,2
34,2
27,7
15,6
19
13,8
15,5
32,1
27,7
31,1
19,9
8,6
DSC: the sample D2 seems to have the
most crystalline organization
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…..
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!