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Introduction to polymer-based drugdelivery systems
micells dendrimers star -shaped polymers
4- and 6-arm starPCL- p PEGMAs synthesis characterization core degradation encapsulation properties
Conclusions
Acknowledgements
Outline
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Introduction drug-delivery systems
Polymer therapeutics term coined by Helmut Ringsdorf and Ruth Duncan
Angew. Chem. Int. Ed. 1981 , 20 , 305-325, Nat. Rev.Drug Discovery 2003 , 2 , 347-360.
Most of clinically used drugs are small hydrophobic moleculeswith molecular weights < 500 g/ mol.
rapid diffusion into healthy tissues small amounts of drugs reach the target sites therapeutics is associated with side effects
Major goal: improving the therapeutic index!(defined as ratio of the toxic dose to the therapeutic dose)
protein -polymer conjugates drug -polymer conjugates supramolecular drug -delivery systems
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Micelles
Single polymer chain
hydrophilicchain
Hydrophobicchain
weakly water-soluble drug
micelle
cmc
Drawbacks:unstable under differentenviromental conditions: high dilution pH temperauture pressure
sterilization
Dendrimers
weakly water-soluble drug
Drawbacks: low loading capacity high costs (multisteps
synthesis) not suitable for large
scale applications
DdS: Properties (II)
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Star-shaped polymers: General conceptStar-shaped polymers can effciently combine the properties of self-assembled micelles and dendrimers
core -shell structure
unimolecular micellar behavior high loading capacity
.. and they circumvent the main drawbacks of these systems: low stability high synthesis costs
guest molecules
6-hydroxycaproic acid
p PEGMA
(bio)degradation
biocompatiblehydrophilic shell
degradablebiocompatible
hydrophobic core
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hydrophobichydrophilic
Br
OBr
O
O
O
O
Br n
OR2
RO
R2O
HO
OO
OR1
RO
R1O
n
O
O
O
O
Br n
OR3
RO
R3O
O O
PEG
p
O
OOH
OHRO
OH
OH
OHOH
OOR 1
OR1R
1O
O
OR 2
OR2R
2O
OOR3
OR 3R3O
O
OOPEG
NEt 3 , THF24-72 h, RT
CuBr/PMDETAtoluene, 90 C
Tin(II)-octoate
130 C, 4 h+
R = H or R = R 1 or
R = R 2 or R = R 3 or
R 1
R 2 R 3
Star-shaped Polymers: Synthesis
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Polymer Conversion
14-arm Star-PCL
Mw 3200~ 100%
24arm Star-PCL
Mw 5600~ 100%
3
4-arm Star-PCLMw 7200 ~ 100%
46-arm Star-PCL
Mw 9800~ 100%
Br
OBr
O
O
O
O
Br n
OR2R
2
O
R2OHO
O
O
OR 1R
1O
R1O
nNEt 3, THF
24-72 h, RT
1.21.41.61.82.02.22.42.62.83.03.23.43.63.84.04.24.4
1.21.41.61.82.02.22.42.62.83.03.23.43.63.84.04.24.4
d , ppm
Quantitative fuctionalization of star PCL
2000 3000 4000 5000 6000 7000 8000 9000 10000
m/z
*
f
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O
O
O
O
Br n
OR2
R2O
R2O
OO
PEG
O
O
O
O
Br n
OR3
R3O
R3O
O O
PEG
p
CuBr/PMDETAtoluene, 90 C
14 16 18 20
0.0
0.4
0.8
1.2 Temp. 70oC, [M]/[I] = 200:1
n o r m a l i z e d R I r e s p o n s e
, a . u
elution volume, mL
10 min30 min1 h2 h3 h4 h5 hStarPCL
14 15 16 17 18 19 20
0.00
0.08
0.16
0.24
0.32
0.40 Temp. 90oC , [M]/[I] = 200:1
R I r e s p o n s e
elution volume, mL
10 min30 min1 h2 h3 h4 hStar-PCL
0 50 100 150 200 2500.0
0.4
0.8
1.2
l n ( [ M
0 ] / [ M ] )
time, minutes
0 50 100 150 200 250 3000.0
0.4
0.8
1.2
l n ( [ M
0 ] / [ M
] )
time, minutes
8.5 9.0 9.5 10.0 10.5 11.0 11.5
0.0
0.2
0.4
0.6
0.8
1.0
Temp. 70 o C, [M]/[I] = 20:1
n o r m a l i z e d R I r e s p o n s e , a
. u
elution volume, mL
10 min20 min40 min
70 min2 h3 h4 h
4-arms StarPCL-Br
14 15 16 17 18 19 20
0.0
0.2
0.4
0.6
0.8
1.0
Temp. 90 o C, [M]/[I] = 20:1
n o r m a l i z e d R I r e s p o n s e
, a . u
.
elution volume, mL
10 min2 h4 hStarPCL-Br
ATRP of PEGMA
ATRP f PEGMA 1H NMR
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ATRP of PEGMA 1H NMR
star-initiator
10 minutes
30 minutes
60 minutes
O
O
O
O
Br n
OR 2RO
R2O O
O
O
O
Br n
OR3
RO
R3O
O O
PEG
p
OR2
OR 2R2O
O OR3
OR3
R3O
O
OOPEG
CuBr/PMDETAtoluene, 90 C
R = R 2 or R = R 3 or
ppm
All arms initiated the polymerization of PEGMA
S PCL PEGMA
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Upscaling of polymer P4, after precipitation: 17 g, PDI = 1.13
polymer P1 P2 P3 P4 P5 P6 P7 P8
M/I 40:1 40:1 200:1 200:1 60:1 60:1 240:1 240:1
no. of arms 4 4 4 4 6 6 6 6PEGMA Mw (Da) 475 1100 475 475 475 1100 475 1,100
Mn (Da)(GPC) 12,600 24,900 25,000 26,600 20,700 39,600 35,000 41,000
Mn (Da)(1H NMR) 21,400 48,000 51,800 59,400 32,100 65,400 83,400 170,000
Conversion 80% 85% 48% 56% 80% 85% 70% 60%
no. of PEGMA/arm 8 8.5 24 28 8 9 26 24
PDI (GPC) 1.3 1.24 1.16 1.13 1.29 1.3 1.18 1.15
Dh (nm)
(DLS, H2O)6 7.6 9.2 9.8 7.2 11.8 13.6 17.4
Dh (nm)(DLS, CH3Cl)
nd 6.4 nd 8.2 5.8 9.2 11.8 13.4
All starPCL- p PEGMA present unimolecular micellar behavior
Star PCL p PEGMAs
ATRP f PEGMA
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8 12 16 20
7.0, 1.176-arm starPCL-Br
(P5 ) 32.1, 1.29(P6 ) 65.4, 1.3
(P7 ) 83.4, 1.18(P8 ) 170, 1.15
Mn
(kg/mol), PDI
elution volume/mL
8 12 16 20
4.6, 1.17
(P1 ) 21.4, 1.30(P2 ) 48.0, 1.24
(P3 ) 52.8, 1.16(P4 ) 59.4, 1.13
4-arm starPCL-Br
Mn
(kg/mol), PDI
elution volume/mL
ATRP of acrylates using star macroinitiators is still a challenge due to star -star coupling reactions not all of the bromine end -capped sites act as initiators for ATRP
Consequences: broad polydispersity indices and unsymmetrical GPC profiles
Our optimized procedure allows the synthesis of well-defined4- and 6-arm starPCL- p PEGMA (PDI
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Selective PCL degradation
O
O
O
Br
O
OPEG
n O
O
O
O
Br
O
OPEG
n
O
O
O
OO
Br O
OPEG
n O
O
O
O
Br
O
OPEG
n
O
O
O
O
Br O
OPEG
n O O
O
O O
Br
O
OPEG
n
O
Br
OO
PEG
OH
OOH
OH
OH
OH
OH
OH
OHO
OH
p
p
p+
p
p
p
p
6
6n
acid or base catalyzed degradation enzymatic degradation
For enzymatic degradation of PCL see i.e. Eur. J. Sci. 2007 , 31 , 119-128.
aq. HCl,dioxane, RT
A id t l d d g d ti
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0.51.01.52.02.53.03.54.04.55.0
0.51.01.52.02.53.03.54.04.55.0
0.51.01.52.02.53.03.54.04.55.0
(a)
(b)
(c)
d , ppm
1 H NMR spectra of (a) p (PEGMA) from the
hydrolysis
of 6-arm starPCL- p PEGMA,(b) 6-arm star-PCL- p PEGMA,(c) 6-arm starPCL-Br.
8 12 16 20 24
PDI 1.17
PDI 1.15
PEGP8 after hydrolysis at 60 oC
P8 after hydrolysis at R.T.
P8
6arm starPCL-Br
Elution volume, mL
room temperature selective hydrolysisof the PCL-core
H2O
Acid catalyzed degradation
Enzymatic degradation of PCL core
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Enzymatic degradation of PCL core
14 16 18 20
0.0
0.2
0.4
0.6
0.8
1.0
1.2
R I r e s p o n s e ,
a . u .
Elution volume, mL
P9 - t 0P9 - 1 dayP9 - 2 daysP9 - 4 days
Lipase from Rhizopus arrhizus
Conditions: lipase/polymer 1:5, in phosphate buffer solution (pH=7), at 37 C
in vitro biodegradable core
D l ti di 3
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Dye encapsulation disperse orange 3
polymer
disperse orange 3
N NN
O
O NH2
water insoluble dye
300 400 500 600 700 800
0.0
0.4
0.8
1.2 20:1
16:112:1
10:1
8:1
4:1
1:1
0
[dye]/[P4],[P4] = 25 M
a b s o r p t i o n / a
. u .
wavelength/ nm
20:118:116:1
14:112:110:19:18:17:16:15:14:13:12:11:10.5 mM dye,0 mM P4
Dye encapsulation (II)
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300 400 500 600
0.0
0.4
0.8
1.2
[dye]/[polymer]
A b s o r p
t i o n
/ a . u .
wavelength/ nm
20:1
18:116:114:112:110:19:18:17:16:15:14:13:12:11:1
300 400 500 600 700
0.0
0.4
0.8
1.2
[dye]/[polymer]
a b s o r p
t i o n
/ a . u .
wavelength/ nm
26:124:122:120:118:116:114:112:1
0 5 10 15 20
0.4
0.8
1.2
a b s o r p
t i o n a
t 4 4 2 n m
/ a . u .
no. of encapsulted molecules of guest 1 per molecule of P4
4-arm starPCL- p PEGMA, P4 6-arm starPCL- p PEGMA, P7
12 16 20 24 28
0.6
0.8
1.0
1.2
a b s o r p
t i o n a
t 4 4 3 n m
/ a . u .
no. of encapsulated molecules of guest 1 per molecule of P7
Dye encapsulation (II)
Dye encapsulation (III)
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Dye encapsulation (III)
Unloaded polymer ( P4 ) Polymer ( P4 ) loaded with disperse orange 3Dh (DLS, H2O) 9.8 nm 11.6 nm
DLS measurements strongly support the formation of unimolecular host-guest architectures.
Simple PEGylation is not sufficient to build up stable unimolecular core-shell systems!
our systems: encapsulation inside the polymer
R. Haag et al., Angew.Chem. Int. Ed. 2007 , 46 , 1265.R. Haag et al., Macromol. Rapid Commun. 2008 , 29 , 172.
in the literature: encapsulation by polymer aggregation
Drug encapsulation: Furosemide
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8 6 4 2 0
f d+e cba
DMF
DMFH2O
P4 + guest 2
P3 + guest 2
P2 + guest 2
guest 2 + DMFin D 2O
P1 + guest 2
/ ppm
8 6 4 2 0
f d+e cba
DMF
H2O DMF
guest 2 + DMFin D 2O
P8 + guest 2
P7 + guest 2
P6 + guest 2
P5 + guest 2
/ ppm
polymer P1 P2 P3 P4 P5 P6 P7 P8
guest 2 4 5 7 7 6 5 10 10
S
Cl
NH
OO
O
NH2
OHO
a
bc
d e
f antihypertensive and antidiuretic activity for the treatmentof excessive fluid accumulation and swelling (edema) of the
body caused by heart failure, cirrhosis, chronic kidney failure,and nephrotic syndrome
Drug encapsulation: Furosemide
Drug encapsulation: Hydrochlorothiazide
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Drug encapsulation: Hydrochlorothiazide
8 6 4 2 0
ba
H2ODMF DMF
P4 + guest 3
P3 + guest 3
P2 + guest 3
P1 + guest 3
guest 3 +DMFin D2O
/ ppm
polymer P1 P2 P3 P4 P5 P6 P7 P8
guest 3 22 18 24 24 34 18 36 36
NH
NHSS
O
O
NH2
Cl
OOa
b
antihypertensive and antidiuretic activity for the treatmentof heart failure, cirrhosis, chronic kidney failure, also effectivefor nephrogenic diabetic insipidus and hypercalciuria
8 6 4 2 0
guest 3 + DMFin H2O
P8 + guest 3
P7 + guest 3
P6 + guest 3
P5 + guest 3
H2O DMFDMF
ba
/ ppm
in D2O
Conclusions
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New water-soluble, well-defined 4- and 6-arm star-shaped polymers as
unimolecular micelles have been successfully synthesized;
High loading encapsulation capacities of different hydrophobic drugs and
other hydrophobic guests;
Room temperature selective degradation of the PCL core has proven the
homogeneous distribution of the PEGMA units over the arms;
Enzymatic degradation experiments using lipase from Rhizopus arrhizus
have demonstrated that the PCL core of the starPCL p PEGMAs is in vitro
biodegradabile;
Potential nanocarriers for parenteral drug administration.
Conclusions
Acknowledgement Infos under
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Acknowledgement http://www.schubert-group.com
Dr. Richard Hoogenboom, Dr. Michael Meier,Prof. Jean-Franois Gohy (CMAT, Belgium), Prof. Dr. Ulrich S. Schubert
3rd Generation: Higher hydrophlicity
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3 Generation: Higher hydrophlicity
O
OH
OH
OH
O
OH
O
O
O
O
Br
Br
Br
OBr
O
Cl
O
O
O
O
Br
Br
PCl 5
Synthesis of homo-branching agents
O
O
O
O
n
OR1
R1O
R1O
O
O
O
O
Br
Br
R 2
Property screening
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Property screening
J. Am. Chem. Soc. 2004 , 126 , 11517.
0,000 0,005 0,010 0,0150,00
0,01
0,02
0,03
0,04
4 6
[ m e t h y l o r a n g e ] / ( m o l / L )
[polymer] /( mol/L)
Methylorange: pH-Indicator
NN
SN O
O
O
Na+
NN
SN
+ O
O
OH Na
+
+H+basic form; yellow color
acidic form; red color
Maximal loading: 6.6 7.2 MO/micelle
INI: approx. 0.5 MO/micelle
Transport of guest-molecules: AUC
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Transport of guest molecules: AUC
unloaded micelles:
Non UV absorbing
loaded micelles:
Guest is UV absorbing300 400 500 600 700
0.00
0.25
0.50
0.75
1.00
1.25
1.50
1.75
2.00
loaded micellesunloaded micelles
A b s o r b a n c e
(nm)0 1000 2000 3000 4000 5000 6000
0.0
0.2
0.4
0.6
0.8
1.0
P1P2P3P4P5P6
N o r m a
l i z e
d c (
M )
Meff
(g/mol)0 3 6 9 12 15 18
0
500
1000
1500
2000
2500
3000
3500
M e
f f ( g / m o
l )
DP PCL block
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