Water-Soluble Degradable Hyperbranched Polyesters

Transcription

Water-Soluble Degradable Hyperbranched Polyesters
Biomacromolecules 2003, 4, 704-712
704
Water-Soluble Degradable Hyperbranched Polyesters: Novel
Candidates for Drug Delivery?
Chao Gao,†,‡ Yimin Xu,† Deyue Yan,*,† and Wei Chen†
College of Chemistry and Chemical Engineering, Shanghai Jiao Tong University, 800 Dongchuan Road,
Shanghai 200240, P. R. China, and The Key Laboratory of Molecular Engineering of Polymers,
Fudan University, Ministry of Education, P. R. China
Received November 22, 2002; Revised Manuscript Received January 29, 2003
A novel approach to hyperbranched polymers is presented in this work. Hyperbranched polyesters with a
large amount of terminal hydroxyl groups are prepared by a one-pot synthesis from commercially available
AB-type and CDn-type monomers (n g 2). In this paper, Michael addition of diethanolamine (CD2) or
N-methyl-D-glucamine (CD5) to methyl acrylate (AB) generates dominantly ADn-type intermediates. Further
self-condensation of intermediates at higher temperature and in the presence of catalyst gives hyperbranched
polyesters. Because of the tertiary amino groups in the backbone and the hydroxyl groups in the linear and
terminal units, the resulting hyperbranched polyester is highly soluble in water. Furthermore, the
hyperbranched polymer is degradable because of its ester units. So, the water-soluble hyperbranched polyesters
might be applied as a novel material for drug delivery.
Introduction
Both dendrimers, and hyperbranched polymers are threedimensional highly branched macromolecules with numerous
functional groups.1-9 Because of their unique features such
as high solubility, low viscosity, and abundance of terminal
groups, dendritic polymers are intriguing to chemists,
biochemists, biologists, and biomedical experts.10 Dendrimers
canbesynthesizedthroughdivergentorconvergentapproaches.11-17
Although its perfect monodisperse structure attracts much
attention of researchers, the preparation of a dendrimer is
generally costly and laborious because of numerous protection, deprotection, and purification steps.18 In contrast,
polydisperse hyperbranched polymers can be obtained by
one-step polycondensation of an ABn-type monomer.19-22
Depending on their special characteristics and properties
aforementioned, dendritic polymers are good candidates as
drug-delivery materials.23-26 The well-known dendrimers
such as Tomalia-type polyamidoamine (PAMAM) dendrimer
and Fréchet-type dendrimer have been widely studied in the
application of drug delivery.27,28 Because polyesters are
highly degradable in water,29-34 much attention of drugdelivery systems is focused on the branched ones. First of
all, drug-polymer conjugates require high water solubility;
otherwise, problems might be caused after injecting them
into the blood stream.23 Extensive works on dendritic
polyesters have been published;35-45 however, as far as we
know, water-soluble ones are rare. On the basis of the
molecular design, this work presents a novel approach to
water-soluble hyperbranched polyesters with high molecular
weight. Through this approach, even water-soluble hyper* To whom correspondence should be addressed. E-mail: [email protected]
sjtu.edu.cn. Fax: +86-21-54741297.
† Shanghai Jiao Tong University.
‡ Fudan University.
branched polyesters containing chiral glucamine units (similar to the structure of glucose) can be easily obtained.
Experimental Section
Materials. Methyl acrylate (MA) was commercially
purchased and purified by reduced-pressure distillation before
use. Diethanolamine (DEOA), N-methyl-D-glucamine
(NMGA), diethylamine, and 1,4-butanediol were purchased
from Aldrich and used as received. Catalysts tetrabytyl
titanate, Ti(C4H9O)4, and zinc acetate anhydrous, Zn(CH3CO2)2, and organic reagents and solvents such as benzoyl
chloride, dimethyl sulfoxide (DMSO), chloroform, methanol,
pyridine, and acetone were analytical pure reagents and used
without purification.
Characterization. Fourier-transform infrared (FT-IR)
measurements were carried out on a Bruker Equinox 55
spectrometer.1H and 13C nuclear magnetic resonance (NMR)
measurements of the resulting hyperbranched polymers were
performed on a 500 MHz Bruker NMR spectrometer with
DMSO-d6 as solvent. In situ 1H NMR measurements were
carried out in the solution of CD3OD. The inverse-gated
spectra were taken when the quantitative analysis of 13C
NMR data was done because of the nuclear Overhauser
effect. Mass spectra were obtained on a HP 1100 mass
spectrograph detector (MSD). The conditions of spray
chamber were given as follows: ionization mode, APCI;
polarity, positive; fragmentor, 70 v; nebulizer pressure, 60
psig; drying gas flow, 7.0 mL/min; drying gas temperature,
325 °C.
Differential scanning calorimetric characterization was
conducted under nitrogen on a PE Pyris-1 DSC thermal
analyzer. All samples were heated at 20 °C/min heating rate
10.1021/bm025738i CCC: $25.00
© 2003 American Chemical Society
Published on Web 03/12/2003
Biomacromolecules, Vol. 4, No. 3, 2003 705
Water-Soluble Degradable Hyperbranched Polyesters
Table 1. Polymerization of Methyl Acrylate (MA) with Diethanolamine (DEOA) or N-methyl-D-glucamine (NMGA)
code
CDn
catalysta
temp (°C)b
Mn1c
Mw/Mn1
ηinh (dL/g)
Mn2d
DB (%)
PAE-01
PAE-02
PAE-03
PAE-04
PAE-05
PAE-06
PAE-07
PAE-08
PAE-09
PAE-10
PAE-11
DEOA
DEOA
DEOA
DEOA
DEOA
DEOA
DEOA
NMGA
NMGA
NMGA
NMGA
Zn(OAc)2
Zn(OAc)2
Ti(C4H9O)4
Ti(C4H9O)4
Ti(C4H9O)4
Ti(C4H9O)4
Ti(C4H9O)4
Zn(OAc)2
Zn(OAc)2
Ti(C4H9O)4
Ti(C4H9O)4
150
140
150
165
140
135
120
145
135
145
135
80 650
50 160
268 340
gel
139 530
86 030
14 740
51 860
38 010
66 320
52 290
1.14
1.40
2.41
0.52
0.25
1.78
115 300
70 850
338 200
53.4
52.5
1.04
1.14
1.52
1.35
1.12
1.13
1.08
0.92
0.55
0.11
0.25
0.18
0.34
0.26
201 430
55.8
a Amount of catalyst was 0.5 g per mole of CD -type monomer. b The temperature within the last 2 h. The initial reaction temperatures were 60 °C for
n
1 h, 100 °C for 2 h, and then 120 °C for 2 h. c The number-average molecular weight of the hyperbranched polymer with hydroxyl end groups. d The
number-average molecular weight of the end-capped hyperbranched polymer.
from 35 to 200 °C for the first scan, then cooled at 20 °C/
min to -80 °C, and immediately heated with 20 °C/min from
-80 to 160 °C for the second scan. Thermogravimetric
analysis (TGA) was performed under nitrogen on a PE
Pyris-7 thermal analyzer; all samples were heated with a
heating rate of 20 °C/min from 25 to 650 °C.
The molecular weight and its distribution of the hyperbranched polymer with hydroxyl end groups were obtained
on the HP 1100 gel permeation chromatograph (GPC) with
water as solvent and PEO as standards, and the column used
was G6000 PW (XL). Optilab Dawn EOS multiangle laser
light-scattering (MALLS) apparatus was used to measure the
molecular weight of the end-capped hyperbranched polymer
with polystyrene as standards and tetrahydrofuran (THF) as
solvent. The inherent viscosity (ηinh) of the resulting polymer
was measured at a concentration of 0.5 g/dL in DMSO at
30 °C.
Synthesis of Hyperbranched Poly(MA-DEOA). A
typical example (PAE-01 in Table 1) is given as follows. In
a flask were placed 0.1 mol of DEOA, 0.105 mol of MA,
and 20 mL of methanol. The mixture was kept at room
temperature (about 25 °C) for 48 h with stirring. Then the
flask was connected with a revolving-distillation apparatus.
Under reduced pressure, the residual MA and methanol in
the revolving-distillation apparatus were removed from the
reaction system. Then 0.05 g of Zn(CH3CO2)2 was added
into the flask. Under vigorous revolving and vacuum
distillation, the mixture was kept at 60 °C for 1 h, 100 °C
for 2 h, 120 °C for 2 h, and 150 °C for 2 h. The raw product
was dissolved in 50 mL of DMSO and then poured into 1000
mL of acetone. The precipitate was collected and purified
by reprecipitation from DMSO solution into acetone. A
yellow rubber-like solid, 12.5 g (yield 78.6%), was obtained.
IR (KBr): 3396.6 cm-1 (-OH), 1730.6 cm-1 (CdO). 1H
NMR (DMSO-d6, ppm): δ 4.08 (-OH), 3.45 (CH2O), 2.45
(CH2N), 1.6 (CH2CdO). 13C NMR (DMSO-d6, ppm): δ
172.345, 171.38, 171.02, 69.23, 67.18, 66.18, 62.53, 59.55,
57.24, 54.97, 53.43, 52.57, 51.79, 48.72, 44.88, 34.93, 33.22,
32.51, 21.79.
Synthesis of Hyperbranched Poly(MA-NMGA). A
typical example (PAE-08 in Table 1) is given as follows. In
a flask were placed 0.1 mol of NMGA and 30 mL of DMSO.
When the mixture was completely dissolved, 0.105 mol of
MA dissolved in 10 mL of methanol was dropped slowly
into the flask within 10 h, and the mixture was kept at room
temperature for 50 h. Then the flask was connected to a
revolving-distillation apparatus. Under reduced pressure, the
residual MA and methanol were removed. Then 0.05 g of
Zn(CH3CO2)2 was added to the flask. Under vigorous
revolving and vacuum distillation, the mixture was kept at
60 °C for 1 h, 100 °C for 2 h, 120 °C for 2 h, and 145 °C
for 2 h. The raw product was dissolved in 40 mL of DMSO
and then poured into 1000 mL of acetone. The precipitate
was collected and purified by reprecipitation from DMSO
solution into acetone. A yellow plastic solid, 22.5 g (yield
79.9%), was obtained. IR (KBr): 3399.5 cm-1 (OH), 1731.5
cm-1 (CdO). 1H NMR (DMSO-d6, ppm): δ 4.6-4.2 (OH),
3.72 (NCH2CHO), 3.58 (CHO), 3.4 (CH2O), 2.68 (CH2N),
2.2 (CH3N), 1.6 (CH2CdO). 13C NMR (DMSO-d6, ppm):
δ 175.4, 172.23, 84.46, 79.72, 79.02, 77.82, 77.4, 72.78569.92 (group), 68.85, 63.82, 62.12, 60.19, 58.98, 54.26,
53.81, 53.56, 52.4, 51.96, 51.22, 42.73, 42.52, 40.82, 37.14,
34.02, 31.84, 30.53, 29.9, 21.8.
End-Capping Reaction. In a flask were placed 5 g of
hyperbranched poly(MA-DEOA) and 30 mL of pyridine;
then 4.2 g of benzoyl chloride was dropped slowly into the
flask within 2 h, and the mixture was kept at 40 °C for 10
h. The mixture was poured into 500 mL of diethyl ether.
The precipitate was collected and dried under vacuum. A
powdery solid (7.1 g) was obtained. 1H NMR (DMSO-d6,
ppm): δ 8.0-7.3 (-Ar-), 3.62 (ArCOOCH2), 3.45 (CH2O),
2.45 (CH2N), 1.6 (CH2CdO).
General Procedure for Test of Degradation Property.
To a flask was added 1 g of solid sample poly(MA-DEOA)
in 100 mL of water. After the sample dissolved completely,
the flask was placed in a water bath to keep the temperature
of the sample at 37.5 °C. The pH of the solution was kept
constant by adding acid or base. An aliquot of the solution
was withdrawn every 10 h and analyzed by GPC.
Results and Discussion
Molecular Design of the Approach and Material. The
classic approach to hyperbranched polymers is the polycondensation of ABn-type monomers, which has been studied
theoretically by Flory19 as early as 1952 (Scheme 1). Being
different from Flory’s approach, this work explored a new
strategy to hyperbranched polymers from two monomers
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Scheme 1. General Approach to Hyperbranched Polymer
based on the principle of nonequal reactivity of different
functional groups. Scheme 2 shows the design idea. Monomer AB contains one A and one B functional group, and
they cannot react with each other. Monomer CDn has one C
functional group and n D functional ones, and C cannot react
with D. At room temperature, the B group of the AB
monomer can easily react with the C group of CDn, but only
at higher temperature and in the presence of catalyst, the A
group can react with the D group. To obtain a water-soluble
polymer that might be used as a drug delivery system, a
secondary amino group (HN-) is selected as C group and
hydroxyl (-OH) is selected as D group. Acrylate group
(CH2dCHCO) plays the role of B group, which can react
with secondary amino group under mild conditions. Methyloxy carbonyl (CH3OCdO) is chosen as A group because it
can react with hydroxyl group at high temperature to form
an ester unit. The ester unit is attractive in the synthesis of
polymer materials because of its degradability. Here, ester
Scheme 2. “AB + CDn” Approach to Hyperbranched Polymer
Gao et al.
units play another very important role to neutralize amines
formed after degradation. Therefore, pH of the aqueous
system can be self-adjusted to about 7, which is an important
parameter for a good drug delivery system.23
In the reaction, Michael addition of C groups to B groups
generates ADn-type species. Further polycondensation of the
ADn species results in hyperbranched polyester with tertiary
amino groups in backbone and end hydroxyl groups. So the
novel approach is a “one-pot two-step” method.
Analysis of Mass Spectrum at the First Stage. Scheme
3 shows the possible reactions between MA and DEOA.
Compound 3 is the targeted molecule. Species 4 is not stable
and will, if formed, further react with DEOA to form species
6. Molecule 6, having four hydroxyl groups, can play the
role of “core molecule” in the preparation of hyperbranched
polymers, which will limit the molecular weight.46,47 Species
5 is also not stable and will further react with DEOA and
MA to form species 7, 8, and 9. Self-condensation of
molecule 9, AD3-type monomer, would give hyperbranched
polyester. So the occurrence of side reactions has no
determined influence on the formation of hyperbranched
polymer with high molecular weight.
Figure 1 displays the mass spectrum of the mixture that
was taken from the reaction system after removing the
residual MA monomer. The peaks of m/z ) 192.3 and 214.2
are assigned to the ion peak of molecule 3 coupled with a
proton (M + 1) and that of molecule 3 coupled with a Na+
(M + 23), respectively. The peaks of m/z ) 351.5, 510.5,
and 691.7 are attributed to the molecular ion peaks of dimer
(M2H+), trimer ((M3H+), and tetramer (M4H+) of 3, respectively. The peaks of m/z ) 373.5 and 532.5 are the
Biomacromolecules, Vol. 4, No. 3, 2003 707
Water-Soluble Degradable Hyperbranched Polyesters
Scheme 3. Possible Reactions in the MA and DEOA System at Initial Stage
corresponding peaks of dimer and trimer of 3 with a captured
Na+ (M2Na+, M3Na+). The fragment peaks of 3 are observed
as two small peaks at m/z ) 118.2 and 174.3. Analysis of
the mass spectrum shows that an AD2-type intermediate does
form dominantly during the initial reaction stage.
If monomer NMGA, instead of DEOA, is used to react
with MA, the same result can be obtained from its corresponding mass spectrum.
In Situ 1H NMR Spectra. The initial reaction process of
monomer 1 and 2 was further monitored by in situ 1H NMR.
Because monomer 2 contains amino and hydroxyl groups,
diethylamine and 1,4-butanediol were used as models to react
with monomer 1, respectively. Figure 2 displays the in situ
1
H NMR spectra of the reaction between methyl acrylate
and diethylamine in solution of CD3OD. Michael addition
of the secondary amino group of diethylamine to the double
bond of methyl acrylate leads to the predicted product. The
reaction between group A (CH3O-) and group C (-HN-)
was not observed in the NMR spectra, which implied that
species 4 and 6 showed in Scheme 3 were hardly generated
at room temperature. On the other hand, the reaction between
Figure 1. Mass spectrum for MA and DEOA reaction system after
removing residual MA. The reaction temperature is 25 °C.
group B (CH2dCHCO) and group C (-HN-) was fast
within the initial several hours, and about 90% of monomers
reacted with each other. However, a small quantity of two
monomers still appeared in the 1H NMR spectra after 72 h,
which indicated that the reaction approached its equilibrium.
In situ 1H NMR spectra of the reaction between methyl
acrylate and 1,4-butanediol are given in Figure 3. Almost
no changes can be observed between the spectrum recorded
at 5 min and the spectrum monitored at 48 h, which
suggested that the reaction between group A and D was
neglectable at room temperature. So the amount of species
5, 7, 8, and 9 described in Scheme 3 should be very small.
Figure 4 shows the in situ 1H NMR spectra of the reaction
between methyl acrylate (MA) and diethanolamine (DEOA).
Similar to the reaction between methyl acrylate and diethylamine, the reaction between MA and DEOA is also fast
within initial several hours, while tiny peaks attributed to
original monomers are still present in the NMR spectrum
after 240 h when the feed ratio of MA to DEOA was 1/1.
This characterization and model reactions indicated that the
reaction between group B and C has equilibrium, and the
possible minor reactions given in Scheme 3 are neglectable
at the tested temperature. Therefore, in our experiments the
amount of MA is a little greater than that of DEOA so that
the latter can be completely reacted. In fact, after small
amount of MA was added to the same reaction system, the
peaks assigned to DEOA disappeared with a relatively fast
rate.
Effect of Reaction Conditions on the Polymerization.
Reaction conditions such as temperature, reaction time, and
catalyst always have strong influence on the polycondensation. In our work, it is vitally important to find suitable
reaction conditions to obtain soluble hyperbranched polymer
with high molecular weight but no gel. The reaction
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Gao et al.
Figure 2. In situ 1H NMR spectra of the reaction system between methyl acrylate and diethylamine in CD3OD: (A) diethylamine; (B) 5 min; (C)
40 min; (D) 90 min; (E) 72 h.
conditions and results are given in Table 1. The molecular
weight distribution of the resulting polymers is very narrow
when compared with the theoretical prediction value.
During the initial stage, higher reaction temperature would
aggravate the side reactions B, C, and D, which would
increase the contents of 4, 5, 6, and 7. Obviously, high
content of 6 or 8 with multifunctional groups would endcap the vinyl groups of ADn to stop the further polycondensation of A with D, which would decrease the molecular
weight of the resulting hyperbranched polymers. Figure 5
displays the mass spectrum of the first stage sample when
the reaction temperature is 60 °C. Indeed, species 4 (m )
159.2), 5 (m ) 159.2), 6 (m ) 264.3), 7 (m ) 245.3), and
8 (m ) 264.3) are present in the mass spectrum as the peaks
at m/z ) 160.1, 265.1, 246.1, and 265.1. So the reaction
temperature was set at room temperature for the first stage.
During the second stage, temperature also has strong
influence on the polymerization. At the last 2 h, temperatures
of 120, 135, 150, or 165 °C were chosen as the reaction
temperature. At the temperature below 135 °C, the hyperbranched polyester with high molecular weight cannot be
obtained, and at the temperature above 165 °C, cross-linking
was observed. Only at the region of 135-150 °C, high
molecular weight polymer was synthesized successfully.
Furthermore, the cyclic structure content in the hyperbranched polymer reported here is very low according to
such high molecular weight. Otherwise, molecular weight
of the resulting polymers would be much lower.36
The effect of catalyst on the reaction is investigated in
the paper. In the same reaction conditions, the molecular
weight of the resulting polymers catalyzed by Ti(C4H9O)4
is larger than that catalyzed by Zn(OAc)2 (Table 1), which
indicates that Ti(C4H9O)4 is a more efficient catalyst for the
condensation reaction than Zn(OAc)2.
Measurement of Molecular Weight. The hydroxylterminated hyperbranched polyesters are highly soluble in
polar solvents such as water, methanol, N,N-dimethylformamide (DMF), and DMSO. The hydroxyl-terminated hyperbranched polymers were end-capped with benzoyl chloride to avoid aggregation in the measurements of molecular
weight. In the 1H NMR spectrum of the end-capped product,
the peak of hydroxyl groups at 4.08 ppm was not observed
and the peaks assigned to benzene rings appeared at 7.38.0 ppm, which indicated that the hydroxyl groups were
reacted with benzoyl chloride. The data in Table 1 showed
that the influence of terminal hydroxyl groups on the
measurement of molecular weight in water is not as great as
prediction. The molecular weights measured with general
GPC in water are in agreement with those measured with
MALLS apparatus in THF if the molar mass of benzoyl was
considered in the determination of the molecular weight of
the end-capped polymers.
Water-Soluble Degradable Hyperbranched Polyesters
Biomacromolecules, Vol. 4, No. 3, 2003 709
Figure 3. In situ 1H NMR spectra of the reaction system between methyl acrylate and 1,4-butanediol in CD3OD: (A) 1,4-butanediol; (B) 5 min;
(C) 48 h.
Loss-Weight Investigation. The polymerization process
of MA and DEOA was monitored with the loss weight of
the reaction system (Figure 6). When 0.1 mol of DEOA was
used as one of the raw materials, 3.203 g of CH3OH would
be lost theoretically as the reaction degree of CH3O groups
reached 100%. In our experiment, 3.210 g of mass was lost,
which is in good agreement with the theoretic value if
experimental errors are considered. On the other hand, almost
no mass lost was observed after 2 h at 150 °C for the
reaction. So the reaction time during the last stage was set
as 2 h in the experiments.
Degree of Branching. Dendritic polymers have highly
branched structures. The degree of branching (DB) is used
to quantitatively describe their branched feature. A highly
branched polymer has dendritic units (ND), linear units (NL),
and terminal units (NT). DB is equal to the ratio of ND and
NT to the total units (ND + NT + NL).35 The DB is 100% for
dendrimers and <100% for hyperbranched polymers. For
the polymer made from AB2-type monomer with two B
groups of equal reactivity, its maximum DB is 50% according to the statistical theory.48-51 For the hyperbranched
polyesters reported here, the DB of poly(MA-DEOA) is
determined by 13C NMR spectroscopy (Figure 7). The
chemical shifts of methyleneoxy (CH2O) moieties of terminal
and linear units are clearly observed in the 13C NMR
spectrum. For a hyperbranched polymer made from AB2-
type monomer, ND ) NT - 1. Therefore,
DB ) (ND + NT)/(ND + NT + NL) ) (NT - 1 + NT)/(NT 1 + N T + NL )
) (2NT - 1)/(2NT + NL - 1) ≈ 2NT/(2NT + NL)
) 1/(1 + NL/2NT)
(1)
Because each terminal unit contains two CH2OH moieties
and each linear unit one CH2OH moiety
DB can be calculated from eq 2.
DB ≈ 1/(1 + NL/2NT) ) 1/(1 + Al/Ak)
(2)
In eq 2, Al and Ak represent the integration area of peak l in
linear units and that of peak k in terminal units, respectively.
DB of poly(MA-DEOA) calculated from the ratio of
integration area of corresponding peaks is listed in Table 1.
The calculated values of DB are little higher than 50%.
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Gao et al.
Figure 4. In situ 1H NMR spectra of reaction between methyl acrylate and diethanolamine in CD3OD: (A) diethanolamine; (B) 1 h; (C) 3 h; (D)
240 h; (E) 0.5 h after small amount of MA was added to the in situ reaction system at 240 h; (F) 2 h after small amount of MA was added to
the in situ reaction system at 240 h.
Because of the complex structure of hyperbranched poly(MA-NMGA), its DB cannot be calculated directly from
the NMR spectrum. On the other hand, the reactivity of the
primary hydroxyl group is higher than that of the secondary
hydroxyl group for NMGA monomer in the condensation
reaction, which might result in the formation of an almost
linear polyester. But in fact, the peak of ester units resulting
from secondary hydroxyl groups at δ172.23 ppm is much
greater than that resulting from primary hydroxyl ones at
175.4 ppm, which suggests that many secondary hydroxyl
groups have been reacted and a highly branched polyester
is fabricated in the reaction. The phenomenon may be caused
by two major factors: first, the higher content of secondary
hydroxyl groups in each unit relatively increases their
concentration; second, the reactivity of secondary hydroxyl
groups is increased in high temperature.
Degradation Property. Sample PAE-05 was used to
investigate the degradation property of the hyperbranched
polyester prepared. The molecular weight of the degraded
sample as a function of time is shown in Figure 8. Under a
basic environment, the hyperbranched polyester is easier to
degrade, which accords with the general principle of
degradation for ester groups. In an acidic environment,
degradation is faster, then slower course as compared to that
in a neutral solution. After 5 days, the molecular weight of
the polyester decreases about one-half of its initial value.
The study on the degradation property of the sample coupled
with drug molecules is in progress and will be reported later.
Biomacromolecules, Vol. 4, No. 3, 2003 711
Water-Soluble Degradable Hyperbranched Polyesters
Figure 7.
13C
NMR spectrum of hyperbranched poly(MA-DEOA).
Figure 5. Mass spectrum for MA and DEOA reaction mixture after
removing residual MA. The reaction temperature is 60 °C.
Figure 8. Molecular weight of degraded PAE-05 as a function of
degradation time at different pH.
Figure 6. The reaction degree of CH3O group and loss weight of
reaction system as a function of reaction time or temperature. The
reaction had been carried out at 60 °C for 1 h and then 100 °C for 1h
before the measurement.
Thermal Properties. The glass transition of the hyperbranched polyesters is about 10-20 °C, which indicates that
the polymer is in the state of rubber at room temperature.
The 5% weight-loss temperature is above 200 °C, and 10%
weight-loss temperature is above 250 °C, which is enough
for a drug-delivery material.
Conclusions
Novel sorts of water-soluble hyperbranched polyesters with
tertiary amino units in the backbones and abundance of
hydroxyl end groups were synthesized by the “AB + CDn”
approach presented in this work. The resulting hyperbranched
polyesters are degradable in water. Investigation of the initial
reaction stage with mass spectrum showed that the ADn-
type intermediate was dominantly formed and its selfcondensation started as soon as generation of the species.
The reaction temperature and catalyst have great influence
on the polymerization. Gelation would occur if the temperature is above 165 °C, whereas high molecular weight of
polymer cannot be prepared if the temperature is below 120
°C. Calculated from the integration area of the peaks of 13C
NMR spectrum, the degree of branching of the hyperbranched polyester made from MA and DEOA is 52.355.8%. Characterization of 13C NMR spectrum displayed that
the poly(MA-NMGA) is also a highly branched macromolecule. The simplicity of the synthesis process, low cost
of raw materials, water-solubility, degradability, amount of
terminal functional groups, highly branched backbone, and
three-dimensional globe-like structure would make the hyperbranched polyesters reported here very attractive as a good
candidates for drug delivery. The study on the application
of the hyperbranched poly(amino ester)s in the field of drug
delivery is in progress and will be published elsewhere.
Acknowledgment. This work was supported by the
National Natural Science Foundation of China (Grant No.
50233030) and the Opening Research Foundation of the Key
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Biomacromolecules, Vol. 4, No. 3, 2003
Laboratory of Molecular Engineering of Polymers of Fudan
University, Ministry of Education.
References and Notes
(1) Kim, Y. H. J. Polym. Sci., Polym. Chem. 1998, 36, 1685.
(2) Inoue, K. Prog. Polym. Sci. 2000, 25, 453.
(3) Malmström, E.; Hult, A. J. Macromol. Sci., ReV. Macromol. Chem.
Phys. 1997, C37, 555.
(4) Fréchet, J. M. J.; Hawker, C. J.; Gitsov, I.; Leon, J. W. J. Macromol.
Sci., Pure Appl. Chem. 1996, A33 (10), 1399.
(5) Fréchet, J. M. J. Science 1994, 263, 1710.
(6) Schlüter, A. D.; Rabe, J. P. Angew. Chem., Int. Ed. 2000, 39, 864.
(7) Fischer, M.; Vögtle, F. Angew. Chem., Int. Ed. 1999, 38, 884.
(8) Newkome, G. R.; Moorefield, C. N.; Vögtle, F. Dendritic Molecules: Concepts, Synthesis, PerspectiVes, VCH: Weinheim, Germanay, 1996.
(9) Malmström, E.; Hult, A. Statistically Branched Dendritic Polymers.
In Dendrimers and Other Dendritic Polymers; Fréchet, J. M. J.,
Tomalia, D. A., Eds.; John Wiley & Sons: West Sussex, U.K., 2001;
Chapter 8, pp 197-208.
(10) Voit, B. J. Polym. Sci., Polym. Chem. 2000, 38, 2505.
(11) Buhleier, E.; Wehner, W.; Vögtle, F. Synthesis 1978, 155.
(12) Tomalia, D. A.; Baker, H.; Dewald, J.; Hall, M.; Kallos, G.; Martin,
S.; Roeck, J.; Ryder, J.; Smith, P. Polym. J. 1985, 17, 117.
(13) Newkome, G. R.; Yao, Z.; Baker, G. R.; Gupta, V. K. J. Org. Chem.
1985, 50, 2003.
(14) Tomalia, D. A.; Baker, H.; Dewald, J.; Hall, M.; Kallos, G.; Martin,
S.; Roeck, J.; Ryder, J.; Smith, P. Macromolecules 1986, 19, 2466.
(15) Newkome, G. R.; Baker, G. R.; Sanuders, M. J.; Russo, P. S.; Gupta,
V. K.; Yao, Z.; Bouillion, J. E. J. Chem. Soc., Chem. Commun. 1986,
752.
(16) Newkome, G. R.; Yao, Z.; Baker, G. R.; Gupta, V. K.; Russo, P. S.;
Saunders, M. J. J. Am. Chem. Soc. 1986, 108, 849.
(17) Hawker, C.; Fréchet, J. M. J. J. Am. Chem. Soc. 1990, 112, 7638.
(18) Johansson, M.; Malmström, E.; Hult, A. TRIP 1996, 4, 398.
(19) Flory, P. J. J. Am. Chem. Soc. 1952, 74, 2718.
(20) Kim, Y. H.; Webster, O. W. Polym. Prepr. 1988, 29 (2), 310.
(21) Kim, Y. H.; Webster, O. W. J. Am. Chem. Soc. 1992, 114, 4947.
(22) Kim, Y. H.; Webster, O. W. Macromolecules 1992, 25, 5561.
(23) Uhrich, K. TRIP 1997, 5, 388.
(24) Cooper, A. I.; Londono, J. D.; Wignall, G.; McClain, J. B.; Samulski,
E. T.; Lin, J. S.; Dobrynin, A.; Rubinstein, M.; Burke, A. L. C.;
Fréchet, J. M. J.; DeSimone, J. M. Nature 1997, 389, 368.
Gao et al.
(25) Esfand, R.; Tomalia, D. A.; Beezer, A. E.; Mitchell, J. C.; Hardy,
M.; Orford, C. Polym. Prepr. 2000, 41 (2), 1324.
(26) Liu, H.; Joshi, N.; Uhrich, K. E. Polym. Prepr. 1996, 37 (2), 147.
(27) Patri, A. K.; Majoros I. J.; Baker, J. R., Jr. Curr. Opin. Chem. Biol.
2002, 6, 466.
(28) Esfand, R.; Tomalia, D. A. Drug DiscoVery Today 2001, 6, 427.
(29) Liu, H.; Uhrich, K. E. Polym. Prepr. 1997, 38 (2), 582.
(30) Jiang, H. L.; Zhu, K. J. Biomaterials 2001, 22, 211.
(31) Arshady, R. J. Bioact. Compat. Polym. 1990, 5, 315.
(32) Domb, A. J. Polym. Prepr. 1990, 31 (1), 252.
(33) Linhardt, R. J.; Flanagan, D. R.; Schmitt, E.; Wang, H. T. Polym.
Prepr. 1990, 31 (1), 249.
(34) Dunne, M.; Corrigan, O. I.; Ramtoola, Z. Biomaterials 2000, 21,
1659.
(35) Lemmouchi, Y.; Schacht, E.; Kageruka, P.; De Deken, R.; Diarra,
B.; Diall, O.; Geerts, S. Biomaterials 1998, 19, 1827.
(36) Feast, W. J.; Keeney, A. J.; Kenwright, A. M.; Parker, D. Chem.
Commun. 1997, (18), 1749.
(37) Hawker, C. J.; Lee, R.; Fréchet, J. M. J. J. Am. Chem. Soc. 1991,
113, 4583.
(38) Turner, S. R.; Voit, B.; Mourey, T. H. Macromolecules 1993, 26,
4617.
(39) Turner, S. R.; Voit, B. Polym. Prepr. 1993, 34 (1), 79.
(40) Turner, S. R.; Walter, F.; Voit, B.; Mourey, T. H. Macromolecules
1994, 27, 1611.
(41) Malmström, E.; Johansson, M.; Hult, A. Polym. News 1997, 22, 128.
(42) Malmström, E.; Johansson, M.; Hult, A. Macromolecules 1995, 28,
1698.
(43) Magnusson, H.; Malmström, E.; Hult, A. Macromolecules 2000, 33,
3099.
(44) Kricheldorf, H. R.; Stoeber, O.; Luebbers, D. Macromolecules 1995,
28, 2118.
(45) Kricheldorf, H. R.; Stukenbrock, T. J. Polym. Sci., Polym. Chem.
1998, 36, 2347.
(46) Hahn, S. W.; Yun, Y. K.; Jin, J.; Han, O. H. Macromolecules 1998,
31, 6417.
(47) Yan, D. Y.; Zhou, Z. P. Macromolecules 1999, 32, 819.
(48) Müller, A. H. E.; Yan, D. Y.; Wulkow, M. Macromolecules 1997,
30, 7015.
(49) Yan, D. Y.; Müller, A. H. E.; Matyjaszewski, K. Macromolecules
1997, 30, 7024.
(50) Hölter, D.; Burgath, A.; Frey, H. Acta Polym. 1997, 48, 30.
(51) Hölter, D.; Frey, H. Acta Polym. 1997, 48, 298.
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