Polypeptide dendrimers: Self-assembly and drug delivery

Article abstract of DOI:10.1007/s11426-010-4218-2

Amphiphilic dendritic poly(glutamic acid)-b-polyphenylalanine copolymers were synthesized using generation 3 dendritic poly(glutamic acid) as the macroinitiator in the ring-opening polymerization of NCA-Phe. The block copolymers self-assembled micelles with polyphenylalanine segments as core and dendritic poly(glutamic acid) segments as shell. The biocompatibility of the micelles was studied. The release of the anticancer drug doxorubicin from the micelles was investigated in vitro. The results showed that the sustaining release of the drug could last for 60 h. The micellar drug release system was efficient in inhibiting the proliferation of HepG2 liver cancer cells, 75% cancer cells were killed under appropriate in vitro incubation.

Full text of DOI:10.1007/s11426-010-4218-2

SCIENCE CHINA
Chemistry
February 2011 Vol.54 No.2: 326–333
doi: 10.1007/s11426-010-4218-2
• ARTICLES •
· SPECIAL ISSUE · In Honor of the 80th Birthdays of Professors SHEN JiaCong, SHEN ZhiQuan and ZHUO RenXi
Polypeptide dendrimers: Self-assembly and drug delivery
XU XiangHui, LI CaiXia, LI HaiPing, LIU Rong, JIANG Chao, WU Yao,
HE Bin* & GU ZhongWei*
National Engineering Research Center for Biomaterials, Sichuan University, Chengdu 610064, China
Received October 29, 2010; accepted November 30, 2010
Amphiphilic dendritic poly(glutamic acid)-b-polyphenylalanine copolymers were synthesized using generation 3 dendritic
poly(glutamic acid) as the macroinitiator in the ring-opening polymerization of NCA-Phe. The block copolymers self-assembled
micelles with polyphenylalanine segments as core and dendritic poly(glutamic acid) segments as shell. The biocompatibility of
the micelles was studied. The release of the anticancer drug doxorubicin from the micelles was investigated in vitro. The re-
sults showed that the sustaining release of the drug could last for 60 h. The micellar drug release system was efficient in inhib-
iting the proliferation of HepG2 liver cancer cells, 75% cancer cells were killed under appropriate in vitro incubation.
self-assembly, dendritic polypeptide block copolymer, drug delivery
hydrogels have been reported to perform effects on tissue
regeneration [13–15].
1 Introduction
Dendritic polypeptides contain unique properties includ-
ing protein-like structure, water solubility, regular structure,
a large amount of branches and peripheral functional groups,
nano-scaled size and unitary molecular weights. In com-
parison with amphiphilic linear copolymer micelles, the
dendritic copolymer micelles have better stability and also
have advantages in fabricating targeting and stimuli-sensitivity
with the functionalization of a large amount of peripheral
groups. For instance, phase behavior of dendritic block co-
polymers is significantly different from the linear block
copolymers [17]. With the functionalization of the periph-
eral groups, the solubility of dendritic block copolymers
was improved, thus led to the improvement of the physical
and chemical properties of their aggregates [18]. The
worm-like nanoparticles were fabricated by self-assembled
dendron/linear/dendron triblock copolymers and used as
vectors for drug delivery [19].
Molecular self-assembly is becoming a widely adopted ap-
proach in biomaterials research for constructing functional
materials and improving their performances [1–3]. Syn-
thetic polypeptides are important polymeric materials that
have inherent biocompatibility. They can mimic the con-
formational structures of natural proteins and impose spe-
cific properties and functions through selective self-assembly
processes. Weak physical interactions within polypeptide
chains can readily lead to different morphologies such as
spherical, short rod-shaped, worm-shaped and vesicular
[4–7]. Exploitations of their special functions have been
extensively pursued in physics, chemistry and biology [4, 8,
9]. Synthetic polypeptides derived from natural amino acids
become important biomedical materials for drug delivery
and tissue repair due to their excellent biocompatibility and
biodegradability. Polypeptides self-assembled drug/gene
carriers were easily modified with targeting and stimuli-
sensitive functions [10–12]. Self-assembly polypeptides
In this paper, a novel self-assembly micellar system con-
taining a dendritic polypeptide is reported. Generation 3
dendritic poly(glutamic acid) was synthesized by a conver-
gent-divergent method [20]. It was used to initiate the ring-
*Corresponding author (email: bhe@scu.edu.cn; zwgu@scu.edu.cn)
© Science China Press and Springer-Verlag Berlin Heidelberg 2011
chem.scichina.com
www.springerlink.com

Xu XH, et al. Sci China Chem February (2011) Vol.54 No.2
327
opening polymerization of L-phenylalanine N-carboxyanhy-
dride (NCA-Phe) to obtain amphiphilic poly(glutamic acid)-
polyphenylalanine block copolymers [21]. The dendron-
linear block copolymers self-assembled into core-shell
structured micelles. Anticancer drug doxorubicin was loaded in
the micelles. The self-assembly of the dendron-linear block
copolymers was investigated by scanning electron micros-
copy (SEM), transmission electron microscopy (TEM), and
dynamic light scattering (DLS). The drug release was stud-
ied in vitro. Confocal laser scanning microscopy (CLSM)
was used to investigate the cellular uptake of the micelles in
HepG2 cells and the in vitro anticancer effect was evaluated
by CCK-8 assays.
was dropwise added and the condensation reaction was
lasted for 24 h. The mixture was washed with aqueous solu-
tions of NaHCO3, NaHSO4 and NaCl for several times.
The organic phase was dried with MgSO4 for 12 h. After
concentration, the product was recrystallized in CH2Cl2/
hexane. Compound 1 in Scheme 1 was filtrated and dried.
Synthesis of generation 3 dendritic poly(glutamic acid)
The tert-butoxycarbonyl of generation 2 dendritic poly
(glutamic acid) was treated with TFA, and the mixture was
stirred for 6 h to remove tert-butoxycarbonyl groups. The
solvent and TFA were removed in vacuum. The rest of the
product was treated with anhydrous diethyl ether. The solid
product was precipitated (product 2, Scheme 1). After add-
ing excess of Boc-Glu-COOH to repeat step 2.3.1, genera-
tion 3 dendritic poly(glutamic acid) was obtained. Genera-
tion 3 dendritic poly(glutamic acid) (product 3, Scheme 1)
was purified by silica gel column.
2 Experimental
2.1 Materials
Protected amino acids Boc-Glu-COOH, H-Glu(OBzl)-OBzl
and N-Cbz-Phe were purchased from GL Biochem Ltd.
(Shanghai). 1-Hydroxybenzotriazole hydrate (HOBt) and
1-ethyl-3-[3-(dimethylamino) propyl] carbodiimide (EDC)
were purchased from GL Biochem Ltd. (Shanghai) and used
as received. N,N-Diisopropylethylamine (DIEA) and trifluo-
roacetic acid (TFA) were purchased from Asta Tech Phar-
maceutical (Chengdu, China). Doxorubicin hydrochloride
was obtained from Zhejiang Hisun Pharmaceutical. Me-
thylene chloride (DCM), tetrahydrofuran (THF), dimethyl
formamide (DMF), ethyl acetate and n-hexane were purified
before use. Dulbecco’s modified Eagle’s medium (DMEM)
was used for cytotoxicity test.
2.4 Amphiphilic dendritic poly(glutamic acid)-b-poly-
phenylalanine copolymer
Preparation of macroinitiator G3-Glu-NH2
Generation 3 dendritic poly(glutamic acid) was deprotected
with TFA in N2 atmosphere to obtain product 4 (Scheme 1).
The pH value was adjusted by NaOH methanol solution, the
mixture was dried under reduced pressure. The left solid
was dissolved in CH2Cl2 and stirred for 1 h, then filtered the
solid out. The macroinitiator was received after the removal
of solvent.
Synthesis of L-Phenylalanine N-carboxyanhydride (NCA-Phe)
2.2 Instruments
The anhydrous CBZ-phenylalanine (Cbz-Phe) was dissolved
in anhydrous THF at 40 °C with the protection of nitrogen.
Then SOCl2 was distilled into the reaction system and the
mixture was stirred for 4 h. Excess anhydrous hexane was
added into the solution, the mixture was kept at 40 °C for
12 h. White precipitate was obtained after filtration. The
precipitate was dissolved in anhydrous ethyl acetate and
recrystallized with hexane to get needle-like crystals.
1H NMR spectra were performed on a Bruker Avance II
NMR spectrometer at 400 MHz with CDCl3 and DMSO-d6
as solvents. FTIR spectra were recorded on a FTIR PE
Spectrometer. Time of flight mass spectrometry Bruker
Autoflex III was used to determine the molecular weight of
the polymers on the substrate of DHB. Dynamic light scat-
tering (DLS) experiments were performed on a Malvern
Zetasizer Nano ZS at 25 °C. The absorbance of doxorubicin
was detected by fluorescence spectrum. The morphologies
of the particles were observed on scanning electron micros-
copy (JSM-5900LV) and Transmission Electron Microscope
(JEM-100CX). The cellular uptake was observed by confo-
cal laser scanning microscopy (Leica TCP SP5), and
doxorubicin was excited at 488 nm with emissions at 595 nm.
Synthesis of dendritic poly(glutamic acid)-b-polyphenylalanine
copolymers
Dry macroinitiator and L-Phe-NCA with the molar ratio of
1:10 were accurately weighted and added into reaction flask.
After the removal of atmosphere, the flask was purged with
nitrogen. DCM/DMF mixed solvents were added at room
temperature and Product 5 in Scheme 1 was generated after
24 h. The protected OBzl groups were removed in the pres-
ence of Pd/C and hydrogen under 0.8 MPa.
2.3 The synthesis of generation 3 dendritic poly(glutamic
acid)
Synthesis of generation 2 dendritic poly(glutamic acid)
2.5 Determination of critical micelle concentration (CMC)
Boc-Glu-COOH and excess H-Glu (OBzl)-OBzl were dis-
solved in CH2Cl2 with HOBT/EDC in N2 atmosphere. DIEA
Critical micelle concentration of the dendritic block co-

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Xu XH, et al. Sci China Chem February (2011) Vol.54 No.2
polymer was determined by fluorescence using pyrene as
probe. The fluorescence excitation wavelength was fixed at
490 nm, and the fluorescence absorbance values of I338 and
I335 were tested for the calculation of critical micelle con-
centration.
by a Leica TCP SP5 fluorescence scope.
2.8 Cellular uptake of micelles
The cellular uptake experiments in human hepatocellular
carcinoma cells HepG2 were performed using confocal la-
ser scanning microscope (CLSM). The cells were seeded in
35 mm glass culture dishes at a density of 1 × 104 cells/well
and adhered for 24 h. The culture medium was removed.
Free Dox and Dox-loaded micellar solutions (Dox concen-
tration: 10 g/mL) were added together with culture me-
dium. After incubated at 37 °C for 2 h, the culture medium
was carefully removed and the cells were washed with PBS
for three times. CLSM images were observed with inverted
CLSM (Leica TCP SP5, Germany). Dox was excited at
485 nm with emissions at 595 nm.
2.6 In vitro drug release
The dendritic block copolymer and doxorubicin were dis-
solved in methanol. Deionized water was dropwise added
into the solution under ultrasonic condition to prepare drug
loaded micelles. Methanol was removed by reduced pres-
sure. The micelles were dialyzed to remove the free drug at
4 °C for 24 h, the doxorubicin-loaded self-assembled mi-
celles were obtained after freeze-dry.
The doxorubicin-loaded micelles were accurately weighed
and dissolved in organic solvent. According to the standard
absorption curve of free doxorubicin, the drug loading was
calculated by the determination of absorption values at the
fluorescence wavelength of 485 nm.
2.9 In vitro cytotoxicity
Cytotoxicity test was used to evaluate in vitro antitumor
activity of the drug loaded micelles. The cytotoxicity of the
drug loaded micelles was measured by CCK-8 assay kit
using Dox·HCl and Dox as controls. Briefly, HepG2 cells
harvested in a logarithmic growth phase were seeded in
three 96-well plates (plate 1 with a concentration of 1 ×104
cells per well for 12 h test, plate 2 with a concentration of
5 × 103 cells per well for 24 h test, and plate 3 with a con-
centration of 3 × 103 cells per well for 48 h test). After being
incubated for 24 h, the medium was removed and free me-
dium was added with drug loaded micelles. The Dox con-
centrations in the wells were from 5 to 15 g/mL. At the
prescribed time intervals (12, 48 and 72 h), the cells were
washed by PBS solution for three times, and replaced with
fresh culture media, 10 L of CCK-8 kit was added and the
plate was incubated for another 2 h at 37 °C. Finally, the
plates were shaken for 10 min, and the absorbance of the
product was measured at 492 nm by a microplate reader.
The doxorubicin-loaded micelles were weighed and dis-
solved in phosphate buffer (pH 7.4). 1 mL of doxorubicin-
loaded micelle solution was added into dialysis tubes
(MWCO 2000). The tubes were submerged in 25 mL phos-
phate buffer at 37 °C and shaken. At given time intervals,
1 mL of outside buffer solution was taken for analysis, and
fresh medium of 1 mL was supplemented. The absorption at
485 nm was investigated.
2.7 Cytotoxicity test
Cell culture
NIH/3T3 cells (a mouse embryonic fibroblast cell line) and
HepG2 (a human hepatocellular carcinoma cell line) were
cultivated in DMEM (Dulbecco’s modified Eagle’s medium,
Invitrogen) supplemented with 10% (v/v) heat-inactivated
fetal bovine serum (FBS, Hyclone) and 1% (v/v) penicil-
lin-streptomycin solution at 37 °C in 5% CO2.
3 Results and discussion
Cytotoxicity assays
The relative cytotoxicity of micelles was evaluated by a cell
counting kit-8 (CCK-8, Dojindo Laboratories, Kumamoto,
Japan). NIH/3T3 cells were seeded in three 96-well plates
for 24 h before experiment (plate 1 with a cell density of 1×
104 cells per well for 12 h test, plate 2 with a cell density of
5 × 103 cells per well for 24 h test, and plate 3 with a cell
density of 3 × 103 cells per well for 48 h test). The medium
was removed and replaced by the pre-prepared growth me-
dia containing the final micellar concentrations of 150, 100
and 50 g/mL, respectively. After incubated for 12, 24 and
48 h, the cells were washed by PBS buffer and replaced by
fresh media containing 10 L CCK-8. The plates were in-
cubated at 37 °C for an additional 2 h. The absorbance was
measured at the wavelength of 492 nm using a microplate
reader 550 (Bio-Rad). both live and dead cells were imaged
The synthesis of dendritic poly(glutamic acid)-b-polyphenyla-
lanine copolymers is shown in Scheme 1. Generation 3 den-
dritic poly(glutamic acid) was further used as a macroini-
tiator to initiate the ROP of NCA-Phe to produce dendron-
linear block copolymers. The synthesis of monomers and
polymerization were carried out under rigorously anhydrous
conditions to avoid side reactions.
The key products in the synthetic process were analyzed
1
using H NMR (400 MHz). As shown in Figure 1(a), the
integral ratio of NCA-Phe (CDCl3) proved that the product
was obtained. In infrared spectrum, there are the character-
istic absorptions of the NCA-Phe anhydride structure ap-
pearing at the 1856 and 1776 cm1, which are the further
evidence of the NCA-Phe. In Figure 1(b), the peaks from

Xu XH, et al. Sci China Chem February (2011) Vol.54 No.2
329
Scheme 1 Synthesis of dendritic poly(glutamic acid)-polyphenylalanine block copolymers.
1.75 to 2.75 ppm are the protons in the skeleton of G3-Glu
(DMSO-d6 as solvent); the chemical shifts at 5.1 ppm and
the peaks from 7.2 to 7.4 ppm are attributed to the charac-
teristic peaks of benzyl protection. According to Figure 1(c),
the integral ratio and position of the protons indicated that
the dendritic poly(glutamic acid)-b-polyphenylalanine co-
polymers were successfully synthesized. Infrared spectros-
copy showed that after the hydrophilic segment put off after
benzyl protection, the absorption of OH in carboxyl group
from 3550 to 3500 cm1 was significantly enhanced. Mean-
while, the time of flight mass spectrometry results indicated
that the strongest signal at m/z 2409.23 was true of the de-
signed molecular weight.
The self-assembly of the dendritic poly(glutamic acid)-b-
polyphenylalanine copolymer micelles is shown in Scheme
2. The segment of dendritic poly(glutamic acid) was hy-
drophilic due to the large amount of peripheral carboxyl
groups, polyphenylalanine segment was hydrophobic [22].
Hydrophobic doxorubicin was loaded in the core of mi-
celles.

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Xu XH, et al. Sci China Chem February (2011) Vol.54 No.2
Figure 1 1H NMR spectrum of NCA-Phe (a), dendron-G3-Glu (b), dendron-linear block copolymers (c).
Scheme 2 Self-assembly of dendritic poly(glutamic acid)-b-polyphenyla-
lanine copolymers and drug loaded.
Figure 2 Critical micelle concentration of dendron-linear block copolymers.
The block copolymers self-assembled into core-shell
structured micelles. The critical micelle concentration
(CMC) is an important parameter to characterize the micel-
lization. The CMC shows the critical concentration at which
the amphiphilic block copolymers assembled spontaneously.
The CMC of the micelles was tested using pyrene as a fluo-
rescent probe. Figure 2 shows the relationship between the
fluorescence intensity ratios (I338/I335) and the block co-
polymer concentrations. The intersection value of the two trend
lines corresponded to the CMC, which was 19.50 g/mL.
The size distributions of the blank and doxorubicin-
loaded micelles were investigated by dynamic light scatter-
ing (DLS). Figure 3 illustrated the size distributions of both
blank and drug loaded micelles, the concentration of the
micelles was 50 g/mL. The polydispersity indexes of blank
and doxorubicin-loaded micelles were 0.320 and 0.394,
respectively. Interestingly, the mean diameter of the drug
loaded micelles was comparable to that of blank micelles. A
possible reason was that the hydrophobic and - stacking
effects between doxorubicin and polyphenylalanine in drug
loaded micelles compressed the size of the micelles, which
led to it comparable to that of blank micelles.
TEM was employed to investigate the structure of both
blank and drug loaded micelles. As shown in Figure 4(a)
and 4(b), there was little discrepancy in the morphology
between blank and drug loaded micelles, the drug loaded
micelles were more explicit in core-shell structure. The pos-
sible reason was that the doxorubicin enhanced the hydro-
phobic effect of micelles due to the additional conjugation
effect between polyphenylalanine and doxorubicin [22, 23].
Figure 4(c) is the SEM micrograph of blank micelles, the

Xu XH, et al. Sci China Chem February (2011) Vol.54 No.2
331
The release profile of the doxorubicin-loaded micelles is
presented in Figure 5. It was carried out in PBS solution
(pH 7.4) at 37 °C. The sustaining release time of the
doxorubicin was more than 60 h, it indicated an attractive
release performance. Both free doxorubicin hydrochloride
and doxorubicin were used as controls. No release effect
was observed in free doxorubicin, it precipitated in PBS for
the hydrophobicity. In the control of free doxorubicin hy-
drochloride, more than 90% of the drug was released within
2 h. In contrast, however, only less than 20% drugs were
released in the micellar system over the same period, it
clearly showed the favorable behavior in controlled release.
The biocompatibility of the self-assembled micelles was
evaluated in NIH/3T3 cells. The CCK-8 assay was em-
ployed to investigate the cytotoxicity via concentration and
time. As shown in Figure 6, different concentrations of self-
assembled blank micelles exhibited high cell viability at
12, 24 and 48 h, respectively. It indicated that the cell vi-
abilities were not obviously affected by concentration and
time. To some extent, the low concentration of the micelles
seemed to promote the cell proliferation.
Figure 3 Distributions of micellar sizes. (a) Self-assembly of dendron-
linear block copolymer; (b) drug loaded nanoparticles.
The cellular uptake of the micelles was studied by CLSM.
Figure 5 Release profiles of the Dox·HCl , Dox and Dox-loaded micelles
(37 °C, pH 7.4).
Figure 4 (a) TEM micrographs of 100 g/mL self-assembly systems; (b)
TEM micrographs of drug loaded nanoparticles; (c) SEM micrographs of
100 g/mL dendron-linear block copolymers self-assembly systems.
concentration of the block copolymers was 100 g/mL. The
micelles were monodisperse spherical particles with the
sizes ranging from 80 to 100 nm.
Figure 6 The cell viability of 3T3 cells after incubation with blank mi-
celles at 37 °C for 12, 24 and 48 h.

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Xu XH, et al. Sci China Chem February (2011) Vol.54 No.2
HepG2 cells were incubated with drug loaded micelles for
2 h, the concentration of doxorubicin was 10 mg/L. It was
found that free doxorubicin hydrochloride rapidly diffused
into the nucleus of HepG2 cells (Figure 7(a)). In Figure 7(b),
the diffusion of free doxorubicin to the nucleus of HepG2
cells was slow, nearly no doxorubicin was observed in cells.
Figure 7(c) showed that the drug loaded micelles were
mainly distributed in the cytoplasm and some of them were
in nucleus. These results indicated that dendron-linear self-
assembled micelles could be a promising candidate for
doxorubicin delivery via phagocytosis.
The in vitro anticancer effects of the drug-loaded mi-
celles were investigated. The influences of time and con-
centration are considered in Figure 8. In Figure 8(a), the
concentration of drug was 10 g/mL, the viabilities of
HepG2 cells were measured at 12, 24 and 48 h. In the free
doxorubicin hydrochloride sample, more than 60% cells
were killed at 12 h. Less than 30% cells were killed at 48 h
in the free hydrophobic doxorubicin sample. Doxorubi-
cin-loaded micelles revealed optimistic effect in the inhibi-
tion of the proliferation of HepG2 cells. When the drug
concentration was increased to 15 g/mL (Figure 8(b)),
doxorubicin-loaded micelles showed a high anticancer ac-
tivity with the killed tumor cells being as high as 75%.
Figure 9 reveals the images of HepG2 cells incubated
with doxorubicin hydrochloride (Figure 9(a)), free doxoru-
bicin (Figure 9(b)), doxorubicin-loaded micelles (Figure 9(c))
and blank group (Figure 9(d)) for 48 h with the drug con-
centration of 10 g/mL. After the HepG2 cells were incu-
bated in a cell culture plate for 48 h, the HepG2 cells increased
significantly (Figure 9(d)). In the doxorubicin hydrochloride
Figure 7 Confocal microscopic images of HepG2 cells incubated with
free DOX·HCl, DOX and DOX-loaded nanoparticles (DOX concentration
10 mg/L).
Figure 8 In vitro cytotoxicity of HepG2 cells. (a) Time effect; (b) con-
centration effect.

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