Preparation of Amphiphilic Copolymers for Covalent Loading of
Paclitaxel for Drug Delivery System
Wulian Chen,a Jin Z. Zhang,b Jianhua Hu,a,d,* Qisang Guo,c and Dong Yang,a,*
a
State Key Laboratory of Molecular Engineering of Polymers, Department of
Macromolecular Science, Fudan University, Shanghai 200433, China
b
Department of Chemistry and Biochemistry, University of California, Santa Cruz,
California 95064, USA
c
Medical Center for Diagnostics & Treat of Cervical Disease, Obstetrics and
Gynecology Hospital, Fudan University, Shanghai 200011, China
d
Key Laboratory of Smart Drug Delivery, Ministry of Education & PLA (Fudan
University), Shanghai 201203, China
CORRESPONDING AUTHOR FOOTNOTE
Prof. Jianhua Hu
Fax: +86-21-64650293
Tel: +86-21-55665280
E-mail: hujh@fudan.edu.cn
Prof. Dong Yang
Fax: +86-21-65640293
Tel: +86-21-65643575
E-mail: yangdong@fudan.edu.cn
Preparation of PEG-Br macroinitiator
PEG-Br macroinitiator was prepared by the esterification of PEG-OH with 2bromoisobutyl bromide according to ref. 48. In a typical procedure, 2-bromoisobutyl
bromide (2.5 mL, 20.0 mmol) in 40 mL of dry toluene was added dropwise to a mixture
of dry toluene (150 mL), PEG-OH (20.0 g, 4.0 mmol) and triethylamine (2.8 mL, 20.0
mmol) in 0 oC. The reaction mixture was stirred at room temperature overnight. After
centrifugation, the filtrates were evaporated to remove most of the solvent and
precipitated in excess diethyl ether. The crude product was dissolved in CH2Cl2 and
washed with saturated NaHCO3 aqueous solution and brine. The organic phase was
then dried with sodium sulfate and precipitated into diethyl ether again. The obtained
white solid, PEG-Br, was dried in vacuo overnight to provide 16.0 g of PEG-Br
macroinitiator. GPC: Mn = 6,000 g/mol, Mw/Mn = 1.02. 1H NMR (δ, ppm,300 MHz,
CDCl3): 1.84 (6H, C(CH3)2Br), 3.37 (3H, OCH3), 3.63 (4H, OCH2CH2).
Because the 2'-hydroxyl group of PTX is significantly reactive, the DIC/DMAPcatalyzed esterification reaction with propiolic acid gave alkynyl-paclitaxel with a high
yield of 83.2%. The chemical structure of alkynl-paclitaxel was characterized by 1H
NMR. As seen from Fig. S1A, the characteristic resonance of the 2'-CH of PTX at 4.80
ppm was completely disappeared after esterification reaction, and a new peak, assigned
to the proton of alkynyl group, appeared at 3.0 ppm. The FT-IR spectra of alkynylpaclitaxel and paclitaxel were shown in Fig. S2. After esterification reaction, the new
and strong peaks appeared at 3336 and 2116 cm-1, indicating the presence of alkynyl
groups.
Fig. S1. 1H NMR spectra recorded in CDCl3 for (A) alkynyl-paclitaxel and (B)
paclitaxel.
Fig. S2. FT-IR spectra of (A) paclitaxel and (B) alkynyl-paclitaxel.
Preparation of 3-Azidopropyl methacrylate (AzPMA)
AzPMA was synthesized according to ref. 48. In a typical procedure, 3-chloropropanol
(6 mL, 71.6 mmol) was added to a mixture of water (50 mL), sodium azide (9.4 g, 144
mmol), and tetrabutylammonium hydrogen sulfate (0.2 g). The mixture was stirred at
80 oC for 24 h, and then at room temperature overnight. The production was extracted
with ether three times, and the organic phase was dried over sodium sulfate. The solvent
was removed on a rotary evaporator, and after vacuum distillation, 3-azidopropanol was
obtained. (yield: 6.6 g, 91.3%). 1H NMR (δ, ppm, 300 MHz, CDCl3): 3.74 (2H,
CH2OH), 3.45 (2H, CH2N3), 2.18 (1H, OH), 1.84 (2H, CCH2C).
A mixture of 3-azidopropanol (6 mL, 64.6 mmol), triethylamine (11.5 mL, 82.5
mmol), hydroquinone (25.5 mg), and methylene chloride (25 mL) was cooled to 0 oC.
Methacryloyl chloride (7.5 mL, 77.6 mmol) was added dropwise over a period of 30
min, and then the mixture was stirred in a cooling bath for 1 h, followed by at room
temperature for 12 h. After reaction, the mixture was diluted with methylene chloride
and extracted successively with an aqueous solution of hydrochloric acid (1/10 v/v),
water, 10 wt% NaOH aqueous solution, and again with water. Then, the solution was
dried over sodium sulfate. The organic solvent was removed in vacuo and light yellow
product was obtained. 1H NMR (δ, ppm, 300 MHz, CDCl3): 6.12 (1H, ＝CH), 5.60
(1H, ＝CH), 4.25 (2H, CH2O), 3.43 (2H, CH2N3), 1.96-1.99 (5H, overlapping CH3C
＝ and CCH2C).
Fig. S3. FT-IR spectra of (A) PEG-b-P(OEGEEMA-co-AzPMA-PTX)1, (B) PEG-bP(OEGEEMA-co-AzPMA-PTX)2, and (C) PEG-b-P(OEGEEMA-co-AzPMA-PTX)3
obtained by three different molar ratio of alkynyl group and azide group (alkynyl:azide
= 1:2, 1:1, 2:1).