Diapositiva 1 - University of Waterloo

Diapositiva 1 - University of Waterloo

Synthesis of Cleavable Amphiphilic Block Copolymers
Deepak Vishnu Dharmangadan, Liying Wang, Qiuying Zhang, Mario Gauthier

*

Institute for Polymer Research, Department of Chemistry, University of Waterloo

Introduction
Amphiphilic block copolymers in solution can self-assemble into different
nanostructures such as micelles, wormlike structures, and polymeric vesicles
(polymersomes).1 One important potential application of amphiphilic block
copolymers is as drug carriers,2,3 to help prevent the deactivation of therapeutic
drugs such as proteins, antibodies and nucleic acids during their travel in the
blood stream.4 Depending on the types of functional groups used and the
external stimuli present, different response mechanisms may come into play
including pH-sensitive, thermosensitive, redox-sensitive, enzyme-sensitive,
photosensitive, and so on.5 Herewith we describe the synthesis of a novel
redox-sensitive initiator for the metal-free ring opening polymerization (ROP) of
lactide. A series of redox-sensitive amphiphilic block copolymers of polylactide
(PLA) with polylysine (PLys) or poly(ethylene glycol) (PEG) segments were also
obtained using the PLA macroinitiator.

b

N

S
S

N

N

f

OH

HS

MeOH, RT
CH3COOH (Cat)

H
N

HS

1

O

e'

O

e

HO

MeOH, RT
CH3COOH (Cat)

f

OH

a

a
O

OH

b'

O
m

a'

O
O

a'

a'

c',d'

e'

O

OH

NH

d

Lactide: Serves as monomer for the hydrophobic block. Polylactide (PLA)based materials are highly biocompatible, biodegradable by enzymes, can
hydrolyze under physiological conditions.

e

S

HO

H2N

N

H
N

S

O

g

N

,

O

8

7

O

f

H
N

O

g

DCM, RT

d

O

g

6

ppm 4

5

S

c

S

a

O

3

e

O

O

c

S

S

m

O

a

O

O

O

O

DCM

H

O

NH

n

f

H2N

+

S

d

O

b

d

e

b

e

H2N

e

O
H
N

c

S

S

m

O

O

a

O

b

O

Why Metal-Free Ring Opening Polymerization?

N

O
N

O

H3C
O

R-OH

Nuc H

CH3

O
O

H3C

R

O
O

8

Normalized intensity
O

d

a

n=17 or 34

n=17 or 34

b
b

d

c

-

6

d

4 ppm 3

5

0.6

*
2

1

0

Polymer

Target Mn
[g/mol]

Mn [g/mol]

PDI

PLA-Boc

2500

2800

1.08

PLA-Boc

5000

5600

1.05

PLA(2.5K)-b-PLys
(1:2)

20300

22500

1.18

0.4

MW Data from NMR

H
0.0

O
10

15

20

Retention time (min)

25

5

4

ppm 3

2

1

0

Synthesized polylactide with low polydispersity index by metal-free
ring-opening polymerization using the novel redox-sensitive initiator

b,e

MW Data from GPC

0.8

5

6

Successfully synthesized a novel redox-sensitive initiator

*

b,e
d

c

a

7

7

Conclusions

b

d e,f
c *

PLA-b-PLys
PLA-Boc
PLA-NH2

0

O

e,f

0.2

n

n

g

f

NH3 Br

O

a

O

8

1.2

Nuc /E

O

n

Ph

c

Allows the synthesis of PLA with low PDI and targeted molecular weights

b

H

n

O

a

1.0

O

O

b

O

H

c

6

S

a

HN

O

Conventional ROP uses metal complexes with organic ligands
Drawbacks: High PDI, metal ions cannot be removed completely, high price

O

H

AcOH, HBr

+

O

a

O

O

S

PEG-OH
PEG-COOH
PEG-b-PLA

O

c

S

H
N

O
m

a

NH3+Br-

Ph

CH3

c

O

0

n

2

Poly(ethylene glycol): Is highly soluble in organic solvents and, therefore,
end-group modifications are relatively easy. PEG is also soluble in water and
has a low intrinsic toxicity making it ideally suited for biological applications.

O

1

H

a

E

2

O

b

O
H
N

O
m

O

Ph

O

Lysine: Serves as monomer for the hydrophilic block. Lysine is an amino
acid that the human body does not produce on its own, but it plays a key role
in the makeup of body proteins.

O

d

HOBt, DIC

TFA, DCM

e

e

R

O
m

NH

f

O

e

O

2

OH

O
O

OH

O

Synthesis of Redox-Sensitive Block Copolymers
(PLA-b-PLys)
O

b

a

O

a'

b'

*

9

Why Lactide, Lysine and Poly(ethylene glycol)?

OH

TEMPO, Iodobenzene diacetate

O

O

The DBU/BA System

H2O:CH3CN (1:1)

H

O

H
N

S

d'

S

c
d *e

1

c
c'

S

b

S

d

O

O

Synthesis of Redox Sensitive Block Copolymers
(PLA-b-PEG)

Synthesis of Novel Redox-Sensitive Initiator

30

Polymer

Target Mn [g/mol]

Measured Mn [g/
mol]

PLA-Boc

2500

2480

PLA-Boc

5000

4500

PLA(2.5K)-b-PLys (1:2)

20300

22100

Mn determined from 1H NMR and GPC are close to the target Mn
Prepared redox sensitive PLA-b-PLyz and PLA-b-PEO block
copolymers with low polydispersity indices

References
1. Li, X.; Chen, G. Polym. Chem. 2015, 6, 14171430. 2. Chen, H.;
He, S. Mol. Pharm. 2015,12, 18851892. 3. Bensaid, F. et al.
Biomacromolecules 2013, 14, 11891198. 4. Ge, Z.; Liu, S. Chem.
Soc. Rev. 2013, 42, 72897325. 5. Tong, R. et al. J. Chem. Soc. Rev.
2014, 43, 69827012. 6. Coady, D. J. et al. Chem. Commun. 2011, 47,
31053107.

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