2009A1883 BL40B2

Drug Incorporation into an Amphiphilic Polymer Micelle Explored with Synchrotron SAXS

aa aa aa aa aa b b

Isamu Akibaa, Naotaka Teradaa, Satoshi Hashidaa, Yusuke Akinoa, Kohei Kamemotoa, Hiroyasu Masunagab,

Kazuo Sakuraia

a b /SPring-8 aThe University of Kitakyushu, bJASRI/SPring-8

-b- ( , - -L- )(PEG-PBLA)(LE540) X (SAXS)

LE540 PBLALE540

LE540

Incorporation of hydrophobic drug (LE540) into a micelle consisting of poly(ethylene glycol)-block--benzyl-L-aspartate) (PEG-PBLA) was explored with synchrotron small-angle X-ray scattering (SAXS)

measurements in vacuo. ecause the diffraction peak attributed to long period of PBLA in hydrophobic core was vanished by adding LE540, the hydrophobic drug is incorporated into hydrophobic core of the PEG-PBLA micelle with core-shell architecture. Analyses of the absolute forward SAXS intensity and by fitting with theoretical model revealed that incorporation of LE540 into the hydrophobic core induced drastic reduction of the scattering-length density, volume expansion of the core and increment of aggregation number without any changes of solvation of hydrophilic PEG chain.

[1]

DDS[2]

DDS

DDS DDS

()

DDS DDS

X(SAXS)

-b- ( , - -L-)(PEG-PBLA) [3]

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LE540Scheme 1 LE540

PEG-PBLA THFTHF

PEG-PBLA/LE540

25mg/ml

1/40

PEG-PBLA LE540 (LLE540) 01.3 3.0 5.8 8.3 wt%

SAXSSAXS SPring-8 BL-40B2

30cm×30cm(RIGAKU R-AXIS VII)

1.8m 0.7 m 1.0S/N

2SAXS 1 SAXS

(I(q) vs. q) I(q) qq

Glatter

[4]

CH3O CH2CH2O CH2 NH COCHNH

CH2COOR

COCH2CHNH

COOR

Hn

ma b3

n=117, m=24, a : b=1 : 3, Degree of benzyl substitution: 82.6%

CH2R = H or

(a) PEG-PBLA

N

N

H3C

COOH

(b) LE540

Scheme 1

Fig. 1 LE540 PEG-PBLAX

4 nm-1

PBLALLE540

LLE540 5.8 wt%

LE540 PBLALE540 PBLA

Fig. 1. MAXS profiles of PEG-PBLA micelles loaded with LE540.

Fig. 2Guinier (ln[I(q)] vs. q2)

LLE540LLE540 3.0 wt%

(I(0)) LLE540LLE540 3.0 wt% I(0)LLE540

GuinierI(q) q [5]

2 2( ) (0)exp( / 3)gI q I q R (1)

I(0) q=0 RgLLE540

3.0 wt% Rg LLE540

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3.0 wt% Rg LLE540I(0)

( )

2 20(0) ( )MI NV

(2)

0

VM NPBLA

LE540LLE540

LLE540 I(0)VM

LLE540 RgI(0) LE540

PEG-PBLA

-6.0

-5.0

-4.0

-6.0

-5.0

-4.0

0.080.060.040.020.00

q2/nm-2

ln[I(

q)]

Fig. 2. Guinier plots of PEG-PBLA micelles loaded with LE540. a) LLE540 = 0, and 1.4 wt%, b) LLE540 = 3.0, 5.8, and 8.3 wt%

2

32

0 3

3 sin( ) cos( )( )

( )( )

3 sin( ) cos( )( )

( )

C c CCC S

M CM

S S SS

S

qR qR qRVV qR

I q NVqR qR qR

qR(3)

C S

( ) RC RS

SAXS

4

GuinierRg

2 22

3 ( )5 ( )C C C S S S S

gC C S S S

V R V RR

V V (4)

(4) (2)2 PBLA

PEGPEG

PEG2

10-7

10-6

10-5

10-4

10-3

10-2

10-1

I(q)/c

m-1

6 7 8 90.1

2 3 4 5 6 7 8 91

2

q/nm-1

Rc = 6.9 nm, Rs = 12.8 nm,

c = 437 e/nm3, s = 339 e/nm

3

/Rs = 0.15

b)

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Fig. 3. SAXS profiles of the PEG-PBLA micelle with LE540 content of 8.3 wt% for PEG-PBLA. Solid lines are theoretical curves of the core-shell model taking the size distribution into account.

Fig.3 LLE540=8.3 wt%SAXS

Table 1Fig. 3 Rc LLE540

Fig. 4Nagg

PBLA c Aagg

PBLA PBLA

x V NNM

MPBLA PBLA PBLAPBLA Vc PBLA

PBLATable 1 ( )

LLE540

PBLA LLE5403.0 5.8 wt%

PBLA

Fig. 4 PBLA

LE540LE540

PBLAPEG-PBLA

Table 1 Characteristic parameters for PEG-PBLA/LE540 micelles resulted from fitting analyses using core-shell sphere model.

LLE540/wt% for

PEG-PBLA RC/nm RS /nm c /cm-2 s /cm-2

0 5.9 12.5 1.38 1011 9.58 1010

1.4 5.9 12.5 1.35 1011 9.58 10103.0 6.1 12.3 1.28 1011 9.55 1010

5.8 6.7 12.5 1.25 1011 9.55 10108.3 6.9 12.5 1.23 1011 9.55 1010

Fig. 4. Plots of Rc and aggregation number of PEG-PBLA for a micelle against LLE540.

1. Zhang, L. F.; Eisenberg, A. Science 1995, 268,1728-1731.

2. Kakizawa, K.; Kataoka, K. Adv. Drug Delivery Rev. 2002, 54, 203-222.

3. Yokoyama, M.; Opanasopit, P.; Okano, T.; Kawano, K.; Maitani, Y. J. Drug Targeting2004, 12, 373-384.

4. Orthaber, D.; Bergmann, A.; Glatter, O. J. Appl. Cryst. 2000, 33, 218-225.

5. Feigin, L. A.; Svergun, D. I. Structure Analysis by Small-angle X-ray and Neutron Scattering; Plenum Press: New York, 1987.

11 SAS2009, Oxford, UK

Polymeric micelle, DDS, SAXS, Core-shell model

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