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New Material for Delivery
System: The Guerbet Glycosides
Membrane Biophysics:Theory and Experiment
Kavli Institute of Theoretical Physics, CAS, China
7th May 2012 – 1st June 2012
Rauzah Hashim
Chemistry Department
University of Malaya
50603 Kuala Lumpur
Zhoukoudian Peking Man
你吃了吗?
Have you eaten?
Acknowledgement
• Kavli Institute of Theoretical Physics China
• Chinese Academy of Science
• Professor Ou-Yang Zhong-Can
• Professor Zhangchun Tu
• Dr. Ci Zhuang
• Staff of KITPC
My Presentation Plan
• Guerbet Glycoside as Nature-like Glycolipid
• Using Guerbet Glycoside as Delivery System
Guerbet Glycosides as Nature-like Glycolipids
R. Hashim, et al. 2012 Liquid Crystals,39 (1), 1-17
Brooks, et al, 2011, Liquid Crystals, 38(11 12), 1725 1734
N. I. M. Zahid et al. 2012, to be submitted
• University of Malaya
• Dr. T. Heidelberg
• Dr. R. S. D. Hussen
• S. M. Mirzadeh
• N. I. M. Zahid
• Khairul Amani
• AIST
• Prof. H. Minamikawa
• Osaka Sangyo University
• Prof. A. Sugimura
• Imperial College
• Prof. J.M. Seddon
• Dr. N. Brook
• Dr. C. Conn (CSIRO)
May 2012
KITPC 2012 Beijing
Motivation
• Glycolipid as cell membrane material
• Strengthen the cell wall
• Assists in cell processes, for example
– Exo-/endocytosis
– Cell recognition
– Cell transport
http://cellbiology.med.unsw.edu.au/units/images/Cell_membran
e.png
• Understand factors controlling them through
liquid crystal science
KITPC 2012 Beijing
Structural Diversity
O
• Sphingolipids
OH
HN
O
HO
HO
O
HO
• Glycosyl phospho polyprenols
Lipids, 2004. 39(10): p. 933-53
OH
HO
HO
OH
H
O
O
O
O
P
O P O
O
O
HO
• Glyco-glycerolipid
O
OH
O
O
HO
HO
n
O
O
OH
O
• Alkyl-Polyglucosides APGs
OH
HO
HO
O
OH
Current Opinion in Colloid and Interface Science. 2002, 7:
395-409
HO
HO
KITPC 2012 Beijing
Dembitsky, V.M., Lipids, 2004. 39(10): p. 933-53
Nonionic Surfactants: Alkyl Polyglucosides.
Surfactant Science Series. Vol. 91 2000,
O
O
OH
n
O
n
Lessons from Nature…
• Membrane functions relate to sugar lipids
– Membrane stability
– Delivery process
– Exo-/endocytosis
• Cell membrane self-assembly relates to LC
O
OH
Liquid Crystals, 2012, 39, 1-17 (invited article)
May 2012
HO
HO
KITPC 2012 Beijing
O
HO
HN
O
H
OH
Liquid Crystals Phases
Liquid Crystals, 2012, 39, 1-17
Chem Phys Lipids, 2000. 104(1): p. 75-91
Chem Phys Lipids, 2007. 148(1): p. 26-50
OH OH
O
HO
HO
O
OH
HO
HO
O
O
O
O
OH
OH
HO
HO
O
OH
O
O
O
HO
O
O
OH
OH
O
HO
HO
OH
O
H2
C
HC
OH O
HO
HO
C
H2
O
OH
O
OH
May 2012
KITPC 2012 Beijing
HO
HO
O
O
O
O
OH
O
Synthetic Glycolipids
• 1, 2- dialkyl/diacyl-glycerol glycolipids
Eg. Biochim Biophys Acta, 2000. 1509(1-2): p. 203-15.
O
OH
OH
O
O
HO
HO
O
O
OH
O
O
HO
HO
O
O
OH
O
• 1,3-glycosyl-glycerol glycolipids
OH
HO
HO
Eg. Langmuir, 1997. 13(9): p. 2564-2571.
OH
HO
HO
O
O
O
OH
O
O
O
O
• Guerbet glycolipids
Thin Solid Films, 2006. 509(1-2): p. 27-35
Liquid Crystals, 2012, 39, 1-17 (invited article)
OH
HO
HO
O
O
O
HO
OH
HO
HO
May 2012
O
OH
KITPC 2012 Beijing
O
HO
HN
O
H
OH
Objectives
• Materials for Delivery Systems
• To mimic Nature (design approach)
– Chain branching
– Derive from natural resources
• Guerbet alcohols
– Available commercially
HO
Nature-like synthetic alkyl branched chain glycolipids: a review on chemical structure and self-assembly
properties, 2011 Invited Article Liquid Crystals,39 (1), 1-17
May 2012
KITPC 2012 Beijing
Guerbet Sugars
• From Guerbet alcohols (by Marcel Guerbet 1909)
• Guerbet alcohols are industrial products
HO
• 5 chain branching lengths available commercially
• Lower melting/boiling points than corresponding straight
chains alcohols
• Many commercial patents filed using Guerbet compounds
• First reported by Nilsson, F., Söderman, O. and Johansson,
I. Langmuir, 1997
May 2012
KITPC 2012 Beijing
Lewis Acid Glycosidation
Glycosidation Step
Acetylation Step
OH
ROH
CH2Cl2
Ac2 O / H2SO4
OH
HO
HO
BF3Et2O
rt N2 3-4 hr
0-60oC
OAc
O
HO
OH
OAc
OAc
O
OAc
NaOAc/Ac2O
SnCl3
Rt N2 -48 hr
Thin Solid Films, 2006. 509(1-2): p. 27-35
May 2012
OAc
OAc
KITPC 2012 Beijing
OAc
O
OR
O
HO
HO
OR
HO
OAc
NaOMe
OAc
ROH
CH2Cl2
Deacetylation Step
OAc
OAc
OAc
Abs MeOH
O
OAc
OR
HO
HO
OH
O
HO
OR
Guerbet Glycosides
Thin Solid Films, 2006. 509(1-2): p. 27-35
• Thermotropic monosacharrides

Guerbet glycosides afford many non-lamellar phases
Q?
May 2012
KITPC 2012 Beijing
Guerbet Glycosides
Thin Solid Films, 2006. 509(1-2): p. 27-35
• Thermotropic disaccharides
Ia3d
Im3m
Q?
Pn3m
Solid
Pn3m
May 2012
Q?
KITPC 2012 Beijing
Chain Branching Effect
Guebert Alcohols
Sugar
Guebert Sugars
Maltose
Transition Temperature LC- Iso
OH
Glucose
OH
O
HO
HO
HO
HO
O
HO
O
O
HO
OH
OH OH
O
HO
HO
OH
HO
Lactose
OH
O
Chain
Length
O
HO
HO
Galactose
OH
HO
HO
OH OH
HO
OH
HO
OH
O
HO
OH
HO
HO
OH
HO
HO
O
O
HO
HO
O
OH
HO
Vill,V. and Hashim, R., 2002. Current Opinion in Colloid & Interface
Cellobiose
Science, 7(5-6), 395-409.
HO
Thin Solid Films, 2006. 509(1-2): p. 27-35
Effect of C-4 epimer
Liquid Crystals, 2007. 34(2): p. 251–265.
Galactoside
Galactolipid found in plant,
esp.
photosynthesis cell
HO
OH
O
HOHO
HO
Axial C4-OH
Increase transition temp,
due to increase in intrahydrogen bonding
OR
Glucoside
Glucolipid is found mainly in bacteria
Chem Phys Lipids, 2000. 104(1): p. 75-91
Thin Solid Films, 2006. 509(1-2): p. 27-35
Glycosidic (/) Linkage
Important to
examine the
orientation of
anomeric linkage
with respect to
C4-OH
OH
-anomer
O
HO
OR
HO
HO
-dodecylmaltoside
-dodecylmaltoside
OR
-anomer
, Auvray et al Eur. Phys. J. E 4, 489–504 (2001)
Thin Solid Films, 2006. 509(1-2): p. 27-35
Intersugar glycosidic (/) linkage
Cellebioside
Lactoside
OH
OH
OH
O
HO
HO
HO
Maltoside
OH
HO
Extended ribbon
O
OR
O HO
HO
OR
HO
Flexible helix
Kennedy, Carbohydrate Chemistry, Clarendon Press, Oxford, 1988
Thin Solid Films, 2006. 509(1-2): p. 27-35
Epimeric/Anomeric Relationship
Cis- conformation of C4-OH/Glycosidic
Trans-conformation of C4-OH/Glycosidic
Simulation[19] Intra-layer HB Tot. HB Simulation [19]
Intra-layer HB Tot. HB
-Glc-C8
-Gal-C8
Expt
-Glc-C8
-Gal-C8
-Glc-C18
-Gal-C18
Expt.
-Glc-C2C6
-Gal-C2C6
-Glc-C10C14
-Gal-C10C14
2.71
2.43
T(SA- Iso)/ °C
107
95
146
145.9
T(Col- Iso)/ °C
55
67
95
104
3.5
3.85
Ref
[24]
[24]
[16]
[21]
[16]
[21]
-Glc-C8
-Gal-C8
Expt
-Glc-C8
-Gal-C8
-Glc-C18
-Gal-C18
Expt
- Glc-C2C6
- Gal-C2C6
- Glc-C10C14
- Gal-C10C14
Carbohydrate Research, 346, (18), 27 December 2011,2948 2956
2.77
2.9
T(SA- Iso)/ °C
116
127
150
164
T(Col- Iso)/ °C
105
111
118
123
3.8
3.5
Ref
[24]
[24]
present
[21]
present
[21]
v/l (in Å2 ) for straight and branched chains
l: the alkyl chain length at full extension and v: the alkyl chain volume
Straight chain
decyl , C10
v/l
(Å2)
20.9
Isoprenoid
chains
3, 7-dimethyl
octyl C10
v/l
(Å2)
26.0
Guerbet chains
v/l
(Å2)
2-ethylhexyl
C8
27.5
2-propylheptyl
C10
29.6
2-butyloctyl
C12
31.1
dodecyl ,
C12
20.9
tetradecyl,
C14
21.0
Hexadecyl,
C16
21.0
2-pentylnony
C14
32.4
Octadecyl,
C18
21.0
2-hexyldecyl
C16
33.4
2-heptylundecyl
C18
34.2
2-octyldodecyl
C20
34.9
oleyl(9Z)octadecyl
C18.1
23.1
3,7,11trimethyl
dodecyl C15
3,7,11,15tetradecyl
hexyl C20
26.2
26.3
Other highly
branched chain
2,4,6,8tetramethylde
cyl
C14
(Å2)
29.3
G. Milereit et al, JPC, 109, 1599
(2005)
Nature-like synthetic alkyl branched chain glycolipids: a review on chemical structure and self-assembly
KITPC 2012 Beijing
properties, 2011 Invited Article Liquid Crystals,39 (1), 1-17
May 2012
v/l
QII Phases in Excess Water
gyroid, G (Ia3d)
diamond, D (Pn3m)
Schwarz primitive, P (Im3m)
• Infinitely Periodic Minimal Surfaces, IPMS
– Pn3m, Im3m and Ia3d relevant to biological membrane
• Hydration packing density :
gyroid, G (Ia3d) > diamond, D (Pn3m) > Schwarz primitive, P (Im3m)
The Journal of Physical Chemistry B, 1998. 102(37): p. 7262-7271
Philos Transact A Math Phys Eng Sci, 2006. 364(1847): p. 2635-55
May 2012
KITPC 2012 Beijing
LC phases in excess water
Pn3m
Ia3d
-GlcOC10C6
R. Hashim, et al. 2012 Liquid Crystals,39 (1), 1-17
Brooks, et cal, 2011, Liquid Crystals, 38(11 12), 1725 1734
May 2012
KITPC 2012 Beijing
Fd3m
Conclusions
• Review self-assembly properties (dry and
hydrated) for synthetic branched Guerbet
glycosides
• Guerbet chains give better hydrophobicity
• Chain branching support non-lamellar
curved phases
• Chain asymmetry leads to denser packing
hydration
May 2012
KITPC 2012 Beijing
Physico-chemical Characterization of
Branched-chain Glycolipids for Drug Delivery
• University of Malaya
• N. Ahmad
• Dr. H. A. Tajuddin
• CSIC, Barcelona
• Prof. C. Solans,
• Dr. J. Esquena
• Dr. R. Ramsch
Physicochemical Characterization of Natural-like Branched-Chain Glycosides toward
Formation of Hexosomes and Vesicles. Langmuir, 2011. 28(5): p. 2395-2403.
May 2012
KITPC 2012 Beijing
Two Guerbet Glycosides
Chemical structures of (A) 2-HDG and (B) 2-HDM
OPM of the Lawrence experiment
for (A) 2-HDG and (B) 2-HDM (L =
isotropic phase and HII = inverted
hexagonal phase, L = isotropic phase,
Lα = lamellar phase, and Sm A =
smectic A phase of 2-HDM). Water
gradient decreases from left to right.
May 2012
KITPC 2012 Beijing
Pseudo Binary Phase Diagrams
(A) 2-HDG and (B) 2-HDM in water as a
function of temperature: One-phase
region of the isotropic phase (gray) and
two-phase region of an inverted
hexagonal liquid crystalline phase (A) and
lamellar liquid crystalline phase (B)
dispersed in water (white).
May 2012
KITPC 2012 Beijing
d-spacing and lattice spacing
in dry and hydrated from SAXS
Hydrated samples are at 5.0% of surfactants (2- HDG and 2-HDM)
May 2012
KITPC 2012 Beijing
OH
Hexosomes Formation from 2-HDG
HO
HO
O
OH
O
(A) Radius distribution of the hexosome dispersion with 0.50 wt % 2-HDG in
water obtained by a Contin data analysis of dynamic light scattering
results.
(B) Corresponding cryo-TEM micrograph of the hexosome dispersion with
0.50 wt % 2-HDG in water. Hexosomes are visible as dark gray, almost
spherically shaped particles.
May 2012
KITPC 2012 Beijing
OH
Vesicles Formation from 2-HDM
HO
HO
O
OH
OHO
HO
O
OH
DLS
O
Cryo-TEM
8
Average
7
gamma*weight %
6
5
Multi-lamellar
vesicle
4
3
2
1
0
0
200
400
600
800
50 nm
50
nm
1000
R, nm
Radius distribution of 2-HDM vesicles
Multi-lamellar vesicles with high
polydispersity - unstable
May 2012
Cryo-TEM micrograph of a 0.50 wt % 2HDM dispersion. MLVs (<200nm) with
polydisperse nature can be observed.
KITPC 2012 Beijing
Effect of Adding Anionic Surfactant (AOT)
to 2-HDM Vesicles
200 nm.
(A) Radius distribution of a 1.0 wt % 2-HDM/AOT dispersion in water. Two main
populations were observed at 80 and 25 nm.
(B) Cryo-TEM micrograph of a 1.0 wt % 2-HDM/AOT dispersion. Spherical
unilamellar vesicles were observed, indicating that AOT induced the
formation of small and large unilamellar vesicles.
May 2012
KITPC 2012 Beijing
Effect of Adding Anionic Surfactant (SDS)
to 2-HDM Vesicles
200 nm.
(A) Radius distribution of a 1.0 wt % 2-HDM/SDS dispersion in water. The
main population was observed at 40 nm.
(B) Cryo-TEM micrograph of a 1.0 wt % 2-HDM/SDS dispersion. SDS induced
the formation of small unilamellar vesicles. The bar represents
May 2012
KITPC 2012 Beijing
Conclusions
• 2-HDG and 2-HDM are nature-like branched-chain
glycolipids with interesting/rich phase behavior.
• 2-HDG, gives a columnar phase in the dry state, in aqueous
forms a hexagonal liquid crystalline dispersion, hexosome
• 2-HDM, shows a smectic A phase. In water forms a
lamellar liquid crystalline dispersion, which leads to the
formation of MLVs
• Additions of AOT and SDS to 2-HDM dispersion induce
the formation of unilamellar vesicles, with higher stability.
May 2012
KITPC 2012 Beijing
Fundamental Science of
Self-Assembly
Principal Investigator
Prof. Rauzah Hashim
Students
Hairul
Amani
COLLABORATIONS
Prof. G. Luckhurst
Dr. B. A. Timimi
Prof. J. M. Seddon
Prof. V. Vill
Prof. G. Tiddy
H. Zimmerman
Dr. Richard Bryce
Prof. A. Jakli
Prof. Ou-Yang
Zhong-Can
Dr S. Romano
Prof. C. Solans
Dr. M. Khanpour
Prof. H. Takezoe
Dr. J. Esquiner
Prof. M. Iwamoto
Dr. O. K.Abou-Zied
Prof. G. Gurzardyn.
Prof. A. Sugimura
Prof.. H.
Minamikawa
AP. Tan Howe Siang
Dr. Charlotte Conn
May 2012
KITPC 2012 Beijing
THANK YOU
Little Girl from Guizhou
May 2012
KITPC 2012 Beijing
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