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New Material for Delivery System: The Guerbet Glycosides

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1 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

2 你吃了吗? Have you eaten?

3 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

4 My Presentation Plan Guerbet Glycoside as Nature-like Glycolipid
Using Guerbet Glycoside as Delivery System

5 Guerbet Glycosides as Nature-like Glycolipids
R. Hashim, et al Liquid Crystals,39 (1), 1-17  Brooks, et al, 2011, Liquid Crystals, 38(11 12), 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

6 Motivation Glycolipid as cell membrane material
Strengthen the cell wall Assists in cell processes, for example Exo-/endocytosis Cell recognition Cell transport Understand factors controlling them through liquid crystal science KITPC 2012 Beijing

7 Structural Diversity Sphingolipids Glycosyl phospho polyprenols
Glyco-glycerolipid Alkyl-Polyglucosides APGs Lipids, (10): p Nonionic Surfactants: Alkyl Polyglucosides. Surfactant Science Series. Vol ,  Current Opinion in Colloid and Interface Science. 2002, 7: KITPC 2012 Beijing Dembitsky, V.M., Lipids, (10): p

8 Natural Glycolipids Ceramide Ganglioside: GM3 Ganglioside: GM1
Gal GlcNAc Gal Glc Ceramides and sphingolipids are involved in structural organisation of membrane, permeability, cell differentiation and apoptosis Sialic acid Ganglioside: GM1 M. Corti et al. Curr. Op. Coll. Int. Sci. 12 (2007) 148–154. May 2012 KITPC 2012 Beijing

9 ? Membrane Functions ? Membrane Components are chiral?
Membrane materials: Plants /galactolipids, bacteria/ glucolipids animals / phospholipids Biological processes controlled by membrane structure? Viruses, bacteria and/or toxins penetrate membrane? Cellular recognition? Interaction of transmembrane proteins? Can we modify membranes to prevent infections? What is the function of liquid crystals in Nature? Liquid Crystals, Vol. 33, Nos. 11–12, 2006, 1351–1352 May 2012 KITPC 2012 Beijing

10 Synthetic Glycolipids
Alkyl-Polyglucosides APGs Balzer, Nonionic Surfactants: Alkyl Polyglucosides. Surfactant Science Series. Vol , May 2012 KITPC 2012 Beijing

11 Lessons from Nature… Membrane functions relate to sugar lipids
Membrane stability Delivery process Exo-/endocytosis Cell membrane self-assembly relates to LC Liquid Crystals, 2012, 39, (invited article) May 2012 KITPC 2012 Beijing

12 Liquid Crystals Phases
Chem Phys Lipids, (1): p Chem Phys Lipids, (1): p May 2012 KITPC 2012 Beijing

13 Synthetic Glycolipids
1, 2- dialkyl/diacyl-glycerol glycolipids 1,3-glycosyl-glycerol glycolipids Guerbet glycolipids Eg. Biochim Biophys Acta, (1-2): p Eg. Langmuir, (9): p Thin Solid Films, (1-2): p Liquid Crystals, 2012, 39, (invited article) May 2012 KITPC 2012 Beijing

14 Objectives To mimic Nature (design approach)
Materials for Delivery Systems To mimic Nature (design approach) Chain branching Derive from natural resources Guerbet alcohols Available commercially 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

15 Guerbet Sugars From Guerbet alcohols (by Marcel Guerbet 1909)
Guerbet alcohols are industrial products 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

16 Lewis Acid Glycosidation
Glycosidation Step Deacetylation Step Acetylation Step Ac2 O / H2SO4 0-60oC NaOAc/Ac2O ROH CH2Cl2 BF3Et2O rt N2 3-4 hr SnCl3 Rt N2 -48 hr NaOMe Abs MeOH Thin Solid Films, (1-2): p May 2012 KITPC 2012 Beijing

17 Guerbet Glycosides Thermotropic monosacharrides
Thin Solid Films, (1-2): p Thermotropic monosacharrides Guerbet glycosides afford many non-lamellar phases Q ? May 2012 KITPC 2012 Beijing

18 Guerbet Glycosides Thermotropic disaccharides Solid Q ? Q ? Ia3d Im3m
Thin Solid Films, (1-2): p Thermotropic disaccharides Pn3m Im3m Ia3d Q ? Q ? Pn3m Solid May 2012 KITPC 2012 Beijing

19 Chain Branching Effect
Guebert Alcohols Sugar Guebert Sugars Glucose Maltose Galactose Lactose Cellobiose Chain Length Transition Temperature LC- Iso Vill,V. and Hashim, R., Current Opinion in Colloid & Interface Science, 7(5-6), Thin Solid Films, (1-2): p

20 Effect of C-4 epimer Galactoside HO HO Glucoside Axial C4-OH
Liquid Crystals, (2): p. 251–265. HO Galactoside Axial C4-OH Increase transition temp, due to increase in intra-hydrogen bonding Galactolipid found in plant, esp. photosynthesis cell HO Glucoside Glucolipid is found mainly in bacteria Chem Phys Lipids, (1): p Thin Solid Films, (1-2): p

21 Glycosidic (/) Linkage
Important to examine the orientation of anomeric linkage with respect to C4-OH OR -anomer OR -anomer , Auvray et al Eur. Phys. J. E 4, 489–504 (2001) -dodecylmaltoside -dodecylmaltoside Change the pyranose ring and enlarge phase diagrams Thin Solid Films, (1-2): p

22 Intersugar glycosidic (/) linkage
Cellebioside OH Lactoside Extended ribbon Maltoside Flexible helix Kennedy, Carbohydrate Chemistry, Clarendon Press, Oxford, 1988 Thin Solid Films, (1-2): p

23 Epimeric/Anomeric Relationship
Trans-conformation of C4-OH/Glycosidic Cis- conformation of C4-OH/Glycosidic Simulation[19] Intra-layer HB Tot. HB Simulation [19] -Glc-C8 2.71 3.5 -Glc-C8 2.77 3.8 -Gal-C8 2.43 3.85 -Gal-C8 2.9 Expt T(SA- Iso)/ °C Ref 107 116 95 127 -Glc-C18 146 [24] -Glc-C18 150 -Gal-C18 145.9 -Gal-C18 164 Expt. T(Col- Iso)/ °C -Glc-C2C6 55 [16] - Glc-C2C6 105 present -Gal-C2C6 67 [21] - Gal-C2C6 111 -Glc-C10C14 - Glc-C10C14 118 -Gal-C10C14 104 - Gal-C10C14 123 Carbohydrate Research, 346, (18), 27 December 2011,

24 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 v/l (Å2) Isoprenoid chains Guerbet chains Other highly branched chain decyl , C10 20.9 3, 7-dimethyl octyl C10 26.0 2-ethylhexyl C8 27.5 2,4,6,8- tetramethylde cyl C14 29.3 dodecyl , C12 2-propylheptyl C10 29.6 tetradecyl, C14 21.0 3,7,11-trimethyl dodecyl C15 26.2 2-butyloctyl C12 31.1 G. Milereit et al, JPC, 109, (2005) Hexadecyl, C16 2-pentylnony C14 32.4 Octadecyl, C18 3,7,11,15-tetradecyl hexyl C20 26.3 2-hexyldecyl C16 33.4 oleyl(9Z)-octadecyl C18.1 23.1  2-heptylundecyl C18 34.2 2-octyldodecyl C20 34.9 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

25 Chain Hydrophobicity Summary
Straight chains Single isoprenoid chains Double isoprenoid chains Guerbet chains v/l ~ 21 Å2 ~ 26 Å2 54.6 Å2 27.5 – 34.9 Å2 Area ~ cross-sectional area of alkyl chains 5/4 x of straight chain* 2x of single isoprenoid chains Tunable by carbon no. in chain melting point of a dry alcohol 24 °C (C12) < 0 °C (Phyt) < 0 °C (Phyt2) < 0 °C (C20) 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

26 QII Phases in Excess Water
gyroid, G (Ia3d) Schwarz primitive, P (Im3m) diamond, D (Pn3m) 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, (37): p Philos Transact A Math Phys Eng Sci, (1847): p May 2012 KITPC 2012 Beijing

27 LC phases in excess water
Pn3m Ia3d Fd3m -Glc-OC10C6 R. Hashim, et al Liquid Crystals,39 (1), 1-17  Brooks, et cal, 2011, Liquid Crystals, 38(11 12),   May 2012 KITPC 2012 Beijing

28 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

29 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, (5): p May 2012 KITPC 2012 Beijing

30 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

31 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

32 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

33 Hexosomes Formation from 2-HDG
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. 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

34 Multi-lamellar vesicles with high polydispersity - unstable
Vesicles Formation from 2-HDM 50 nm Cryo-TEM Multi-lamellar vesicle Multi-lamellar vesicles with high polydispersity - unstable Radius distribution of 2-HDM vesicles DLS Cryo-TEM micrograph of a 0.50 wt % 2-HDM dispersion. MLVs (<200nm) with polydisperse nature can be observed. May 2012 KITPC 2012 Beijing

35 Effect of Adding Anionic Surfactant (AOT) to 2-HDM Vesicles
200 nm. Radius distribution of a 1.0 wt % 2-HDM/AOT dispersion in water. Two main populations were observed at 80 and 25 nm. 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

36 Effect of Adding Anionic Surfactant (SDS) to 2-HDM Vesicles
200 nm. Radius distribution of a 1.0 wt % 2-HDM/SDS dispersion in water. The main population was observed at 40 nm. 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

37 Nano-emulsion Droplets Size & Stability – Dynamic Light Scattering
2-HDG possesses a higher impact on droplets radius, leading to smallest droplets radius and higher stability compared to Crem EL (reference system) and Crem EL/2-HDM nano-emulsions at storage temperature of 25.0°C 2-HDM does not change significantly the oil droplet radius, but forms stable nano-emulsions Oil droplet radius (nm) of with water/surfactant/MCT oil nano-emulsions as a function of storage time at 25.0 °C. Nano-emulsions of (I) Cremophor® EL, (II) 85/15 Crem EL/2-HDG and (III) 85/15 Crem EL/2-HDM. May 2012 KITPC 2012 Beijing

38 Nano-emulsion Stability – Light Backscattering
Backscattering (%) of (a) Water/Crem EL/MCT oil, (b) Water/Crem EL/2-HDG/MCT oil and (c) Water/Crem EL/2-HDM/MCT oil nano-emulsions as a function of tube height (mm). Data are given for different period of time up to 24 hours. Water content was fixed to 90 wt%, whereas oil/surfactant ratio was 40/60 and Crem EL/Glycolipid ratio was 85/15. ~110 nm ~70 nm The smallest the droplets size, the more droplets are in the sample, hence the higher the backscattering intensity is. (a) (b) (c)

39 Nano-emulsion Droplets Size – Cryo-TEM
(b) Nano-emulsion droplets size images under cryo-TEM of ternary (a) Water/Crem EL/ MCT oil (b) Water/Crem EL/2-HDG/MCT oil and (c) Water/Crem EL/2-HDM/MCT oil at 25.0 °C. May 2012 KITPC 2012 Beijing

40 In-Vitro Release of Ketoprofen from Nano-emulsions
Release profile of KT from the MCT oil solution and from the three nano-emulsions: water/Crem EL/MCT oil, water/Crem EL/2-HDG/MCT oil and water/Crem EL/2-HDM/MCT oil as a function of time at 25.0 ºC. The nano-emulsion composition was 90 wt% water content, whereas O/S and Crem EL/Glycolipid ratios of 40/60 and 85/15 respectively. The release of Ketoprofen was faster from three nano-emulsions compared to a standard MCT oil solution. Ketoprofen in nano-emulsions were efficiently delivered compared to Ketoprofen in oil solution.

41 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

42 Fundamental Science of Self-Assembly
Principal Investigator Prof. Rauzah Hashim Hairul Amani Students

43 COLLABORATIONS Prof. A. Jakli Dr. Charlotte Conn Prof. G. Luckhurst
Dr. B. A. Timimi Prof. J. M. Seddon Prof. G. Tiddy Dr. Richard Bryce Prof. V. Vill H. Zimmerman Prof. A. Jakli Prof. Ou-Yang Zhong-Can Dr S. Romano Prof. C. Solans Dr. J. Esquiner Dr. M. Khanpour Prof. H. Takezoe Prof. M. Iwamoto Prof. A. Sugimura Prof.. H. Minamikawa Dr. O. K.Abou-Zied Prof. G. Gurzardyn. AP. Tan Howe Siang Dr. Charlotte Conn May 2012 KITPC 2012 Beijing

44 THANK YOU Little Girl from Guizhou May 2012 KITPC 2012 Beijing

45 END May 2012 KITPC 2012 Beijing

46 Acknowledgements

47 Acknowledgements


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