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Rauzah Hashim Chemistry Department University of Malaya 50603 Kuala Lumpur New Material for Delivery System: The Guerbet Glycosides Zhoukoudian Peking.

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Presentation on theme: "Rauzah Hashim Chemistry Department University of Malaya 50603 Kuala Lumpur New Material for Delivery System: The Guerbet Glycosides Zhoukoudian Peking."— Presentation transcript:

1 Rauzah Hashim Chemistry Department University of Malaya Kuala Lumpur New Material for Delivery System: The Guerbet Glycosides Zhoukoudian Peking Man Membrane Biophysics:Theory and Experiment Kavli Institute of Theoretical Physics, CAS, China 7 th May 2012 – 1 st June 2012

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 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 2012KITPC 2012 Beijing 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

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 e.png 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 Gal Natural Glycolipids Ganglioside: GM1 Gal GlcNAc Ganglioside: GM3 M. Corti et al. Curr. Op. Coll. Int. Sci. 12 (2007) 148–154. Ceramide May 2012KITPC 2012 Beijing Glc Sialic acid

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? May 2012KITPC 2012 Beijing Liquid Crystals, Vol. 33, Nos. 11–12, 2006, 1351–1352

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

11 Lessons from Nature… Membrane functions relate to sugar lipids – Membrane stability – Delivery process – Exo-/endocytosis Cell membrane self-assembly relates to LC May 2012KITPC 2012 Beijing Liquid Crystals, 2012, 39, 1-17 (invited article)

12 Liquid Crystals Phases May 2012 KITPC 2012 Beijing Chem Phys Lipids, (1): p Chem Phys Lipids, (1): p Liquid Crystals, 2012, 39, 1-17

13 Synthetic Glycolipids 1, 2- dialkyl/diacyl-glycerol glycolipids 1,3-glycosyl-glycerol glycolipids Guerbet glycolipids May 2012KITPC 2012 Beijing Eg. Biochim Biophys Acta, (1-2): p Eg. Langmuir, (9): p Thin Solid Films, (1-2): p Liquid Crystals, 2012, 39, 1-17 (invited article)

14 Objectives Materials for Delivery Systems Nature To mimic Nature (design approach) – Chain branching – Derive from natural resources Guerbet alcohols – Available commercially May 2012KITPC 2012 Beijing 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

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 2012KITPC 2012 Beijing

16 Lewis Acid Glycosidation May 2012KITPC 2012 Beijing Acetylation Step Glycosidation StepDeacetylation Step Ac 2 O / H 2 SO o C NaOAc/Ac 2 O ROH CH 2 Cl 2 BF 3 Et 2 O rt N hr ROH CH 2 Cl 2 SnCl 3 Rt N hr NaOMe Abs MeOH Thin Solid Films, (1-2): p

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

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

19 Glucose Maltose Galactose Lactose Cellobiose Chain Branching Effect Guebert Alcohols Sugar Guebert Sugars 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 HO Glucoside HO Galactoside Galactolipid found in plant, esp. photosynthesis cell Glucolipid is found mainly in bacteria Axial C4-OH Increase transition temp, due to increase in intra- hydrogen bonding Thin Solid Films, (1-2): p Chem Phys Lipids, (1): p Liquid Crystals, (2): p. 251–265.

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

22 Intersugar glycosidic (  /  ) linkage Cellebioside OH Lactoside Maltoside Flexible helix Extended ribbon 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]19Intra-layer HBTot. HB Simulation [19]19Intra-layer HBTot. HB  -Glc-C  -Glc-C  -Gal-C  -Gal-C ExptT(S A - Iso)/ °CRefExptT(S A - Iso)/ °CRef  -Glc-C8 107  -Glc-C8 116  -Gal-C8 95  -Gal-C8 127  -Glc-C18 146[24]  -Glc-C18 150[24]  -Gal-C [24]  -Gal-C18 164[24] Expt.T(Col- Iso)/ °CExpt T(Col- Iso)/ °C  -Glc-C2C6 55[16]  - Glc-C2C6 105present  -Gal-C2C6 67[21]  - Gal-C2C6 111[21]  -Glc-C10C14 95[16]  - Glc-C10C14 118present  -Gal-C10C14 104[21]  - Gal-C10C14 123[21] Carbohydrate Research, 346, (18), 27 December 2011,

24 v/l (in Å 2 ) for straight and branched chains May 2012KITPC 2012 Beijing l: the alkyl chain length at full extension and v: the alkyl chain volume Straight chain v/l (Å 2 ) Isoprenoid chains v/l (Å 2 ) Guerbet chains v/l (Å 2 ) Other highly branched chain v/l (Å 2 ) decyl, C , 7-dimethyl octyl C ethylhexyl C ,4,6,8- tetramethylde cyl C dodecyl, C propylheptyl C tetradecyl, C ,7,11- trimethyl dodecyl C butyloctyl C G. Milereit et al, JPC, 109, 1599 (2005) Hexadecyl, C pentylnony C Octadecyl, C ,7,11,15- tetradecyl hexyl C hexyldecyl C oleyl(9Z)- octadecyl C heptylundecyl C octyldodecyl C 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

25 Chain Hydrophobicity Summary May 2012KITPC 2012 Beijing Straight chains Single isoprenoid chains Double isoprenoid chains Guerbet chains v/lv/l ~ 21 Å 2 ~ 26 Å Å – 34.9 Å 2 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 (Phyt 2 ) < 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

26 Q II Phases in Excess Water 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) May 2012KITPC 2012 Beijing 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

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

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 2012KITPC 2012 Beijing

29 Physico-chemical Characterization of Branched-chain Glycolipids for Drug Delivery Physicochemical Characterization of Natural-like Branched-Chain Glycosides toward Formation of Hexosomes and Vesicles. Langmuir, (5): p University of Malaya N. Ahmad Dr. H. A. Tajuddin CSIC, Barcelona Prof. C. Solans, Dr. J. Esquena Dr. R. Ramsch May 2012KITPC 2012 Beijing

30 Two Guerbet Glycosides May 2012KITPC 2012 Beijing 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 H II = 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.

31 Pseudo Binary Phase Diagrams May 2012KITPC 2012 Beijing (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).

32 d-spacing and lattice spacing in dry and hydrated from SAXS May 2012KITPC 2012 Beijing Hydrated samples are at 5.0% of surfactants (2- HDG and 2-HDM)

33 Hexosomes Formation from 2-HDG May 2012KITPC 2012 Beijing (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.

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

35 Effect of Adding Anionic Surfactant (AOT) to 2-HDM Vesicles May 2012KITPC 2012 Beijing (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. 200 nm.

36 Effect of Adding Anionic Surfactant (SDS) to 2-HDM Vesicles May 2012KITPC 2012 Beijing (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 200 nm.

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 2012KITPC 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 ~110 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 (c) (a) (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 2012KITPC 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 2012KITPC 2012 Beijing

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

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

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

45 END May 2012KITPC 2012 Beijing

46 Acknowledgements

47


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