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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