Saint-Petersburg State Chemical-Pharmaceutical Academy Biopolymeric systems of targeted delivery of taxanes for anticancer therapy Ph. D student Golyshev A. A. Supervisor Ph. D, Skorik Y. A.
My supervisor and me (www. skorik. pro) Anton Golyshev (27. 12. 1989) Yury Skorik (11. 10. 1973) MS in Chemistry 2012 Chemistry Ph. D in Chemistry 1998 Urals State University (Ekaterinburg, Department of the Saint. Russian Federation) Petersburg State University MS in Chemistry 1995 Urals (Organic Chemistry) State University (Ekaterinburg, School: Academic gymnasium of Russian Federation) Saint-Petersburg state university yury_skorik@mail. ru anton_golishev@mail. ru
My home Russian Federation (Russia) 6700 km 10 h flight India Area 17 mln. km 2 3, 3 mln. km 2 Population 144 mln. 1200 mln. Population density 8. 4/km 2 Towns with more than 1 mln. people 15 379. 6/km 2 46 3
Education systems Russia (from USSR) Ph. D student Russia (modern) India 3 -5 3 -5 2 (master) 4 (bachelor) University 5 (specialist) 2 School 10 Kindergarten Start 10 maximum 5 2 minimum 2 years old minimum 3 years old 4
AG, SPb. SU Academic gymnasium of Saint -Petersburg state university (since 1963). Students 500 Main building of the Saint -Petersburg State University (since 1730) Students ˃ 30. 000 Staff ˃ 13. 000 5
Chemical Faculty of SPb. SU Students 2000 Research Areas: Analytical Methods Biomedical Chemistry Chemical sensors Colloid nanosystems Material science, nanotechnology & nanomaterials Organic Synthesis Organometallic & Coordination Chemistry Simulation & Modeling of Nanostructures 6
University diploma work Characteristycal chromatographic and electrophoretic steroid hormones profiles as an additional diagnostic criteria of endocrinal pathologies» « Methods: -HPLS (high performance liquid chromatography) -HPTLC (high performance thin layer chromatography) -capillary electrophoresis 7
Micellar electrokinetic chromatography Steroid hormones profile of healthy patient Steroid hormones profile of a patient with Icing-Cushing disease 8
Mathematical modeling of samples analysis MC 1 -MC 2 MC 3 -MC 4 ps – diseased patients ns – healthy patience 9
Ph. D student 10
Institute of macromolecular compounds (since 1948) Saint-Petersburg State Chemical. Pharmaceutical Academy (since 1919) Students 2200 11
Taxanes Docetaxel (DTX): R 1=-COOC(CH 3)3; R 2=H Paclitaxel (PTX): R 1=-COCC 6 H 5; R 2=-COCH 3 Táxus baccáta High anticancer activity Water insoluble Widespread drug High general toxicity 12
Chitosan Crab chitosan: -80% of particles have a size 0, 125 -0, 25 mm -molecular mass 80 k. Da (according to viscosimetry) -degree of deacetylation 93% (according to 1 H-NMR, elemental analysis). 13
Synthesis strategy Noncovalent bonding (self assembled nanoparticles) Covalent bonding (conjugates) 14
Main synthetic idea For both strategies we should synthesize separately 1) water-soluble chitosan derivatives 2) water-insoluble chitosan derivatives (containing model substitution group for self assembled nanoparticles and conjugated PTX or DTX for conjugates) 3) combine two approaches in one compound 15
Water-soluble compounds glutaric anhydride (GA) succinic anhydride (SA) -nontoxic (tricarbon acid cycle) -easy to synthesize in different reaction conditions -GC is almost unknown substance 16
Water-soluble compounds Homogeneous Heterogeneous (1% acetic acid solution) (chitosan/water dispersion) With a pre-activation of chitosan (stirring for 7 days in water) Without a pre-activation of chitosan For all: -anhydride amount (1: 1, 1: 3, 1: 5 per mole content of «N» from elemental analysis) -temperature (20, 50, 80 C) -time (0, 5 -7 hours) 17
Results of water-soluble compounds synthesis 1) GC with DS 14 -79% (per all «N» mole content) and SC with DS 11 -72% was synthesized. 2) DS of chitosan increases with increasing of amount of anhydride in both heterogeneous and homogeneous conditions. 3) Heterogeneous synthesis provides a product with higher DS (about 20% higher) as compared with homogeneous synthesis. But this synthesizes gives not so equally samples then homogeneous synthesizes. 4) DS decreases with increasing of temperature. We suppose that this effect related with different temperature dependence of the reaction of primary interest and of the side reaction (hydrolysis of anhydride). 5) Pre-activation of chitosan was not as effective as expected — 18 the DS is roughly the same in both cases.
Water-insoluble compounds -cholesterol is a nontoxic substance -using the same anhydrides 19
Water-insoluble compounds -Cholesterol + SA -DTX+SA -Cholesterol + GA -DTX+GA -PTX+SA -PTX+GA For all: -anhydride amount (1: 1, 1: 3, 1: 5, 1: 10 mole ratio) -time (NMR measurements 1 -170 hours) 20
Results of water-insoluble compounds synthesis 1) NMR-kinetic measurements for all cases 2) Reaction conditions (anhydride amount, time) to achieve 100% substitution for all substances 3) Monosubstitution for DTX+SC and DTX+GC Docetaxel (DTX): R 1=-COOC(CH 3)3; R 2=H Paclitaxel (PTX): R 1=-COCC 6 H 5; R 2=-COCH 3 21
Combination of two parts 22
Work Plan TASK 1: PREPARATION &CHARACTERIZATIONS OF NANOPARTICLES (3 months) -Preparation of carrier (SC/GC nanoparticles), size and zeta potential measurements -Loading of taxanes (PTX/DTX), size and zeta potential measurements -Drug encapsulation, loading and release analysis from nanoparticles -Blood compatibility studies (Hemolysis assay) TASK 2: IN VITRO CELL CULTURE STUDIES (3 months) -In vitro toxicity studies two cancer cell lines -Cellular uptake studies using microscopic techniques -Flowcytometric assays TASK 3: MANUSCRIPT PREPARATION 23
Thank you for your attention! 24
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