click chemistry for synthesis of chitosan nanocarriers and biomaterials ingólfur magnússon 12. may...
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Click chemistry for synthesis of chitosan nanocarriers and biomaterials
Ingólfur Magnússon12. May 2014
Introduction of PhD work
• The aim is to develop click chemistry based procedures for versitle, efficient and chemoselective synthesis of chitosan derivatives
• TBDMS chitosan will be used to synthesize chitosan derivatives with substituents like terminal alkyne, azide and maleimide.– These are further modified by click chemistry– Reducing end functionalization– Grafting in polymers backbone
• Chitosan derivatives will be used in casting films (membranes)– With different N-acetylation– With photo-crosslinking agents– In collaboration with the blood bank
My PhD committee
• Margrét Þorsteinsdóttir, University of Iceland• Ólafur Eysteinn Sigurjónsson, Univeristy of
Reykjavik, Blood Bank of Iceland• Knud J. Jensen, University of Denmark• Stefán Jónsson, Actavis
PhD requirements
• Publish 3 articles• Take minimum 24 ECTS units in courses at the
University of Iceland• Teach at least 200 hours during the study period• Status:– Started February 2012– I have finished both the teaching and 24 ECTS units– No publication yet, that work is in process– Aim to finish before December 2015
Conferences
• CLINAM-European Foundation for Clinical Nanomedicine– Basel, Switzerland, 23-26th of June 2013
• EFNÍS- The Icelandic Chemical Society– Reykjavík, Iceland, 28th of October 2013
• Conference about researches in life and health science-University of Iceland– Reykjavík, Iceland, 3rd of January
• Translational nanomedicine-University of Angers– Angers, France, 27-29th of August 2014
Some of the work I have been doing
Maleimide chitosan
N
OH
O
O
OON
Cl
O
O
OON
OH
O
OO
O
HNO
O
N
O
O
O
O
TBDMS
TBDMS
O
O
HNO
O
N
O
O
O
O
TBDMS
TBDMS
O
NH2
O
O
O
TBDMS
TBDMS
O
N
O
O
Cl
O
HNO
O
N
O
O
OH
HO
X
Chitosan with photo crosslinking agents
OO
O
OH
HONH3
OH
NH
O
HO
O
Cl
n m
OO
O
OH
HONH3
OH
NH
O
HO
O
n mS
O
O
MeO
OO
O
OTBDMS
TBDMSONH2
OTBDMS
NH
O
TBDMSO
O
n m
1, 2
3, 4
OO
O
OH
HONH2
OH
NH
O
HO
O
n m
5, 6
MeOH /HCl
O
NHO
O
O
TBDMS
TBDMS
O
O
NHO
OH
HO
O
O
NHO
O
O
TBDMS
TBDMS
O
O
NHO
OH
HO
O
N3
N3
7 8
9 10
O
NHO
O
O
TBDMS
TBDMS
O
O
NHO
OH
HO
O
11 12
Project work plan
Article 1
Chitosan maleimde article
• Focus on publishing article on the synthesis part
• Last step in the synthesis has been problematic because of hydrolysis of the maleimide group at acidic conditions
• Develop method to deprotect the TBDMS groups with low degradation/changing of the maleimide group
Chitosan maleimide (article 1)
• Degree of substitution of maleimide will be 1%, 5% and 10 %• Click reaction will be done with 7-mercapto-4-methylcoumarin (fluorescence agent)• If time allows, maleimide grafted chitosan might be reacted to proteins/peptides and
other fluorescence agents – and biological data will then be obtained from coworkers• Publication in journal like: Carbohydrate Polymers, European Polymer Journal,
Macromolecules etc.
O
O
N
O
HO
O
NH2
OH
HO
HO
DS 90 %
O
O
O
S
(H2C)5
NOO
Main results in Chitosan Maleimide article 1
• Synthesis and characterization data– NMR, IR, Fluorescence, Mass, GPC etc.
• Microscopy studies• Nanoparticle formation• Chitosan maleimide-sulfhydryl click reaction
with proteins• Focus on the synthesis part in this article
Article 2
Photo crosslinking reagents – article 2
Compound DS (%) DS (%) DS (%) DS (%)
A 1 2 5 10-15
B 1 2 5 10-15
C 1 2 5 10-15
Cl
O
Cl
O
Cl
O
N3methacryloyl chloride cinnamoyl chloride4-azidobenzoyl chloride
A B C
• The casting ability to form membranes of these chitosan derivatives will be investigated• Photoactivation of the membranes and the effects of that on their properties • Cell culture studies in collaboration with the blood bank (Óli Eysteins)• Publication in journals like: Biomaterials, Journal of Natural Products, Journal of Medicinal
Chemistry etc.
Results included in Article 2(Photo crosslinking chitosan membranes)
• Synthesis and characterization data– NMR, IR, Mass, GPC etc.
• Casting in membranes• Effects of photoactivation on membranes
properties• Coating implants with chitosan derivatives• Cell studies in colloboration with the blood bank– Effects of chitosan on osteogenic differentiation– Microscopic studies
Article 3
Sulfhydryl derivatives of Chitosan
• Recently started this work• Click reactions with maleimide• Casting membranes
O
HNO
O
O
TBDMS
TBDMS
O
HNO
O
O
TBDMS
TBDMS
Ethanol
SK
O O
HNO
OH
HO
O
HNO
OH
HO
MeOH
HCl
Br
O O
S
O
S
O
O
SH
O
NaOMe
MeOH
Sulfhydryl derivatives of Chitosan
• Properties that will be investigated– Muchoadesive– Adsorption– Toxicity– Microscopy
• Chitosan sulfhydryl membranes– Cell studies in collabaration with the blood bank
• Publication in journals like: Polymer Chemistry European Polymer journal , Journal of Sulfur Chemistry and etc.
Results included in Article 3 (Sulfhydryl chitosan)
• Synthesis and characterization data– NMR, IR, Mass, GPC etc.
• Click reactions with fluorescent maleimide• Casting in membranes• Membranes properties– Adsorption– Muchoadesive
• Cell studies
Article 4
Project in Denmark
• Focus on reducing end functionalization of chitosan– Fluorescent end-labeling of chitosan
• Grafting peptide or protein in chitosan backbone with click chemistry
• Nano particle formation (DLS)
Target molecules for Denmark
OHO
HO
OH
NH3
NO
LinkerO
N
O
HO
O
NH2
OH
HO
HO
N
N
N
DS 10 %
DS 90 %
N N
N
A
OHO
HO
OH
NH3
NO
Linker N
SO
O
A
O
N
O
HO
O
NH2
OH
HO
HO
N
N
N
DS 10 %
DS 90 %
Denmark
• It is the aim that the work in Denmark will result in article• I will focus on the synthesis and characterization of
these compounds.• This work will be published in synthetic chemistry
journal.• All biological test will be done in collaboration with
coworkers (Blood Bank and PCI Biotech)• Publication in journals like: Advances in Polymer Science,
Pharmaceutical Research, International Journal of Nanomedicine and etc.
Results to be included in article 4 (Denmark)
• Synthesis and characterization data– NMR, IR, Fluorescence, Mass, GPC etc.
• Report peptide synthesis of chitosan – Click chemistry
• Oxime synthesis on chitosan reducing end• Microscopy studies• Nanoparticle formation
Thank you for listening
• Any questions?
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