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Potential Improvement inPhotodynamic Therapy for Cancer
Charles Abrams
January 25, 2002
Senior Seminar - Journal ClubBeloit College
Cyclodextrin Dimers as Cleavable Carriers of Photodynamic Sensitizers
Baugh, S.D.P., Breslow, R.*, et.al.
J. Am. Chem. Soc. 2001, 123, 12488.
What is Photodynamic Therapy ?
What is Photodynamic Therapy ?
Human figure from A.D.A.M. Inside Story, A.D.A.M. Software, Atlanta, 1994.
What is Photodynamic Therapy ?
National Cancer Institute website, cis.nci.nih.gov/fact/7_7.htm accessed 1/17/02
What is Photodynamic Therapy ?
visible laser
National Cancer Institute website, cis.nci.nih.gov/fact/7_7.htm accessed 1/17/02
What is Photodynamic Therapy ?
visible laser
National Cancer Institute website, cis.nci.nih.gov/fact/7_7.htm accessed 1/17/02
What is Photodynamic Therapy ?
National Cancer Institute website, cis.nci.nih.gov/fact/7_7.htm accessed 1/17/02
What is Photodynamic Therapy ?
This sucks!
National Cancer Institute website, cis.nci.nih.gov/fact/7_7.htm accessed 1/17/02
Patient mustavoid sunlight!
New Idea: Encapsulate Photosensitizers
Möser, J.G.; Ruebner, A.; et.al. in Proc. 8th Internat. Symp. on Cyclodextrins; Szetli, J.Ed. Kluwer: Boston 1996; pp71-76
New Idea: Encapsulate Photosensitizers
Möser, J.G.; Ruebner, A.; et.al. in Proc. 8th Internat. Symp. on Cyclodextrins; Szetli, J.Ed. Kluwer: Boston 1996; pp71-76
New Idea: Encapsulate Photosensitizers
visible laser
Möser, J.G.; Ruebner, A.; et.al. in Proc. 8th Internat. Symp. on Cyclodextrins; Szetli, J.Ed. Kluwer: Boston 1996; pp71-76
New Idea: Encapsulate Photosensitizers
visible laser
Möser, J.G.; Ruebner, A.; et.al. in Proc. 8th Internat. Symp. on Cyclodextrins; Szetli, J.Ed. Kluwer: Boston 1996; pp71-76
New Idea: Encapsulate Photosensitizers
visible laser
Möser, J.G.; Ruebner, A.; et.al. in Proc. 8th Internat. Symp. on Cyclodextrins; Szetli, J.Ed. Kluwer: Boston 1996; pp71-76
New Idea: Encapsulate Photosensitizers
visible laser
Möser, J.G.; Ruebner, A.; et.al. in Proc. 8th Internat. Symp. on Cyclodextrins; Szetli, J.Ed. Kluwer: Boston 1996; pp71-76
New Idea: Encapsulate Photosensitizers
visible laser
Möser, J.G.; Ruebner, A.; et.al. in Proc. 8th Internat. Symp. on Cyclodextrins; Szetli, J.Ed. Kluwer: Boston 1996; pp71-76
New Idea: Encapsulate Photosensitizers
visible laser
Möser, J.G.; Ruebner, A.; et.al. in Proc. 8th Internat. Symp. on Cyclodextrins; Szetli, J.Ed. Kluwer: Boston 1996; pp71-76
New Idea: Encapsulate Photosensitizers
Möser, J.G.; Ruebner, A.; et.al. in Proc. 8th Internat. Symp. on Cyclodextrins; Szetli, J.Ed. Kluwer: Boston 1996; pp71-76
New Idea: Encapsulate Photosensitizers
Möser, J.G.; Ruebner, A.; et.al. in Proc. 8th Internat. Symp. on Cyclodextrins; Szetli, J.Ed. Kluwer: Boston 1996; pp71-76
Encapsulate withcyclodextrin dimers
which havephotocleavable linkers
Möser, J.G.; Ruebner, A.; et.al. in Proc. 8th Internat. Symp. on Cyclodextrins; Szetli, J.Ed. Kluwer: Boston 1996; pp71-76
What Is Cyclodextrin?
OHO
HO OH
OH
OH
What Is Cyclodextrin?
OHO
HO OH
O
OH
O
HO OH
OH
OH
What Is Cyclodextrin?
O
HO OH
OH
OH
OHO
HO OH
O
OH
O
HO OH
O
OH
What Is Cyclodextrin?
O
HO OH
OH
OH
OHO
HO OH
O
OH
O
HO OH
O
OH
5
What Is Cyclodextrin?
O
HO OH
O
OH
OO
HO OH
O
OH
O
HO OH
O
OH
5
What Is Cyclodextrin?
Cyclodextrin 3D structure from Chem3D
What Is Cyclodextrin?
Why a Cyclodextrin Dimer?
Möser, J.G.; Ruebner, A.; et.al. in Proc. 8th Internat. Symp. on Cyclodextrins; Szetli, J.Ed. Kluwer: Boston 1996; pp71-76
Why a Cyclodextrin Dimer?
Möser, J.G.; Ruebner, A.; et.al. in Proc. 8th Internat. Symp. on Cyclodextrins; Szetli, J.Ed. Kluwer: Boston 1996; pp71-76
Why a Cyclodextrin Dimer?
Möser, J.G.; Ruebner, A.; et.al. in Proc. 8th Internat. Symp. on Cyclodextrins; Szetli, J.Ed. Kluwer: Boston 1996; pp71-76
Why a Cyclodextrin Dimer?
Möser, J.G.; Ruebner, A.; et.al. in Proc. 8th Internat. Symp. on Cyclodextrins; Szetli, J.Ed. Kluwer: Boston 1996; pp71-76
What Is The Linker?
Ruebner, A., Breslow, R., et. al. PNAS 1999, 14692.
What Is The Linker?
Ruebner, A., Breslow, R., et. al. PNAS 1999, 14692.
S
HN
S
O
S
HN
S
O
S
HN
S
O
S
HN
S
O
S
HN
S
O
S
HN
S
O
OO
O O
O2, light, sensitizer
Spontaneous
What Is The Linker?
Ruebner, A., Breslow, R., et. al. PNAS 1999, 14692.
S
HN
S
O
S
HN
S
O
S
HN
S
O
S
HN
S
O
S
HN
S
O
S
HN
S
O
OO
O O
O2, light, sensitizer
Spontaneous
What Is The Linker?
Ruebner, A., Breslow, R., et. al. PNAS 1999, 14692.
S
HN
S
O
S
HN
S
O
S
HN
S
O
S
HN
S
O
S
HN
S
O
S
HN
S
O
OO
O O
O2, light, sensitizer
Spontaneous
Dimer Structures
Linker Design
Baugh, S.D.P, Breslow, R., et. al. JACS 2001, 123, 12488.
SS S
S
S SNH
NH
S
HN
S
O
S
HN
S
O
OO
S SNH
NH
OO
22 Å
20 Å
18 Å
16 Å
Photosensitizers
N
N
N
NN
N
NN
Zn
phthalocyanines
Baugh, S.D.P, Breslow, R., et. al. JACS 2001, 123, 12488.
Photosensitizersphthalocyanines
C
C
N
N
N
N
N
NN
N
NN
4
1) Li, pentanol 140 °C, 2 hr2) Zn(OAc)2, K2CO3 DMF, 20 h
60% yield!
Zn
Baugh, S.D.P, Breslow, R., et. al. JACS 2001, 123, 12488. Supplementary material, p. S14
Photosensitizers
Baugh, S.D.P, Breslow, R., et. al. JACS 2001, 123, 12488.
N
NO N
N
O
N
NON
N
O
HO2C
Zn
Photosensitizers
Baugh, S.D.P, Breslow, R., et. al. JACS 2001, 123, 12488.
N
NO N
N
O
N
NON
N
O
HO2C
Zn
Bindinggroups
O
O
O
O
O
O
O
Photosensitizers
Baugh, S.D.P, Breslow, R., et. al. JACS 2001, 123, 12488.
N
NO N
N
O
N
NON
N
O
HO2C
Zn
25 Å
23 Å
17 Å
23 Å
Bindinggroups
O
O
O
O
O
O
O
Photosensitizers
Baugh, S.D.P, Breslow, R., et. al. JACS 2001, 123, 12488.
N
NO N
N
O
N
NON
N
O
HO2C
Zn
Solubilizinggroups
CO2H
SO3H
Bindinggroups
O
O
O
O
O
O
O
Binding Study
S
HN
S
OS
HN
S
O
SO3H O 20.0
S SNH
NH
OO
O
O 6.05
S SNH
NH
OO
O
O
19.4
O
O 17.6
SS S
S
O
O13.0
7
6
5.3
12
17
15
18
14
15
2113
SO3H
SO3H
SO3H
SO3H
18
Binding Constant
(x 105 M-1)Time for 50%cleavage (min)
Baugh, S.D.P, Breslow, R., et. al. JACS 2001, 123, 12488.
S
HN
S
OS
HN
S
O
SO3H O 20.0
S SNH
NH
OO
O
O 6.05
S SNH
NH
OO
O
O
19.4
O
O 17.6
SS S
S
O
O13.0
7
6
5.3
12
17
15
18
14
15
2113
SO3H
SO3H
SO3H
SO3H
18
Binding Constant
(x 105 M-1)Time for 50%cleavage (min)
Baugh, S.D.P, Breslow, R., et. al. JACS 2001, 123, 12488.
S
HN
S
OS
HN
S
O
SO3H O 20.0
S SNH
NH
OO
O
O 6.05
S SNH
NH
OO
O
O
19.4
O
O 17.6
SS S
S
O
O13.0
7
6
5.3
12
17
15
18
14
15
2113
SO3H
SO3H
SO3H
SO3H
18
Binding Constant
(x 105 M-1)Time for 50%cleavage (min)
Baugh, S.D.P, Breslow, R., et. al. JACS 2001, 123, 12488.
S
HN
S
OS
HN
S
O
SO3H O 20.0
S SNH
NH
OO
O
O 6.05
S SNH
NH
OO
O
O
19.4
O
O 17.6
SS S
S
O
O13.0
7
6
5.3
12
17
15
18
14
15
2113
SO3H
SO3H
SO3H
SO3H
18
Binding Constant
(x 105 M-1)Time for 50%cleavage (min)
Baugh, S.D.P, Breslow, R., et. al. JACS 2001, 123, 12488.
S
HN
S
OS
HN
S
O
SO3H O 20.0
S SNH
NH
OO
O
O 6.05
S SNH
NH
OO
O
O
19.4
O
O 17.6
SS S
S
O
O13.0
7
6
5.3
12
17
15
18
14
15
2113
SO3H
SO3H
SO3H
SO3H
18
Binding Constant
(x 105 M-1)Time for 50%cleavage (min)
Baugh, S.D.P, Breslow, R., et. al. JACS 2001, 123, 12488.
S
HN
S
OS
HN
S
O
SO3H O 20.0
S SNH
NH
OO
O
O 6.05
S SNH
NH
OO
O
O
19.4
O
O 17.6
SS S
S
O
O13.0
7
6
5.3
12
17
15
18
14
15
2113
SO3H
SO3H
SO3H
SO3H
18
Binding Constant
(x 105 M-1)Time for 50%cleavage (min)
Baugh, S.D.P, Breslow, R., et. al. JACS 2001, 123, 12488.
S
HN
S
OS
HN
S
O
SO3H O 20.0
S SNH
NH
OO
O
O 6.05
S SNH
NH
OO
O
O
19.4
O
O 17.6
SS S
S
O
O13.0
7
6
5.3
12
17
15
18
14
15
2113
SO3H
SO3H
SO3H
SO3H
18
Binding Constant
(x 105 M-1)Time for 50%cleavage (min)
Baugh, S.D.P, Breslow, R., et. al. JACS 2001, 123, 12488.
S
HN
S
OS
HN
S
O
SO3H O 20.0
S SNH
NH
OO
O
O 6.05
S SNH
NH
OO
O
O
19.4
O
O 17.6
SS S
S
O
O13.0
7
6
5.3
12
17
15
18
14
15
2113
SO3H
SO3H
SO3H
SO3H
18
Binding Constant
(x 105 M-1)Time for 50%cleavage (min)
Baugh, S.D.P, Breslow, R., et. al. JACS 2001, 123, 12488.
Conclusions
Baugh, S.D.P, Breslow, R., et. al. JACS 2001, 123, 12488.
• Reduced 50% cleavage time to 5.3 minutes
• Proved cleavage is catalyzed by photosensitizer
• Determined need for solubilizing group
• Demonstrated effectiveness of CD dimer as an in-vitro encapsulating agent
• In-vivo studies “projected”
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