1 ladek zdrÓj 2003. 2 laser spectroscopic study of phthalocyanine derivatives synthesized for...
TRANSCRIPT
![Page 1: 1 LADEK ZDRÓJ 2003. 2 LASER SPECTROSCOPIC STUDY OF PHTHALOCYANINE DERIVATIVES SYNTHESIZED FOR PHOTODYNAMIC THERAPY András Grofcsik Budapest University](https://reader035.vdocuments.site/reader035/viewer/2022062720/56649f165503460f94c2cb62/html5/thumbnails/1.jpg)
1
LADEK ZDRÓJ
2003
![Page 2: 1 LADEK ZDRÓJ 2003. 2 LASER SPECTROSCOPIC STUDY OF PHTHALOCYANINE DERIVATIVES SYNTHESIZED FOR PHOTODYNAMIC THERAPY András Grofcsik Budapest University](https://reader035.vdocuments.site/reader035/viewer/2022062720/56649f165503460f94c2cb62/html5/thumbnails/2.jpg)
2
LASER SPECTROSCOPIC STUDY OF PHTHALOCYANINE DERIVATIVES SYNTHESIZED FOR PHOTODYNAMIC
THERAPY
András Grofcsik
Budapest University of Technology and Economics
Department of Physical Chemistry
![Page 3: 1 LADEK ZDRÓJ 2003. 2 LASER SPECTROSCOPIC STUDY OF PHTHALOCYANINE DERIVATIVES SYNTHESIZED FOR PHOTODYNAMIC THERAPY András Grofcsik Budapest University](https://reader035.vdocuments.site/reader035/viewer/2022062720/56649f165503460f94c2cb62/html5/thumbnails/3.jpg)
3
Photodynamic therapy (PDT)
Hematoporphyrin derivative (HpD)
Phthalocyanines (Pc)
Synthesis
Photophysical properties
in solutions
in vesicles
5-Amino-levulinic acid (ALA)
![Page 4: 1 LADEK ZDRÓJ 2003. 2 LASER SPECTROSCOPIC STUDY OF PHTHALOCYANINE DERIVATIVES SYNTHESIZED FOR PHOTODYNAMIC THERAPY András Grofcsik Budapest University](https://reader035.vdocuments.site/reader035/viewer/2022062720/56649f165503460f94c2cb62/html5/thumbnails/4.jpg)
4
Cancer therapies surgery radiotherapy chemotherapy
Photodynamic therapy (PDT): use of visible light in combination with a photosensitiser
![Page 5: 1 LADEK ZDRÓJ 2003. 2 LASER SPECTROSCOPIC STUDY OF PHTHALOCYANINE DERIVATIVES SYNTHESIZED FOR PHOTODYNAMIC THERAPY András Grofcsik Budapest University](https://reader035.vdocuments.site/reader035/viewer/2022062720/56649f165503460f94c2cb62/html5/thumbnails/5.jpg)
5
Number of publications in PDT
0
500
1000
1500
2000
2500
3000
1981-85 1986-90 1991-95 1996-2000
![Page 6: 1 LADEK ZDRÓJ 2003. 2 LASER SPECTROSCOPIC STUDY OF PHTHALOCYANINE DERIVATIVES SYNTHESIZED FOR PHOTODYNAMIC THERAPY András Grofcsik Budapest University](https://reader035.vdocuments.site/reader035/viewer/2022062720/56649f165503460f94c2cb62/html5/thumbnails/6.jpg)
6
Administration of
photosensitizer
Irradiation with visible light
Photosensitizer accumulates in
the tumour.
Tumour is selectively destroyed
Steps of photodynamic therapy
![Page 7: 1 LADEK ZDRÓJ 2003. 2 LASER SPECTROSCOPIC STUDY OF PHTHALOCYANINE DERIVATIVES SYNTHESIZED FOR PHOTODYNAMIC THERAPY András Grofcsik Budapest University](https://reader035.vdocuments.site/reader035/viewer/2022062720/56649f165503460f94c2cb62/html5/thumbnails/7.jpg)
7
Photodynamic effect:Cell destruction by
photosensitiser + visible light + O2
)()()( 110 TPSPSP ISCh
ProductsOesBiomolecul
OSPOTP
*2
1
*2
102
31 )()(
•TYPE II: energy transfer
•TYPE I: electron-transfer: Radicals and radical ions
![Page 8: 1 LADEK ZDRÓJ 2003. 2 LASER SPECTROSCOPIC STUDY OF PHTHALOCYANINE DERIVATIVES SYNTHESIZED FOR PHOTODYNAMIC THERAPY András Grofcsik Budapest University](https://reader035.vdocuments.site/reader035/viewer/2022062720/56649f165503460f94c2cb62/html5/thumbnails/8.jpg)
8
vessel
blood
The wavelength dependence of depth of penetration of light into soft tissue
![Page 9: 1 LADEK ZDRÓJ 2003. 2 LASER SPECTROSCOPIC STUDY OF PHTHALOCYANINE DERIVATIVES SYNTHESIZED FOR PHOTODYNAMIC THERAPY András Grofcsik Budapest University](https://reader035.vdocuments.site/reader035/viewer/2022062720/56649f165503460f94c2cb62/html5/thumbnails/9.jpg)
9
Requirements for the photosensitiser:
• Selective accumulation in malignant tissues• High absorbance between 600 and 800 nm• Chemical homogenity• Long triplet lifetime and sufficient triplet energy
(>94 kJ/mol)• Chemical, biological and photochemical stability• Little or no dark toxicity• Simple and cheap syntesis
![Page 10: 1 LADEK ZDRÓJ 2003. 2 LASER SPECTROSCOPIC STUDY OF PHTHALOCYANINE DERIVATIVES SYNTHESIZED FOR PHOTODYNAMIC THERAPY András Grofcsik Budapest University](https://reader035.vdocuments.site/reader035/viewer/2022062720/56649f165503460f94c2cb62/html5/thumbnails/10.jpg)
10
The first sensitiser used in clinical PDT:Hematoporphyrin derivative (HpD) Photofrin®
It is a mixture of compounds.
![Page 11: 1 LADEK ZDRÓJ 2003. 2 LASER SPECTROSCOPIC STUDY OF PHTHALOCYANINE DERIVATIVES SYNTHESIZED FOR PHOTODYNAMIC THERAPY András Grofcsik Budapest University](https://reader035.vdocuments.site/reader035/viewer/2022062720/56649f165503460f94c2cb62/html5/thumbnails/11.jpg)
11 Hematoporphyrin
![Page 12: 1 LADEK ZDRÓJ 2003. 2 LASER SPECTROSCOPIC STUDY OF PHTHALOCYANINE DERIVATIVES SYNTHESIZED FOR PHOTODYNAMIC THERAPY András Grofcsik Budapest University](https://reader035.vdocuments.site/reader035/viewer/2022062720/56649f165503460f94c2cb62/html5/thumbnails/12.jpg)
12
HPLC analysis of HpD
![Page 13: 1 LADEK ZDRÓJ 2003. 2 LASER SPECTROSCOPIC STUDY OF PHTHALOCYANINE DERIVATIVES SYNTHESIZED FOR PHOTODYNAMIC THERAPY András Grofcsik Budapest University](https://reader035.vdocuments.site/reader035/viewer/2022062720/56649f165503460f94c2cb62/html5/thumbnails/13.jpg)
13
• Selective accumulation in malignant tissues• High absorbance between 600 and 800 nm• Chemical homogenity• Long triplet lifetime and sufficient triplet energy
(>94 kJ/mol)• Chemical, biological and photochemical stability• Little or no dark toxicity• Simple and cheap syntesis
Requirements for the photosensitiser:
![Page 14: 1 LADEK ZDRÓJ 2003. 2 LASER SPECTROSCOPIC STUDY OF PHTHALOCYANINE DERIVATIVES SYNTHESIZED FOR PHOTODYNAMIC THERAPY András Grofcsik Budapest University](https://reader035.vdocuments.site/reader035/viewer/2022062720/56649f165503460f94c2cb62/html5/thumbnails/14.jpg)
14
”Second generation" photosensitisers:
porphyrins
chlorins
bacteriochlorins
phthalocyanines (Pc)
naphthalocyanines
5-Aminolevulinic acid (ALA)
![Page 15: 1 LADEK ZDRÓJ 2003. 2 LASER SPECTROSCOPIC STUDY OF PHTHALOCYANINE DERIVATIVES SYNTHESIZED FOR PHOTODYNAMIC THERAPY András Grofcsik Budapest University](https://reader035.vdocuments.site/reader035/viewer/2022062720/56649f165503460f94c2cb62/html5/thumbnails/15.jpg)
15Phthalocyanine
![Page 16: 1 LADEK ZDRÓJ 2003. 2 LASER SPECTROSCOPIC STUDY OF PHTHALOCYANINE DERIVATIVES SYNTHESIZED FOR PHOTODYNAMIC THERAPY András Grofcsik Budapest University](https://reader035.vdocuments.site/reader035/viewer/2022062720/56649f165503460f94c2cb62/html5/thumbnails/16.jpg)
16
00,20,40,60,8
11,21,41,61,8
500 550 600 650 700 750
(nm)
Ab
sorb
an
ce
b
a
Absorpion spectrum of a porphyrin (a) and a phthalocyanine (b) derivative (Ethanol solutions,
c = 1.5*10-5 mol dm-3)
![Page 17: 1 LADEK ZDRÓJ 2003. 2 LASER SPECTROSCOPIC STUDY OF PHTHALOCYANINE DERIVATIVES SYNTHESIZED FOR PHOTODYNAMIC THERAPY András Grofcsik Budapest University](https://reader035.vdocuments.site/reader035/viewer/2022062720/56649f165503460f94c2cb62/html5/thumbnails/17.jpg)
17
Synthesis
4 M = 2H
M = Zn
ROH, DMF, K2CO3
60 W, 20 min
3
21
60 W, 3 minDBU
Zn(OAc)2
60 W, 15 minK2CO3
ROH, DMF CN
CNRO
CN
CNNO2
OR
RO
OR
N N
N
NN N
N
N
OR
M
![Page 18: 1 LADEK ZDRÓJ 2003. 2 LASER SPECTROSCOPIC STUDY OF PHTHALOCYANINE DERIVATIVES SYNTHESIZED FOR PHOTODYNAMIC THERAPY András Grofcsik Budapest University](https://reader035.vdocuments.site/reader035/viewer/2022062720/56649f165503460f94c2cb62/html5/thumbnails/18.jpg)
18
N
NN
M
NN
Phthalocyanine derivatives
I: M: Zn R: 4-tert-Bu-Ph-
II: M: Zn R: CH3O(CH2)2O(CH2)2-
III: M: Zn R: (2,6-dimethyl-4- N,N-dimethylamino- methylen)-phenyl-
IV: M: H2
R: CH3O(CH2)2O(CH2)2-
![Page 19: 1 LADEK ZDRÓJ 2003. 2 LASER SPECTROSCOPIC STUDY OF PHTHALOCYANINE DERIVATIVES SYNTHESIZED FOR PHOTODYNAMIC THERAPY András Grofcsik Budapest University](https://reader035.vdocuments.site/reader035/viewer/2022062720/56649f165503460f94c2cb62/html5/thumbnails/19.jpg)
19
Structure of III
![Page 20: 1 LADEK ZDRÓJ 2003. 2 LASER SPECTROSCOPIC STUDY OF PHTHALOCYANINE DERIVATIVES SYNTHESIZED FOR PHOTODYNAMIC THERAPY András Grofcsik Budapest University](https://reader035.vdocuments.site/reader035/viewer/2022062720/56649f165503460f94c2cb62/html5/thumbnails/20.jpg)
20
Experimental setup for studying triplet states
![Page 21: 1 LADEK ZDRÓJ 2003. 2 LASER SPECTROSCOPIC STUDY OF PHTHALOCYANINE DERIVATIVES SYNTHESIZED FOR PHOTODYNAMIC THERAPY András Grofcsik Budapest University](https://reader035.vdocuments.site/reader035/viewer/2022062720/56649f165503460f94c2cb62/html5/thumbnails/21.jpg)
21
Triplet lifetime and triplet absorption spectrum
II
IlgA
0
0
tOkAlnAln 20 400 450 500 550 600
0,000
0,002
0,004
0,006
0,008
0,010
0,012
0,014
Ethanol solution of I
(7,7*10--6 mol/dm
3)
Abs
orba
nce
[nm]
0 500 1000 1500 2000 2500
-0,03
-0,02
-0,01
0,00
0,01
0,02 Triplet decay
Abs
orba
nce
t [ns]
![Page 22: 1 LADEK ZDRÓJ 2003. 2 LASER SPECTROSCOPIC STUDY OF PHTHALOCYANINE DERIVATIVES SYNTHESIZED FOR PHOTODYNAMIC THERAPY András Grofcsik Budapest University](https://reader035.vdocuments.site/reader035/viewer/2022062720/56649f165503460f94c2cb62/html5/thumbnails/22.jpg)
22
Reaction of triplet Pc with molecular oxygen:
21
023
1 )()( OSPcOTPc
The rate constant can be determined from the decay curves.
![Page 23: 1 LADEK ZDRÓJ 2003. 2 LASER SPECTROSCOPIC STUDY OF PHTHALOCYANINE DERIVATIVES SYNTHESIZED FOR PHOTODYNAMIC THERAPY András Grofcsik Budapest University](https://reader035.vdocuments.site/reader035/viewer/2022062720/56649f165503460f94c2cb62/html5/thumbnails/23.jpg)
23
0,0 0,1 0,2 0,3 0,4 0,5 0,6 0,7 0,80
5
10
15
20
25
I 0 [m
V]
Laser energy [mJ]
Ref I II IIIIV
Quantum yield of singlet oxygen formation
refref
phtalphtal m
m
![Page 24: 1 LADEK ZDRÓJ 2003. 2 LASER SPECTROSCOPIC STUDY OF PHTHALOCYANINE DERIVATIVES SYNTHESIZED FOR PHOTODYNAMIC THERAPY András Grofcsik Budapest University](https://reader035.vdocuments.site/reader035/viewer/2022062720/56649f165503460f94c2cb62/html5/thumbnails/24.jpg)
24
Triplet lifetimes (), second order rate constants and quantum yields of singlet oxygen formation
Pc (solvent) I (Et) I (To) II (Et) II (To) III (Et) IV (To)
(ns) 306 287 381 263 231 504
k*10-9
(M-1s-1)1.55 1.67 1.25 1.81 2.09 0.95
0.47 0.58 0.42 0.44 0.59 0.19
![Page 25: 1 LADEK ZDRÓJ 2003. 2 LASER SPECTROSCOPIC STUDY OF PHTHALOCYANINE DERIVATIVES SYNTHESIZED FOR PHOTODYNAMIC THERAPY András Grofcsik Budapest University](https://reader035.vdocuments.site/reader035/viewer/2022062720/56649f165503460f94c2cb62/html5/thumbnails/25.jpg)
25
Photosensitisers in vesicles
Vesicles are simple models of cell membranes.
DPPC (dipalmitoylphosphatidylcholine)
![Page 26: 1 LADEK ZDRÓJ 2003. 2 LASER SPECTROSCOPIC STUDY OF PHTHALOCYANINE DERIVATIVES SYNTHESIZED FOR PHOTODYNAMIC THERAPY András Grofcsik Budapest University](https://reader035.vdocuments.site/reader035/viewer/2022062720/56649f165503460f94c2cb62/html5/thumbnails/26.jpg)
26
![Page 27: 1 LADEK ZDRÓJ 2003. 2 LASER SPECTROSCOPIC STUDY OF PHTHALOCYANINE DERIVATIVES SYNTHESIZED FOR PHOTODYNAMIC THERAPY András Grofcsik Budapest University](https://reader035.vdocuments.site/reader035/viewer/2022062720/56649f165503460f94c2cb62/html5/thumbnails/27.jpg)
27
![Page 28: 1 LADEK ZDRÓJ 2003. 2 LASER SPECTROSCOPIC STUDY OF PHTHALOCYANINE DERIVATIVES SYNTHESIZED FOR PHOTODYNAMIC THERAPY András Grofcsik Budapest University](https://reader035.vdocuments.site/reader035/viewer/2022062720/56649f165503460f94c2cb62/html5/thumbnails/28.jpg)
28
Temperature dependence of the rate constant (III in DPPC vesicles)
RT
EexpAk a
Arrhenius plot: Ea = 60.7 kJ
20
20,4
20,8
21,2
21,6
22
0,00300 0,00305 0,00310 0,00315 0,00320 0,00325 0,00330 0,00335 0,00340 0,00345
1/T [1/K]
ln k
![Page 29: 1 LADEK ZDRÓJ 2003. 2 LASER SPECTROSCOPIC STUDY OF PHTHALOCYANINE DERIVATIVES SYNTHESIZED FOR PHOTODYNAMIC THERAPY András Grofcsik Budapest University](https://reader035.vdocuments.site/reader035/viewer/2022062720/56649f165503460f94c2cb62/html5/thumbnails/29.jpg)
29
Use of 5-amino-levulinic acid (ALA) for PDT
COOH
CH2
CH2
C
O
CH2 NH2
ALA stimulates the cellular synthesis of an endogenous photosensitiser: Protoporphyrin IX
Administration of exogenious ALA causes the build-up of phototoxic levels of Protoporphyrin IX
![Page 30: 1 LADEK ZDRÓJ 2003. 2 LASER SPECTROSCOPIC STUDY OF PHTHALOCYANINE DERIVATIVES SYNTHESIZED FOR PHOTODYNAMIC THERAPY András Grofcsik Budapest University](https://reader035.vdocuments.site/reader035/viewer/2022062720/56649f165503460f94c2cb62/html5/thumbnails/30.jpg)
30
Advantages (over HpD):
•Treatment follows 2-4 hours after administration
•Systemic clearence of photosensitiser within 24 hours
•Treatment can be repeated within two days
•ALA can be administered topically
The method was approved by FDA in the 90s) In Hungary clinical trials started in 2001 (National Medical Center)
![Page 31: 1 LADEK ZDRÓJ 2003. 2 LASER SPECTROSCOPIC STUDY OF PHTHALOCYANINE DERIVATIVES SYNTHESIZED FOR PHOTODYNAMIC THERAPY András Grofcsik Budapest University](https://reader035.vdocuments.site/reader035/viewer/2022062720/56649f165503460f94c2cb62/html5/thumbnails/31.jpg)
31
Basal cell carcinoma - before treatment
![Page 32: 1 LADEK ZDRÓJ 2003. 2 LASER SPECTROSCOPIC STUDY OF PHTHALOCYANINE DERIVATIVES SYNTHESIZED FOR PHOTODYNAMIC THERAPY András Grofcsik Budapest University](https://reader035.vdocuments.site/reader035/viewer/2022062720/56649f165503460f94c2cb62/html5/thumbnails/32.jpg)
32
After PDT with ALA
![Page 33: 1 LADEK ZDRÓJ 2003. 2 LASER SPECTROSCOPIC STUDY OF PHTHALOCYANINE DERIVATIVES SYNTHESIZED FOR PHOTODYNAMIC THERAPY András Grofcsik Budapest University](https://reader035.vdocuments.site/reader035/viewer/2022062720/56649f165503460f94c2cb62/html5/thumbnails/33.jpg)
33
PARTICIPANTS Miklós Kubinyi
István Bitter
Viktor CsokaiJanka Tatai Klára Szegletes
Éva BacskayJános Brátán
Tamás VidóczyPéter BaranyaiLajos Csokonai Vitéz
![Page 34: 1 LADEK ZDRÓJ 2003. 2 LASER SPECTROSCOPIC STUDY OF PHTHALOCYANINE DERIVATIVES SYNTHESIZED FOR PHOTODYNAMIC THERAPY András Grofcsik Budapest University](https://reader035.vdocuments.site/reader035/viewer/2022062720/56649f165503460f94c2cb62/html5/thumbnails/34.jpg)
34
The End