Full Paper
[
1]
tion and is well described by a two-compartment model with
a distribution half-life of 1.1 h and a terminal half-life of 31 h.
Plasma pharmacokinetics of Photofrin in human subjects fol-
lows a three-compartment model with half-lives of 2.08 min
tographic films. Over one century later, dynamics provide a ra-
tionale to select the best photosensitizers for PDT.
[
50]
(
distribution), 19.8 h, and 12.9 days. Clinical pharmacokinet- Experimental Section
ics of Foscan is unusual because Cmax is observed approximate-
5
,10,15,20-Tetrakis(2,6-difluoro-3-N-methylsulfamoylphenyl)
ly 24 h post-i.v. injection and then the elimination half-life is
porphyrin (F PMet)
2
[
51]
4
5.5 h. The elimination of F BMet is faster than those of Pho-
2
[14a]
A mixture of F2P
and chlorosulfonic acid (1:680) was added to
tofrin and Foscan and should reduce the skin photosensitivity
after the treatment, often cited as the major inconvenience of
PDT. Interestingly, PDT was more effective with DLI=24 h than
with DLI=72 h, which correlates better with the amount of
photosensitizer in the vascular compartment than in the
tumor.
a round-bottomed flask equipped with a magnetic stirrer. The mix-
ture was kept at 1108C until the tetrachlorosulfonylated compound
was observed by TLC. After cooling, dichloromethane was added,
and the excess amount of acid was removed with a saturated solu-
tion of sodium bicarbonate in water. After evaporation the crude
was redissolved in dichloromethane and a solution of methylamine
in THF (2.0m) was added. The reaction was kept at 208C until full
consumption of the starting materials. Finally the solution was ex-
tracted with HCl (0.1m) and water. After chromatography with
Conclusion
silica gel (dichloromethane/ethyl acetate), F PMet was obtained in
2
A library of tetraphenylbacteriochlorins with fluorine or chlor-
ine atoms in the ortho positions of the phenyl groups was ex-
plored to select the “ideal” PDT photosensitizer because such
1
7
0% yield. H NMR (400 MHz, CDCl ): d=ꢀ2.84 (s, 2H), 2.87–2.90
3
(m, 12H), 4.73 (m, 4H), 7.45–7.54 (m, 4H), 8.42–8.49 (m, 4H),
19
8
.84 ppm (s, 8H); F NMR (376.5 MHz, CDCl ): d=ꢀ104.17 to
3
[
10]
bacteriochlorins can be economically synthesized,
exhibit
ꢀ
104.11 (m, 4F); ꢀ98.54 to ꢀ98.49 ppm (m, 4F); HRMS (ESI-FIA-
[
52]
a lower tendency to aggregate, combine strong absorptions
in the phototherapeutic window with efficient formation of
TOF): m/z calcd for C H F N O S : 1131.1327; found: 1131.1328
48 35 8 8 8 4
+
[M+H ]; elemental analysis calcd (%) for C H F N O S ·H O: calcd
48
34
8
8
8
4
2
[
14a,21b]
long-lived triplet states,
bear electron-withdrawing
C 50.17, H 3.16, N 9.75, S 11.16; found: C 50.47, H 3.18, N 9.39, S
10.94.
[53]
groups that stabilize the macrocycle against oxidation, and
[
54]
provide steric protection. We found that the interaction be-
tween these bacteriochlorins and molecular oxygen led to su-
peroxide ions and hydroxyl radicals in addition to singlet oxy-
5,10,15,20-Tetrakis(2,6-difluoro-3-N-methylsulfamoylphenyl)
bacteriochlorin (F BMet)
2
[
9d,15,55]
gen,
and the combined effects of these ROS were re-
This bacteriochlorin was prepared on the multigram scale with our
[
7,16c]
markably efficient in the destruction of tumor cells.
How-
[13]
solvent-free method. A mixture of F PMet and p-toluenosulfonyl-
2
ever, empirical correlations with lipophilicity or with electronic
factors were insufficient to drive the last stage of PDT photo-
sensitizer discovery.
hydrazide (1:40) was ground in a Schlenk tube and then evacuated
with a vacuum pump. Next, the reactor was heated at 1408C for
60 min, and then brought back to room temperature. After chro-
matography with silica gel (dichloromethane/ethyl acetate), F BMet
A new path to discovery was opened with the finding that
2
1
was obtained in 85% yield. H NMR (400 MHz, CDCl ): d=ꢀ1.38 (s,
3
the strength of the {sensitizer···O } interaction is revealed by
2
9
ꢀ1 ꢀ1
2H), 2.77–2.84 (m, 12H), 4.06 (s, 8H), 4.65–4.71 (m, 4H), 7.39–7.43
the quenching rate constant. Values of k ꢁ2ꢃ10 m
s
in
q
19
(
m, 4H), 8.00–8.03 (m, 4H), 8.24–8.29 ppm (m, 4H); F NMR
ethanol indicate the ability to generate superoxide ion in addi-
tion to singlet oxygen, especially in hydroxylic solvents where
the nascent superoxide ion is stabilized by hydrogen bonding.
(
376.5 MHz, CDCl ): d=ꢀ105.09 to ꢀ104.95 (m, 4F); ꢀ99.48 to
3
ꢀ
99.37 ppm (m, 4F); HRMS (ESI-FIA-TOF): m/z calcd for
+
C H F N O S : 1135.1640; found: 1135.1612 [M+H ]; elemental
48
39
8
8
8 4
However, kq depends on E* and lowering Eox increases the
analysis calcd (%) for C H F N O S ·H O: C 50.00, H 3.50, N 9.72, S
48 34 8 8 8 4 2
ox
photodecomposition quantum yield, F . The bleaching of the
11.12; found: C 49.88, H 3.47, N 9.38, S 10.94.
pd
photosensitizer becomes a limiting factor of PDT efficacy when
ꢀ
5
F >10 , which requires E >0.8 V versus SCE. The simulta-
Other porphyrin derivatives
pd
ox
9
ꢀ1 ꢀ1
neous fulfillment of the conditions k ꢁ2ꢃ10 m
s
in etha-
q
The other photosensitizers employed in this study were available
nol and E >0.8 V versus SCE should lead to photosensitizers
ox
from previous studies or were synthesized according to the litera-
that drive both type I and type II reactions without compromis-
ing photostability.
[10,13]
ture.
mTHPP was synthesized by means of the nitrobenzene
and mTHPC was synthesized with our solvent-free
[56]
method,
[13]
The dynamics of the interaction between the photosensitizer
triplet state and oxygen determine both the nature of the ROS
generated and the stability of the photosensitizer towards
method. Details are given in the Supporting Information.
Animals and tumor model
such ROS. F BMet attains a delicate balance between a high
2
The animal model used for dark toxicity, biodistribution, and phar-
macokinetic studies was the DBA mouse bearing the Cloudman
S91-I3 melanoma. Following approval by the Jagiellonian Universi-
ty Committee for Ethics of Experiments on Animals (decision no.
degree of charge transfer to oxygen and an adequate resist-
ance to oxidation. It is an example of how the dynamics of the
interaction between light, a photosensitizer, and oxygen can
be tuned to increase tissue damage. Interestingly, in 1904 the
term “photodynamic” was used to distinguish PDT from the
physicochemical processes occurring in the emulsions of pho-
8
9/2008 from 11 December 2008 and no. 11/2011, 23 February
2011), mice (20–30 g) from the Animal House of the Polish Acade-
my of Science Medical Research Center (Warsaw, Poland) enrolled
&
&
Chem. Eur. J. 2014, 20, 1 – 13
10
ꢂ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!