94
2.3 DDS (FFAG-DDS )
2.3.1 Drug Delivery SystemDDS
2.3.2 B1-1 P-Me()
A B P-Me()
B1-1 (1) -
BNCT 4-Boronophenylalanine(BPA) Grignard Pinacolborane Cross-coupling
B1-2
95
4-Boronocinnamic acid(BCA) BPA EthylesterBPA-OEt 4-Boronobenzylcysteine Ethylester(BBC-OEt)BBC-OEt
B1-2 BCA B1-3 4-Buromotoluene
Trimethoxyborane Grignard (71)93Sommelet 49 Methyl(triphenyl- phosphoranylidene)acetate Wittig (82),99 BCA49
96
B1-3 4-Boronocinnamic acidBCA 4-BPA-OEt B1-4 H.R.Snyder1958
BPA 4-Buromotoluene Trimethoxyborane Grignard (71)93Diethyl Acetoamidomalonate 657592 DL-BPA30 DL-BPA 10w% 2 DL-BPA-OEtHCl97
B1-4 4-Boronophenylalanine EthylesterBPA-OEt
97
B1-5 BCC-OEt 4-Buromotoluene Trimethoxyborane Grignard (71)93L-Cysteine 1 C-S L-BBC98 BPA-OEt BBC 10w% 2
L-BBC-OEtHCl92
B1-5 4-Boronobenzylcysteine Ethylester BBC-OEt BCABPA-OEt BBC-OEt B1-6B1-7
- EC-027EC-028 EC-031
B1-6 BCA -
98
B1-7 BPA-OEtBBC-OEt -
(2) o-- 3 BCABPA-OEtBBC-OEt
1 DDS 1
10 2 o-o-C-Co- B1-8 o-
4-Carboran-1-yl-methoxybenzoic acid (CMBA) O-[(Carboran-1-yl)methyl]-3-hydroxytyrsinol (CMHT-ol)
B1-8 o-
99
CMBA B1-9 4-Hydroxy-benzoic acid Propargylbromide (90) Decaborane (41)(81) CMBA(30)
B1-9 4-Carboran-1-ylmethoxybenzoic acid (CMBA)
B1-10 CMHT-ol 4-Hydroxy-benzaldehyde
Propargylbromide (88) Ethane dithiol (95)Decaborane (54)(82)Ethyl Isocyanatoacetate (75)(85)(87) CMHT-ol(:20)
B1-10 O-[(Carboran-1-yl)methyl]-3-hydroxytyrosiol(CMHT-ol
100
CMBA B1-11 - EC-032
B1-11 (3) ICP-AES
ICP-AES
ICP-AES () DDS
3,945
101
102
2.4 DDS ()
[] BOPP NCT
EC031 EC032EC031 2 EC032
[] BNCT DDS DDS
phaseII
DDS []
EC032 in vitro
[] C69L U87U251 4
EC031 EC032 96 103 24 EC031 EC032 0520502001000 M 48 MTS Cell titer96 10 l 2 490 nm 96 1024 20 M EC031 EC032 0 30 1 2 6 12
103
PBS Triton X 405 nm:670 nm
[]
B2-1 MTS
( B2-1) EC031 EC032 LD50 EC031 500 MEC032 1000 M
C6 reference
0
0.2
0.4
0.6
0.8
1
1.2
1 10 100 1000
EC031
EC032
L reference
0
0.2
0.4
0.6
0.8
1
1.2
1.4
1 10 100 1000
M
EC031
EC032
U251 reference
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
1 10 100 1000
M
EC031
EC032
U87 reference
0
0.2
0.4
0.6
0.8
1
1.2
1 10 100 1000
M
EC031
EC032
104
B2-2
10 20 M B2-2
EC031 1 EC032 24 EC032 EC031 108
C6 10 405&670nm -ohr
0
50
100
150
200
250
300
350
400
0 5 10 15 20 25 30
ph
oto
n/U
nit
EC031
EC032
C6 20 405&670nm -0hr
0
100
200
300
400
500
600
0 5 10 15 20 25 30
ph
oto
n/U
nit
EC031
EC032
9L 10 405&670nm -0hr
0
50
100
150
200
250
300
350
400
450
0 5 10 15 20 25 30
ph
oto
n/U
nit
EC031
EC032
9L 20 405&670nm -0hr
0
100
200
300
400
500
600
0 5 10 15 20 25 30
ph
oto
n/U
nit
EC031
EC032
10405670 nm -0hr
0
20
40
60
80
100
120
0 5 10 15 20 25 30
ph
oto
n/U
nit
10
10
20405670 nm -0hr
0
20
40
60
80
100
120
140
0 5 10 15 20 25 30
ph
oto
n/U
nit
20
20
10405670 nm -0hr
0
50
100
150
200
250
300
350
400
450
0 5 10 15 20 25 30
ph
oto
n/U
nit
10
10
20405670 nm -0hr
0
100
200
300
400
500
600
0 5 10 15 20 25 30
ph
oto
n/U
nit
20
20
105
C6 151 g/10 cell U251 146 g/10 cell []
Borocaptate Sodium(BSH) BoronophenylalanineBPA BSH gBPA 60 kg 250 mg/kg 15 g 10 100
BSH BPA [6,9,15,17]
EC032 (LD50 1000 M )
BSH BPA 2 BSH 12 -SH
BPA
BPA BSH BPA [14]
EC032 EC031 EC032
LDL [12,13]
EC032
106
B2-1 24 gB/108cell
1. Matsumura A, Shibata Y, Yamamoto Y, Yoshida F, Isobe T, Nakai T, Haykawa Y, Kiriya Mi, Shimojo N, Ono K, Sakata I, Nakajima S, Okumura M, Nose T, A new boronated porphyrin (STA-BX909) for neutron capture therapy: an in vitro survival assay and in vivo tissue uptake study. Cancer Letters 1999;141, 203-209 2. Ceberg C. P., Brun A., Kahl S. B., Koo M. S.. Person B. R., Salford L. G. A., A coparatice study on the pharmacokinetics and biodistribution of boronated porphyrin (BOPP) and sulfhydryl boron hydride (BSH) in the RG2 rat glioma model. J. Neurosurg. 1995;83, 86-92 3. Daniel E. Callahan, Trudy M. Forte, S. M. javed Afzal, Dennis F. Deen, Stephen B. Kahl, Kathleen A. Bjornstad, William F. Bauer, Eleanor A. Blakely, Boronated protoporphyrin (BOPP): Localization in lysosomes of the human glioma cell line SF-767 with uptake modulated by lipoprotein levels. Int. J. Radiation Oncology Biol. Phys 1999;45(3), 761-771 4. M. F. Issac, S. B. Kahl, Synthesis of ether- and carbonlinked polycarboranyl porphyrin dimmers for cancer therapies. J Organomet Chem 2003;680, 232-243 5. J.S. Hill, SB Kahl, A.H. Kaye, S.S. Stylli, M. Koo, M.F. Gonzales, N.J. Vardaxis, C.I. Johhson, Selective tumor uptake of boronated porphyrin in an animal model of cerebral glioma. PNAS 1992;89, 1785-1789 6. M. Miura, P. L. Micca, C. D. Fisher, C. R. Gordon, J. C. Heinrichs, D. N. Slatkin, Evaluation of carborane-containing porphyrins as tumour targeting agents for boron neutron capture therapy. Br J Radiol. 1998;71(847):773-81. 7. M. Rosental, B. Kavar, J. Hill, D. Morgan, R. Nation, S. Stylli, Phase and pharmacokinetic study of photodynamic therapy for high-grade gliomas using a novel boronated porphyrin. J. Clin. Oncol. 2001;19, 519-524 8. Paul G. Spizzirri, Jon S. Hill, Stephen B. Kahl, Kenneth P. Ghiggino, Photophysics and intracellular diatribution of a boronated porphyrin phototherapeutic agent. Photochemistry and photobiology 1996;64(6), 975-983 9. P. R. Gavin, S. L. Kraft, R. Huiskamp, J. A.Coderre .A review: CNS effects and normal tissue tolerance in dogs, J Neurooncol. 1997;33(1-2):71-80. Review. 10. R. G. Fairchild, S. B. Kahl, B. H. Laster, J. Kalef-Ezra, E. A. Popenoe, In vitro determination of uptake, retention, distribution, biological efficacy, toxicity of boronated
9L cell U251 cell BSH (30M) 2 0.93 BX909 (30M 52 170 EC032 (20M) 151 146
107
compounds for neutron capture therapy: a comparison of porphyrins with sulfhydryl boron hydrides. Cancer Research 1990;50, 48604865 11. Rolf F. Barth, Jeffrey A. Coderre, M. Graca h. Vincente, Thomas E. Blue, Boron neutron capture therapy of cancer: current status and future prospects. Clin Cancer Res 2005;11(11), 3987-4002 12. Sara Novick, Brenda laster, Michael R. Quastel, Postitive cooperativity in the cellular uptake of a boronated porphyrin. The International Journal of Biochemistry & Cell Biology 2006;38, 1374-1381 13. Shibata Y, Matsumura A, Yoshida F, Yamamoto T, Nakai K, Nose T, Sakata I, Nakajima S, Competitive uptake of porphyrin and LDL via the LDL receptor in glioma cell lines: flow cytometric analysis. Cancer Lett. 2001; 10;166(1), 79-87 14. Yamamoto T, Nakai K, Matsumura A, Boron neutron capture therapy for glioblastoma. Cancer Lett. 2008;18;262(2):143-52 15. Y. Kinashi, S. Masunaga, K. Ono. Mutagenic effect of borocaptate sodium and boronophenylalanine in neutron capture therapy.Int J Radiat Oncol Biol Phys. 2002;54(2):562-7. 16. Wei Chen, Samir C. Mehta, D. Robert Lu, Selective boron drug delivery to brain tumors for boron neutron capture therapy. Advanced Drug Reviews 1997;26, 231-247 17. W. Yang, R. F. Barth, J. H. Rotaru, C. P. Boesel, D. A. Wilkie, J. C. Bresnahan, M. Hadjiconstantinou, V. M. Goettl, D. D. Joel, M. M. Nawrocky. Boron neutron capture therapy of brain tumors: functional and neuropathologic effects of blood-brain barrier disruption and intracarotid injection of sodium borocaptate and boronophenylalanine. J. Neurooncol. 2000;48(3):179-90.
108
2.5 DDS DDS
DDS
DDS DDS BNCT
DDS
B3-1
BSH
BSH BSH BSH BSHDMBL 14DPBL 16DSBL 18 BSH DMCBL DPCBLDSCBL BCBCC 10
B3-2B3-3 BL25%.BL50%BL25%, BC25%BL50%
B3-1
n = 16: Stearoyln = 14: Parmitoyln = 12: Myristoyl
O NH
O
OO
O
H3C(H2C)n
O
H3C(H2C)n
S
2-O
OS
O
OO
O
H3C(H2C)n
O
H3C(H2C)n
2-
DMBL (n = 12)DPBL (n = 14)DSBL (n = 16)
DMCBL (n = 12)DPCBL (n = 14)DSCBL (n = 16)
O Y
OS
2-
BC (Y = CH2)BCC (Y = NHCOCH2)
n = 16: Stearoyln = 14: Parmitoyln = 12: Myristoyl
O NH
O
OO
O
H3C(H2C)n
O
H3C(H2C)n
S
2-O
OS
O
OO
O
H3C(H2C)n
O
H3C(H2C)n
2-
DMBL (n = 12)DPBL (n = 14)DSBL (n = 16)
DMCBL (n =
