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Friso, Elisabetta (2008) Studio di derivati tetrapirroloci boronati come agenti foto- e radio- sensibilizzanti per il trattamento del melanoma melanotico mediante terapia combinata PDT-BNCT. [Tesi di dottorato]

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Abstract (inglese)

Photodynamic therapy (PDT) and boron neutron capture therapy (BNCT) represent two therapeutic modalities which are presently used for the treatment of a variety of solid tumours. Both techniques involve the systemic administration of an intrinsically non-cytotoxic sensitising agent to the tumour-bearing patient, followed by irradiation with red light (? > 600 nm) for PDT and thermal neutrons for BNCT. The research activities described in this dissertation were aiming at assessing the possibility to utilize one agent as both a photo- and a radio-sensitising agent in the treatment of melanotic melanoma. This tumour is know as being very aggressive and is characterized by a poor prognosis, at least by using the currently available therapeutic modalities.
In particular, PDT involves the use of a physical (visible light) and a chemical (the photosensitiser) active principle, whose concerted action promotes a sequence of photophysical processes, eventually leading to the generation of a hyper-reactive derivative of oxygen, named singlet oxygen. This oxygen derivative can diffuse within generally very short distances (around 0.1 ?m) from its production site, since it can be chemically intercepted by a large number of cell/tissue constituents, such as unsaturated lipids, aromatic amino acid residues and nucleotides, which are present in its microenvironment. The possibility to combine the action of the two factors (light+sensitiser) is at the basis of the observed selectivity of the photoinduced biological damage and the consequent biological effects.
BNCT is based on the selective interaction of 10B, a non radioactive boron isotope, with low energy thermal neutrons yielding 11B. This boron derivative is highly unstable and undergoes decomposition into two very fast particles, namely 7Li and 4He (or ? particles), which are very reactive and induce cell death within a range shorter than the cell diameter owing to their short average pathway. The strictly limited field of action of singlet oxygen and fast particles could guarantee a therapeutic effect which is localized in the tissue where the sensitiser molecule has been accumulated. In this connection, one should achieve a large ration of sensitiser concentration in the tumour to the peritumoural normal tissues.
At present, two molecules are largely used as radiosensitiser for BNCT applications, that is boron-phenylalanine (BPA) and borocaptate (BSH), both of which exhibit a reduced selectivity of tumour targeting, as well as a fast clearance from the tumour. Thus, new carriers for boron are being explored for BNCT applications. Porphyrins, chlorins and phthalocyanines are already used as efficient PDT agents and show a large affinity for various tumours; hence, these molecules could represent interesting carriers of 10B associated with them: in this case, the added advantage would be represented by the possibility to use just one compound for both PDT and BNCT and consequently develop a combination PDT+BNCT therapy. Towards this goal, new synthetic strategies have been defined fort he introduction of boronated substituents in the peripheral positions of the tetraazaisoindole macrocycle of phthalocyanines and the tetrapyrrole macrocycle of porphyrins in an effort to achieve large endocellular boron concentrations, which enhance the probability of thermal neutron capture.
In the present dissertation, we studied some phthalocyanines coordinated with different metal ions (Zn for ZnB4Pc, MeOks, OHks, PEGks, Diks or Si in the case of SiB2Pc) and different numbers of boron atoms per sensitiser molecule (18 atoms in MeOks, OHks, PEGks and SiB2Pc or 36 atoms in ZnB4Pc and Diks). In order to explore the possible effect of the chemical characteristics of the central macrocycle on the photo-/radio-sensitising efficacy, also a one porphyrin (H2TCP) and one chlorin (TPFC) have been investigated.
In all cases, the boron-loaded phthalocyanines, porphyrins and chlorins studied by us showed a good affinity for melanotic melanoma B16F1 cells, even though the amount of sensitiser bound with the cells was dependent on the nature of the central macrocycle (e.g., chlorin > porphyrin), the physico-chemical properties of the peripherally bound moieties and the nature of the coordinated metal ion. The boronated compounds were preferentially partitioned in the subcellular membranous systems and their photosensitising efficiency was related with the total amount of cell-bound sensitiser.
In vivo studies performed on C57BL/6 mice bearing a subcutaneously transplanted B16F1 melanotic melanoma demonstrated that all the boronated phthalocyanines, chlorins and porphyrins had a good affinity for the tumour and some selectivity of tumour targeting as compared with peritumoural compartments. However, H2TCP appeared to be devoid of any significant phototherapeutic activity at a difference from TPFC and ZnB4Pc. Both the latter derivatives photoinduce a significant decrease in the rate of tumour growth when the neoplastic lesion is irradiated with red light at 3 h after sensitiser injection. This suggests that PDT under these conditions largely acts via induction of vascular damage. The chlorin is also efficient as a phototherapeutic agent at 24 h after injection, and in this case it acts mainly through direct damage of the malignant cells.
Lastly, TPFC and ZnB4Pc appear to be also promising radiosensitising agents, since they induce an important response of the melanotic melanoma to thermal neutron irradiation at 24 h after sensitiser injection.
Overall, our data support the possibility to obtain a synergistic or additive effect against melanotic melanoma by a combined PDT + BNCT therapeutic approach in the presence of one photo-/radio-sensitising agent.

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Tipo di EPrint:Tesi di dottorato
Relatore:Jori , Giulio
Dottorato (corsi e scuole):Ciclo 20 > Scuole per il 20simo ciclo > BIOCHIMICA E BIOTECNOLOGIE > BIOCHIMICA E BIOFISICA
Data di deposito della tesi:29 Dicembre 2008
Anno di Pubblicazione:2008
Parole chiave (italiano / inglese):PDT, BNCT, porfirine, clorine, ftalocianine
Settori scientifico-disciplinari MIUR:Area 05 - Scienze biologiche > BIO/10 Biochimica
Struttura di riferimento:Dipartimenti > Dipartimento di Biologia
Codice ID:1309
Depositato il:29 Dic 2008
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Agarwal M. L., Larkin H. E., Zaidi S. I., Mukthar H. e Oleinick N. L. (1993) “Phospholipase activation triggers apoptosis in photosensitized mouse lymphoma cells”. Cancer Res. 53: 5897-5902. Cerca con Google

Ara G., Aprile J. R., Malis C. D., Kane S. B., Cincotta, L., Foley J., Bonventre J. V. e Oseroff A. R. (1987) “Mechanism of mitochondrial photosensitization by the cationic dye, NN1-Bis(2-ethyl-1,3- dioxylene)kryptocyanine (EDCK): preferential inactivation of complex I in the electron transport chain”. Cancer Res. 47: 6580-6585. Cerca con Google

Barth R.F., Soloway A.H. e Fairchild (1990) Boron neutron capture therapy for cancer”. Cancer Res. 50: 1061-1070. Cerca con Google

Berg K. (1992) “The unpolymerized form of tubulin is the target for microtubule inhibition by photoactivated tetra(4- sulfonatophenyl)porphine”. Biochim. Biophys. Acta 1135: 147-153. Cerca con Google

Berg K., Madslien K., Bommer J. C., Oftebro R., Winkelman J. W. E Moan J. (1991) “Light induced relocalization of sulfonated mesotetraphenilporphines in NHIK 3025 cells and effects of dose fractionation”. Photochem. Photobiol. 53: 203-210. Cerca con Google

Boekelheide K., Eveleth J., Tatum A. H. e Winkelman J. W. (1987) “Microtubule assembly inhibition by porphyrins and related compounds”. Photochem. Photobiol. 46: 657-661. Cerca con Google

Boissy R.E. (1988) “The melanocyte”. Dermatologic Clinics 6.2: 161- 173. Cerca con Google

Boukamp P., Petrussevska R. T., Breitkreutz D., Hornung J., Marknam A. e Fusening N. E. (1988) “Normal keratinization in a spontaneusly immortalized aneuploid human keratinocyte cell line”. Cell. Biol. 106: 761-771. Cerca con Google

Ceberg C.P., Persson A., Brun A., Huiskamp R., Fyhr A-S., Persson B.R.R., e Salford L.G. (1995) “Performance of BSH in patients with astrocytoma grades III-IV- a basis for boron neutron capture therapy”. J. Neurosurg. 83: 79-85. Cerca con Google

Ceberg C.P., Brun A., Kahl S.B., Koo M.S., Persson B.R.R., e Salford L.G. (1995) “A comparative study on the pharmacokinetics and biodistribution of boronated porphirin (BOPP) and sulphydryl boron hydride (BSH) in the RG2 rat glioma model. J. Neurosurg. 83: 86-92. Cerca con Google

Coderre J.A., Button T.M., Micca P.L., Fisher C.D., Nawrocky M.M. e Liu H.B. (1994) “Neutron capture therapy of the 9L rat gliosarcoma using the p-borophenylalanine-fructose complex”. Int. J. Radiat. Oncol. Biol. Phys. 30: 643-652. Cerca con Google

Dougherty T. J., Henderso B. W., Jori G., Kessel D., Korbelik M., Moan J. e Peng Q. (1998) “Photodynamic therapy”. J. Natl. Cancer Inst. 90: 889-905. Cerca con Google

Dubbelman T. M. A. R., Van Steveninck A. L. e Van Steveninck J. (1982) “Haematoporphyrin-induced photooxidation and photodynamic cross-linking of nucleic acids and their constituents”. Biochim. Biophys. Acta 719: 47-52. Cerca con Google

Edwards S.M., Donelly T.A., Sayre R.M., Rehins L.A. (1994) “Quantitative in vitro assessment of phototoxicity using a human skin model”, Photodermatol. Photoimmunol. Photomed. 10, 111-117 Cerca con Google

Fabris C., Valduga G., Miotto G., Borsetto L., Jori G., Garbisa S. e Reddi E. (2001) “Photosensitization with Zn (II) phthalocyanine as a switch in the decision between apoptosis and necrosis”. Cancer Res. 61: 7495-7500. Cerca con Google

Fairchild R.G., Kahl S.B., Laster B.H., Kalef-Ezra J., Popenoe E.A. (1990). “In vitro determination of uptake, retention, distribution, biological efficacy and toxicity of boronated compounds for neutron capture therapy: a comparison of porphyrins and sulphydryl boron hybrids”. Cancer Res. 50: 4860-4865. Cerca con Google

Fitzpatrick T.B., Szabò G. (1959) “The melanocyte: cytology and cytochemistry“. J. Invest. Dermatol. 32: 197-209 Cerca con Google

Fritsch C., Goetz G., Ruzicka T. (1998) “Photodynamic therapy in dermatology”. Arch. Dermatol. 134: 207-214. Cerca con Google

Fountain J.W., Bale S.J., Housman D. E., Dracopoli N. C. (1990) “Genetics of melanoma”. Cancer Surveys 9: 645-671 Cerca con Google

Gavin P.R., Huiskamp R., Wheeler F.J., Kraft S.L. e DeHaan C.E. (1993) “Large animal normal tissue tolerance using an epithermal neutron beam and borocaptate sodium” Stralhententher. Onkol. 165: 225-228. Cerca con Google

Girotti A. W. (1990) “Photodynamic lipid peroxidation in biological systems”. Photochem. Photobiol. 51: 497-509. Cerca con Google

Gurtu V., Kain S. R. e Zhang G. (1997) “Fluorimetric and colorimetric detection of caspase activity associated with apoptosis”. Anal. Biochem. 251:98-102. Cerca con Google

Grichnik J.M. (2008) “Melanoma, nevogenesis, and stem cell biology”. Journal of Investigative Dermatology 128: 2365-2380. Cerca con Google

Hawthorne M.F., Shelly K., e Schmidt P.G. (1990) “Liposomal delivery of boron for BNCT. Abstract from the fourth international symposium in neutron capture therapy for cancer. Sidney, Australia:UICC. Cerca con Google

Hetts S. W. (1998) “To die or not to die. An overview of apoptosis and its role in disease”. J. Am. Med. Assoc. 297: 300-307. Cerca con Google

Hu F. e Cardell R. R. (1963) “The ultrastructure of pigmented melanoma cells in continuous culture” The Journal of Investigative Dermatology 67-79 Cerca con Google

Ishimaru A. (1978) “Wave propagation and scattering in random media”. Academic Press, New York. Cerca con Google

Jori G. (1980) “The molecular biology of photodynamic action”. In: Lasers in Photomedicine and Photobiology (Pratesi, R. e Sacchi, C. A., eds.) Springer-Verlag, Berlin, Heidelberg, New York p.58. Cerca con Google

Jori G. (1992) “Far-red absorbing photosensitizers: their use in the photodynamic therapy of tumors”. J. Photochem. Photobiol. A: Chem. 62: 371-378. Cerca con Google

Jori G. e Spikes J. D. (1984) “Photobiochemistry of porphyrins”. In: Topics in Photomedicine (Smith, K. C., ed.) Plenum Press, New York pp. 183-318. Cerca con Google

Kalani A.D., Jack A., Montenegro G., Degliuomini J., Wallack M.K. (2008) “Immunotherapy as an adjuvant therapy in the management of advanced, surgically resectec, melanoma”. 143.1: 59-70. Cerca con Google

Kirkwood J.M., Tarhini A.A., Panelli M.C., Moschos S.J., Zarour H.M., Butterfield L.H., Gogas H.J. (2008) “Next generation of immunotherapy for melanoma”. J. Clin. Oncol. 26.20: 3445-3455. Cerca con Google

Koritowski W., Pilas B., Sarna T., Kalyanaraman B. (1987) “Photoinduced generation of hydrogen peroxide and hydroxyl radicals in melanins”. Photochem.Photobiol. 45.2:185-190. Cerca con Google

Krinsky N. I. (1982) “Photobiology of carotenoid protection”. In: The Science of Photomedicine (Regan, J. D. e Parrish, J. A., eds.) Plenum Press, New York pp. 347-407. Cerca con Google

Langlois R., Ali, H., Brassieur R., Wagner J. R. e Van Lier J. E. (1986) “Biological activities of phthalocyanines IV. Type II sensitized photooxidation of L-tryptophan and cholesterol by sulfonated metallophthalocyanines”. Photochem. Photobiol. 44: 117-123. Cerca con Google

Larsson B.S. (1991) “Melanine-affinic thioureas as selective melanoma seekers”. Melanoma Res. 1: 85-90. Cerca con Google

Leman J. A. e Morton C. A. (2002) “Photodynamic therapy: applications in dermatology”. Expert Opin. Biol. 2: 45-53. Cerca con Google

Leung J. (1994) “Photosensitizers in photodynamic therapy”. Semin. Oncol. 21: 4-10. Cerca con Google

Liotta L. A., Guirguis R., Stracke M. (1987) “Review article: Biology of melanoma invasion and metastasis”. Pigment Cell Research 1: 5-15. Cerca con Google

Matalka K.Z., Bailey M.Q., Barth R.F., Saubus A.E., Adams D.M., Soloway A.H., James S.M., Goodman J.H., Coderre J.A., Fairchild R.G. e Rofstad E.K. (1992) “A rat model for the treatment of melanoma metastatic to the brain by means of neutron capture therapy”. In: Allen B.G., Moore D. e Harrinton B. (Eds): Progress in neutron capture therapy for cancer. Plenum Press, NewYork, pp. 429-434. Cerca con Google

McLaren A. e Sugar D. (1964) “Absorption and luminescence spectra of nucleoproteins and their components”. In: Photochemistry of Proteins and Nucleic Acids (Alexanders, P., Baco, Z. M., eds.) Pergamon Press, Oxford pp. 29-51. Cerca con Google

Moan J., Berg K., Kvam E., Western A., Malik Z., Ruck A. e Schneckenburger H. (1989) “Intracellular localization of photosensitizers”. In: Photosensitizing Compounds: Their Chemistry, Biology and Clinical Use (Bock, G., Marnett, S., eds.) Wiley, Chichester, UK, (Ciba Foundation Symposium 146) pp. 95-107. Cerca con Google

Moan J., Christensen T. e Jacobsen P. B. (1984) “Porphyrin-sensitized photoinactivation of cells in vitro”. In: Porphyrin Localization and Treatment of Tumors. Progress in Clinical and Biological Research. (Doiron, D. R., Gomer, C. J., eds.) Alan R. Liss, Inc., New York, vol. 170, pp. 419-442. Cerca con Google

Moan J., Johannessen J. V., Christensen T., Espevik T. e McGhie J. B. (1982) “Porphyrin-sensitized photoinactivation of human cells in vitro”. Am. J. Pathol. 109: 184-192. Cerca con Google

Moan J., McGhie J. B. e Jacobsen P. B. (1983) “Photodynamic effects on cells in vitro exposed to hematoporphyrin derivative and light”. Photochem. Photobiol. 37: 599-604. Cerca con Google

Moan J. e Vistnes A. I. (1986) “Porphyrin photosensitization of protein in cell membranes as studied by spin-labelling and by quantification of DTNB-reactive SH-groups”. Photochem. Photobiol. 44: 15-19. Cerca con Google

Moor A. C. E. (2000) “Signaling pathways in cell death and survival after photodynamic therapy”. J. Photochem. Photobiol. B: Biol. 57: 1- 13. Cerca con Google

Noodt B. B., Berg K., Stokke T., Peng Q. e Nesland J. M. (1996) “Apoptosis and necrosis induced with light and 5-aminolaevulinic acidderived protoporphyrin IX”. Br. J. Cancer 74: 22-29. Cerca con Google

Oleinick N. L. (1998) “Apoptosis in response to photodynamic therapy”. Photodynamic News 1: 6-9. Cerca con Google

Parrish J. A., Ying C. Y., Pathak M. A. e Fitzpatrick T. B. (1974) “Erythemogenic properties of long-wave ultraviolet light”. In: Sunlight and man (Pathak, M. A., Harber, L. C., Seiji, M. e Kukita, A. eds.) University of Tokyo Press, Tokyo, pp. 131-141. Cerca con Google

Petterson O.-A., Carlsson J e Grusell E. (1992) “Accumulation of 10B in the central degenerative areas of human glioma and colon carcinoma spheroids after sulphydryl boron hydride administration”. Cancer Res. 52.6: 1587-1591. Cerca con Google

Reddi E., Zhou C., Biolo R., Menegaldo E. e Jori G. (1990) “Liposomeor LDL-administered Zn(II)-phthalocyanine as a photodynamic agent for tumors. I. Pharmacokinetic properties and phototherapeutic efficiency”. Br. J. Cancer 61: 407-411. Cerca con Google

Reyftman J. B., Santus R., Molière P. e Kohen E. (1986) “Fluorescent products formed by porphyrin photosensitization in ionic micelles”. Photobiochem. Photobiophys. 11: 197-208. Cerca con Google

Rodgers M. A. J. (1985) “Activated oxygen”. In: Primary Photoprocesses in Biology and Medicine (Bensasson, R. V., Jori, G., Land, E. J. e Truscott, T. J., eds.) Plenum Press, New York, pp. 181- Cerca con Google

195. Cerca con Google

Rong F.-G., e Soloway A.H. (1994) “Synthesis of 5-tethered carborane containing pyrimidine nucleosides as potential agents for DNA incorporation”. Nucleus.-Nucleot. 13: 2021-2034. Cerca con Google

Rodriguez R.Q.,e Kinsella T.J. (1991) “Halogenated pyrimidines as radiosensitizers for high grade glioma:revisited”. Int.J.Radiat.Biol. 74: 793-798. Cerca con Google

Scott L. J. e Goa K. L. (2000) “Verteporfin”. Drugs and Aging 16: 139- 146. Cerca con Google

Selman S. H., Kreimer-Birnbaum M. e Onandhuri K. (1986) “Photodynamic treatment of trasplantable bladder tumors in rodent after pretreatment with chloroaluminium tetrasulfophthalocyanine”. J. Urol. 136: 141-145. Cerca con Google

Smith P. K., Kron R. I., Hermanson G. T., Mallia A. K., Garten F. H., Provenzano M. D., Fujimoto E. K., Goeke N. M., Olson B. J. e Klenk D. C. (1985) “Measurement of protein using bicinchoninic acid”. Anal. Biochem.150:76-85. Cerca con Google

Specht K. G. e Rodgers M. A. J. (1991) “Plasma membrane depolarization and calcium influx during cell injury by photodynamic action”. Biochim. Biophys. Acta 1070: 60-68. Cerca con Google

Spiegelvogel B.E., Sood A., Powell W.,Tomasz J.,Porter K.,e Shaw B.R. (1993) “Chemical and enzymatic incorporation of boron in DNA”. In: Soloway A.H., Barth R.F.,e Carpenter D.E. (Eds). Advances inneutron capture therapy, Plenum Press,New York, pp. 389-393. Cerca con Google

Spikes J. D. (1986) “Phthalocyanine as photosensitizers in biological systems and photodynamic therapy”. Photochem. Photobiol. 43: 691- 699. Cerca con Google

Spikes J. D. (1989) “Photosensitization”. In: The Science of Photobiology (Smith, K. C., ed.) Plenum Press, New York, pp. 79-110. Cerca con Google

Spikes J. D. e Bommer J. C. (1986) “Zinc-tetrasulphophthalocyanine as a photodynamic sensitizer for biomolecules”. Int. J. Radiat. Biol. 50: 41-45. Cerca con Google

Stefandiou M., Tosca A., Themelis G., Vazgiouraki E. e Balas C. (2000) “In vivo fluorescence kinetics and photodynamic therapy efficacy of delta-aminolevulinic acid-induced porphyrins in basal cell carcinomas and actinic keratoses; implications for optimisation of photodynamic therapy”. Eur. J. Dermatol. 10: 351-356. Cerca con Google

Straight R. C., Vincent G. M., Hammond E. H. e Dixon J. A. (1985) “Porphyrin retention and photodynamic treatment of diet-induced atherosclerotic lesions in pigs”. In: Photodynamic Therapy of Tumours and Other Diseases. (Jori, G. and Perria, C. A., eds.) Padova, Libreria Progetto, pp. 349-352. Cerca con Google

Svaasand L. O., Martinelli E., Gomer G. J. e Profio A. E. (1990) “Optical characteristic of tumours in the visible and near-infrared”.Proc. SPIE 1203:2-21. Cerca con Google

Valduga G., Reddi E., Jori G., Cubeddu R., Taroni P. e Valentini G. (1992) “Steady state and time-resolved spectroscopic studies on zinc(II)-phthalocyanine in liposomes”. J. Photochem. Photobiol. B: Biol. 16: 331-340. Cerca con Google

Valenzeno D. P. (1987) “Photomodification of biological membranes with emphasis on singlet oxygen mechanism”. Photochem. Photobiol. 46: 147-160. Cerca con Google

Wilson B. C., Jeeves W. P. e Lowe D. M. (1985) “In vivo and postmortem measurements of the attenuation spectra of light in mammalian tissues”. Photochem. Photobiol. 42: 153-162. Cerca con Google

Woodburn K. W., Vardaxis N. J., Hill J. S., Kaye A. H. e Phillips D. (1991) “Subcellular localization of porphyrin using confocal laser scanning microscopy”. Photochem. Photobiol. 54: 725-732. Cerca con Google

Zaidi S. I., Oleinick N. L., Zaim M. T. e Mukhtar H. (1993) “ Apoptosis during photodynamic therapy-induced ablation of RIF-1 in C3H mice: electron microscopic, histopathologic and biochemical evidence”. Photochem. Photobiol.58: 771-776. Cerca con Google

Zhou H., Henzel W. J., Liu X., Lutschug A. e Wang X. (1997) “Apaf-1, a human protein homologous to C. elegans CED-4, participates in cytochrome c-dependent activation of caspase-3”. Cell 90: 405-413. Cerca con Google

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