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. [Ph.D. thesis]
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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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