Drug – bio-affecting and body treating compositions – In vivo diagnosis or in vivo testing – Diagnostic or test agent produces in vivo fluorescence
Patent
1998-05-11
2000-03-14
Dees, Jose' G.
Drug, bio-affecting and body treating compositions
In vivo diagnosis or in vivo testing
Diagnostic or test agent produces in vivo fluorescence
600317, A61K 4900
Patent
active
060369418
DESCRIPTION:
BRIEF SUMMARY
Fluorescent substances with photosensitizing activity are known which are able to locate themselves in preferably the tumour tissues and which are suitable for the diagnosis and photodynamic treatment of tumours (T. J. Dougherty: Photosensitizers: Therapy and detection of malignant tumours. Photochem. Photobiol., 45, 879-889, 1987).
The diagnosis is based on the fact that by excitation at an appropriate wavelength tumour mass is distinguished from the surrounding healthy tissue by virtue of the more intense emission of fluorescence as a consequence of a greater quantity of the fluorescent photosensitising substance accumulated in tumour.
The photodynamic treatment is based on activation of the above-mentioned substance by irradiation with light of appropriate wavelength, with the production of highly toxic species (singlet oxygen, obtained by transfer of energy from the fluorescent photosensitizer in the triplet state) which cause irreversible damage to the biological tissue which contains those substances, with consequent necrosis (J. G. Parker: Optical detection of the photodynamic production of singlet oxygen in vivo. Laser Surg. Med., 6, 258-265,1986).
Among the numerous substances able to ensure an adequate photodynamic yield, particular attention has been paid to the porphyrin derivatives which are currently used in clinical practice for treating tumours of various kinds (T. J. Dougherty: Photodynamic Therapy. Photochem. Photobiol., 58, 895-900, 1983). In particular, two substances are the most widely used, both derived from hematoporphyrin by chemical treatment and known as HpD (Hematoporphyrin-derivative) and Photofrin.RTM..
The use of acetoxymethyl esters of pH-sensitive amphipathic photosensitizers for photodynamic therapy involving endocytosis of lipophilic carriers leading to lysosomal uptake of the esterified photosensitizers by target cells has been proposed. Some esters of pheophorbide a and of chlorin e6 have been tested under in vitro conditions but not uniform results have been obtained. In fact, in contrast to the ability of chlorin e6 triacetoxymethyl ester and pheophorbide a acetoxymethyl ester to serve as a substrate for lysosomal enzymes, both methyl and phytyl esters of pheophorbide a were untouched by the esterases (D. Sahai et al., Photochem. and Photobiol., 58, 6, 803-808,1993).
Notwithstanding the validity of the premises on which they are based, fluorescence diagnosis and photodynamic therapy have notable limitations, as specified below.
The gradient of concentration of the fluorescent photosensitising substance between the tumour and the healthy tissue often is not sufficient to show the tumour mass with sufficient distinctness and to activate an efficacious photodynamic action. In particular, in the case of Photofrin.RTM. at the doses normally used (2.5-5 mg/Kg b.w.) the gradient of concentration between tumour tissue and the surrounding healthy tissue is such as to require careful dosing of the light to avoid undesirable side effects to the healthy part of the organ.
Further, the cutaneous photosensitization deriving from the need to use relatively high doses of the drug to obtain acceptable gradients of concentration between tumour tissue and normal tissue, imposes the need to avoid exposing the patients to any light source.
At the root of the objective difficulty of optimising photodynamic treatment, numerous problems can be identified, concerning in particular the exact definition of the modalities of interaction between the fluorescent photosensitising substance and the biological substrate leading to the preferential drug accumulation in tumour, and of the biological mechanisms which lead to the necrosis of the tumour mass (Eli Glastein: Photodynamic Therapy--Lots of questions but presently few answers. J. Natl. Cancer Inst., 80, 1584-1585, 1988; Chi-Wei Lin: Selective localisation of photosensitizers in tumours: review of the phenomenon and possible mechanism. In: Photodynamic therapy of neoplastic disease. D. Kessel ed.; vol. 2, CRC Press, pp. 79-101,1990).
Other grou
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American Society for Laser Medicine and Surgery Abstracts, 6, pp. 258-265 (1986).
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Baglioni Piero
Bottiroli Giovanni
Croce Anna Cleta
Monici Monica
Consiglio Nazionale Delle Ricerche
Dees Jos,e G.
Hartley Michael G.
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