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PORFIRINAS E APLICAÇÕES BIOLÓGICAS. José A. S. Cavaleiro. Dep artamento de Química, Universidade de Aveiro. Photofrin. Complex mixture of haematoporphyrin oligomers (dimers – hexamers). 1 – Light absorption. 2 - Fluoresc e nc e. 3 – Internal conversion. 4 – Intersystem Crossing, ISC.
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PORFIRINASE APLICAÇÕES BIOLÓGICAS José A. S. Cavaleiro Departamento de Química, Universidade de Aveiro
Photofrin • Complex mixture of haematoporphyrin oligomers (dimers – hexamers)
1 – Light absorption 2 - Fluorescence 3 – Internal conversion 4 – Intersystem Crossing, ISC S 5 - Phosphorescence n 6 - Type II Mechanism S 2 7 - Type I Mechanism S 1 T 3 1 1 O 2 4 7 Radical or ions radicals 3 O 2 1 2 6 5 S o Photosensitisers’ medicinal applications Energy Modified Jablonski Diagram
Fluorescence properties of haematoporphyrin (Hp) 1867, Thudichum Effect of Hp and light on red blood cells; skin reactions in mice exposed to light after Hp administration (photosensitivity, phototoxicity) 1910, Hausmann 1913, Meyer-Betz 1st report of human photosensitization by porphyrins (he injected himself with 200 mg of Hp; subsequently noticed prolonged pain and swelling in light-exposed areas) 1924, Policard 1st report of fluorescent porphyrin localization in a malignant tumour (he observed the Hp red fluorescence in a rat sarcoma illuminated with UV light) Localization and fluorescence of exogenously administrated porphyrins in malignant tumours 1942, Auler and Banzer
1948, Figge and Weiland Tumour localizing properties of porphyrins and application in the diagnosis and treatment of tumours. 240 mice with induced and transplanted tumours 50 non-tumours bearing mice Porphyrin localization in each tumour-type; fluorescence within 24-28h of administration; 10-14 days persistence. Hp effects in 3 patients with head and neck malignancies (no fluorescence detected; lower doses in humans – 30-120 mg) 1951, Manganiello and Figge Intravenous administration of Hp dihydrochloride to patients before excision of variety of benign and malignant lesions. Fluorescence was observed and increased in proportion to Hp dose. Higher doses allowed a breast cancer detection. 1955, Figge et al.
1955, Peck Hp fluorescence in biliary and bladder systems (in animals and humans); with a high dosage (1000 mg) one patient exhibited fluorescence in a cervical carcinoma Hp can play a role as a diagnostic tool for cancer But... a major disadvantage was the large dose of photosensitiser, which led to phototoxicity.
1955, Schwartz Used Hp was a mixture of porphyrins; after purification, “pure” Hp localized poorly in tumours, but residue left behind showed great affinity for tumours tissues. Hp derivative (HpD) described. Hp-dihydrochloride + sulphuric /acetic acid, precipitation with sodium acetate. The precipitated + NaOH and pH adjusted to 7.4. 1960, Lipson
1976, Kelly The 1st published account of clinical PDT with HpD human bladder tumour cells transplanted into mice could be destroyed using PDT The 1st extensive clinical survey with HpD 25 patients with cutaneous or sub-cutaneous malignancies 1978, Dougherty 1993 Canadian authorities granted the 1st regulatory approval (bladder, oesophagus) for cancer PDT using Photofrin (commercialised by QLT Phototherapeutics, Vancouver) Subsequent approvals: France (oesophagus, bladder); Germany(lung); Japan (lung, oesophagus, stomach, cervix); Netherlands (lung, oesophagus); USA (oesophagus, lung)
Inactivation results: Survival of S.aureus ATCC cells incubated for 10 min. with different concentrations of porphyrins and irradiated for 30 min with white light (50 mW/cm2)
Inactivation results: Survival ofE. colicells incubated for 10 min with different concentrations of porphyrins and irradiated for 30 min with white light (50 mW/cm2)
PORFIRINAS COMO AGENTES ANTIVIRAIS E ANTIFÚNGICOS Síntese e aplicação de porfirinas em formulações antivirais (pat. Nº 102 572) Aplicação de porfirinas em formulações antifúngicas (pat. Nº 102 581)
