Svetlana V. Kudrevich

PEG-coated Poly(lactic acid) Nanoparticles for the Delivery of Hexadecafluoro Zinc Phthalocyanine to EMT-6 Mouse Mammary Tumours

Hexadecafluoro zinc phthalocyanine (ZnPcF16), a second generation sensitizer for the photodynamic therapy of cancer, was incorporated in three vehicles: poly(d,l‐lactic acid) (PLA) nanoparticles, polyethylene glycol (PEG)‐coated nanoparticles and a Cremophor EL (CRM) oil‐water emulsion. Nanoparticles were prepared by the salting‐out procedure. Biodistribution of the dye was assessed by fluorescence in EMT‐6 mammary tumour bearing mice after intravenous injection of 1 μmol kg−1 ZnPcF16.

Photodynamic therapy of tumours with hexadecafluoro zinc phthalocyanine formulated in PEG-coated poly(lactic acid) nanoparticles

Hexadecafluoro zinc phthalocyanine (ZnPcF16), a second‐generation sensitizer for the photodynamic therapy (PDT) of cancer, was formulated in polyethylene‐glycol‐coated poly(lactic acid) nanoparticles (PEG‐coated PLA‐NP) and tested in EMT‐6 tumour‐bearing mice for its photodynamic activity. The tumour response was compared to that induced by the same dye formulated as a Cremophor EL (CRM) emulsion. Formulation in the biodegradable NP improved PDT response of the tumour while providing prolonged tumour sensitivity towards PDT.

AZAANALOGS OF PHTHALOCYANINE : SYNTHESES AND PROPERTIES

Abstract Structural data, nomenclature, synthetic routes and spectral properties of the majority of known azaanalogs of phthalocyanines are presented. Among the synthetic procedures, the preparation and purification of both lipophilic and water soluble azaphthalocyanines are described. The physico-chemical properties of these compounds are strongly influenced by the presence of exocyclic nitrogen atoms, which are more basic than the meso atoms of the porphyrazine macroring. This increased basicity of the azaanalogs, compared with the corresponding phthalocyanines, explaines their tendency to form stable hydrates and their specific affinity for protons in acidic media. The hypsochromic shift of the Q-band in the electronic spectra of the azaanalogs of phthalocyanine, naphthalocyanine and anthracyanine, resulting from the aza substitution in the fused benzo rings, is shown to depend on the number and position of the heterocyclic N atoms in the macrocycle. The effect of aza substitution on the absorption spectra becomes more pronounced in the case of linearly annelated azaphthalocyanines. In contrast, sequential linear annelation alone induces a strong bathochromic displacement of the Q-band. The recent data concerning the angular annelation of octaazanaphthalocyanine suggest that each angularly condensed benzo ring contributes to a hypsochromic shift of the main absorption maximum of 10–15 nm. Such data are essential in the design of new phthalocyanine related compounds with ‘tuned’ absorption maxima and selected solubility, as substrates for new materials.

Novel water-soluble phthalocyanines substituted with phosphonate moieties on the benzo rings

Abstract The synthesis and characterization of a series of phthalocyanine derivatives bearing phosphonate substituents directly bound to the aromatic rings of the phthalocyanine is described. These novel water-soluble phthalocyanine tetraphosphonates are of interest for different applications, particularly as photosensitizers in photodynamic therapy. Furthermore, this synthetic approach allows for more versatility in the preparation of hydrophilic macrocycles.

Photodynamic activities and biodistribution of fluorinated zinc phthalocyanine derivatives in the murine EMT-6 tumour model.

The photodynamic properties and biodistribution pattern of zinc dodecafluoro‐4‐sulphophthalocyanine (ZnPcF12S1), zinc hexadecafluorophthalocyanine (ZnPcF16) and zinc phthalocyanine (ZnPc) were evaluated in the murine EMT‐6 tumour model. All 3 dyes were formulated as a Cremophor oil–water emulsion after initial solubilization in methanol, acetone and pyridine, respectively. Comparison of their phototoxicity after in vitro incubation with EMT‐6 cells and exposure to various fluences of red light showed that ZnPcF12S1 is about 50 times more active than ZnPcF16, reflecting better cell‐penetrating properties. Solubilisation of ZnPc in 1‐methyl‐2‐pyrrolidinone prior to formulation resulted in loss of photo‐activity upon dilution in serum due to precipitation of the dye in the aqueous environment. In contrast, initial solubilisation in pyridine likely forms a ZnPc‐pyridinium salt, and this preparation was 6 times more phototoxic than ZnPcF12S1. In vivo comparison of monosulphonated ZnPcF12S1 with perfluorinated ZnPcF16 showed improved pharmacokinetics in mice, including lower liver and spleen retentions and higher tumour‐to‐non‐target tissue ratios. However, photodynamic therapy (PDT) of the EMT‐6 tumour in BALB/c mice with red light, 24 or 48 hr post‐injection of 1 μmol · kg−1 of ZnPcF12S1 induced mortality. Lowering the drug and/or light dose or extending the time interval between drug administration and irradiation to 72 hr avoided adverse effects but also resulted in poor tumour response. The best tumour control (25% of animals) was obtained at 0.1 μmol · kg−1 and a fluence of 400 J · cm−2 at 24 hr post‐injection. In contrast, ZnPcF16 required a 20‐fold higher drug dose to induce a similar tumour response. The systemic shock following PDT with the amphiphilic ZnPcF12S1 likely results from extensive cellular effects. Int. J. Cancer 72:289–294, 1997.

Syntheses of monosulfonated phthalocyanines, benzonaphthoporphyrazines and porphyrins via the Meerwein reaction

A variety of monosulfonated phthalocyanine, benzonaphthoporphyrazine and porphyrin derivatives have been prepared as single positional isomers in moderate to high yield using modified Meerwein reaction conditions. These amphiphilic dyes have a potential application as photosensitizers in the photodynamic therapy of cancer.

LANGMUIR-BLODGETT FILM FORMATION AND SPECTROSCOPIC CHARACTERIZATION OF SULPHONATED DERIVATIVES OF ZINC PHTHALOCYANINE

Langmuir film formation characteristics of two sulphonated derivatives of zinc phthalocyanine, zinc 11,18,25-tri(tert-butyl)-4-sulphophthalocyanine (Na[ZnPctSO3]) and zinc dodecafluoro-4-sulphophthalocyanine (Na[ZnPcF12SO3]), were studied. The surface pressure–area isotherm of Na[ZnPctSO3] showed distinct gaseous, liquid and solid phases, whereas that corresponding to Na[ZnPcF12SO3] followed the trend of other phthalocyanine derivatives that lack amphiphilic character. The floating films were transferred to several substrates. The starting materials and the Langmuir–Blodgett films were characterized using ultraviolet–visible, Fourier transform infrared, Raman, resonant Raman and surface-enhanced resonant Raman spectroscopy. A relationship between the molecular organization in the films and the nature of the substituents is inferred from the spectroscopic data.