PDT Sensitizers Research Articles

Enhanced Visible Light Absorption and Photophysical Features of Novel Isomeric Magnesium Phthalocyaninates with Cyanophenoxy Substitution

Novel metal-free and Mg(II) [3/4-(3,4-dicyanophenoxy)phenoxy]-substituted phthalocyanines were obtained and characterized using NMR, IR, UV-vis spectroscopy, and mass spectrometry. This substitution provided compounds with good solubility in organic media, and thus their spectroscopic and fluorescent properties were studied. The formation of the investigated phthalocyanine complexes with central magnesium ions led to the stabilization of macrocyclic molecules in solution, preventing aggregation through specific and universal solvation. From meta-substitution to para-substitution, insignificant spectroscopic changes were observed. The complexes exhibited higher values of molar light absorption coefficients and fluorescence quantum yields (up to 55%) compared to ligands. The efficiency of both the fluorescence-quenching and singlet oxygen generation processes in the case of magnesium [3/4-(3,4-dicyanophenoxy)phenoxy]phthalocyaninates was found to exceed that of the unsubstituted zinc phthalocyaninate, which suggests the potential applicability of these compounds as PDT sensitizers.

Ring-Fused meso-Tetraarylchlorins as Auspicious PDT Sensitizers: Synthesis, Structural Characterization, Photophysics, and Biological Evaluation.

Novel 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-fused meso-tetraarylchlorins, with different degrees of hydrophilicity (with methyl ester, hydroxymethyl, and carboxylic acid moieties), have been synthesized and their photophysical characterization as well as in vitro photocytotoxicity assessment against human melanoma and esophageal and bladder carcinomas was carried out. An integrated analysis of the photosensitizers’ performance, considering the singlet oxygen generation data, cell internalization, and intracellular localization, allowed to establish relevant structure-photoactivity relationships and the rationalization of the observed photocytotoxicity. In the diacid and monoalcohol series, chlorins derived from meso-tetraphenylporphyrin proved to be the most efficient photodynamic therapy agents, showing IC50 values of 68 and 344 nM against A375 cells, respectively. These compounds were less active against OE19 and HT1376 cells, the diacid chlorin with IC50 values still in the nano-molar range, whereas the monohydroxymethyl-chlorin showed significantly higher IC50 values. The lead di(hydroxymethyl)-substituted meso-tetraphenylchlorin confirmed its remarkable photoactivity with IC50 values below 75 nM against the studied cancer cell lines. Subcellular accumulation of this chlorin in the mitochondria, endoplasmic reticulum, and plasma membrane was demonstrated.

Non-aggregated Porphyrins: An Approach to Develop High-performance PDT Sensitizers

Non-aggregated Porphyrins: An Approach to Develop High-performance PDT Sensitizers

Vascular targeting to the SST2 receptor improves the therapeutic response to near-IR two-photon activated PDT for deep-tissue cancer treatment

BackgroundBroader clinical acceptance of photodynamic therapy is currently hindered by (a) poor depth efficacy, and (b) predisposition towards establishment of an angiogenic environment during the treatment. Improved depth efficacy is being sought by exploiting the NIR tissue transparency window and by photo-activation using two-photon absorption (2PA). Here, we use two-photon activation of PDT sensitizers, untargeted and targeted to SST2 receptors or EGF receptors, to achieve deep tissue treatment. MethodsHuman tumor lines, positive or negative for SST2r expression were used, as well as murine 3LL cells and bovine aortic endothelial cells. Expression of SST2 receptors on cancer cells and tumor vasculature was evaluated in vitro and frozen xenograft sections. PDT effects on tumor blood flow were followed using in vivo scanning after intravenous injection of FITC conjugated dextran 150K. Dependence of the PDT efficacy on the laser pulse duration was evaluated. Effectiveness of targeting to vascular SST2 receptors was compared to that of EGF receptors, or no targeting. ResultsTumor vasculature stained for SST2 receptors even in tumors from SST2 receptor negative cell lines, and SST2r targeted PDT led to tumor vascular shutdown. Stretching the pulse from ~120fs to ~3ps led to loss of the PDT efficacy especially at greater depth. PDT targeted to SST2 receptors was much more effective than untargeted PDT or PDT targeted to EGF receptors. General significanceThe use of octreotate to target SST2 receptors expressed on tumor vessels is an excellent approach to PDT with few recurrences and some long term cures.

Squaraine dyes as PDT sensitizers: Specific functionalization for biological targeting

Squaraine dyes as PDT sensitizers: Specific functionalization for biological targeting

New Halogenated Water‐Soluble Chlorin and Bacteriochlorin as Photostable PDT Sensitizers: Synthesis, Spectroscopy, Photophysics, and in vitro Photosensitizing Efficacy

Chlorin and bacteriochlorin derivatives of 5,10,15,20-tetrakis(2-chloro-5-sulfophenyl)porphyrin have intense absorptions in the phototherapeutic window, high water solubility, high photostability, low fluorescence quantum yield, long triplet lifetimes, and high singlet oxygen quantum yields. Biological studies revealed their negligible dark cytotoxicity, yet significant photodynamic effect against A549 (human lung adenocarcinoma), MCF7 (human breast carcinoma) and SK-MEL-188 (human melanoma) cell lines upon red light irradiation (cutoff λ<600 nm) at low light doses. Time-dependent cellular accumulation of the chlorinated sulfonated chlorin reached a plateau at 2 h, as previously observed for the related porphyrin. However, the optimal incubation time for the bacteriochlorin derivative was significantly longer (12 h). The spectroscopic, photophysical, and biological properties of the compounds are discussed in relevance to their PDT activity, leading to the conclusion that the bacteriochlorin derivative is a promising candidate for future in vivo experiments.

Photodynamic Activity of Ascorbic Acid-modified TiO2 Nanoparticles upon Visible Illumination (&amp;gt;550 nm)

Abstract Though both TiO2 and ascorbic acid are noncytotoxic in the dark or under visible irradiation, ascorbic acid-modified TiO2 nanoparticles were found to exhibit efficient DNA and cancer cell damage ability under visible light irradiation, opening a new pathway for developing highly efficient PDT sensitizers.

The small stones of Coimbra in the huge tetrapyrrolic chemistry building

Improvements over the Rothemund classical reaction methods have allowed the development of capacity to obtain a wide range of structures that were earlier unavailable. Performing the reaction in a mixed nitrobenzene/carboxylic acid medium allowed improvements of yield and purity of the porphyrin obtained, and in some cases the control of the oxidation level of the macrocycle. More recently, novel microwave synthetic methodologies were exploited to achieve important improvements in simple porphyrin chemistry. Tidy sulphonations of simple porphyrins opened the way to diverse desired, inexpensive structures in a very simple manner. The option to concentrate interests on improvements of synthetic methods to obtain simple and diversified tetrapyrrolic structures proved to be advantageous. Interesting biomimetic oxidation and photooxidation systems and PDT sensitizers were developed and significant knowledge was achieved in these specific and related areas. This review presents a view of our own results in the synthetic area, and outlines the contributions therefrom to the study of biomimetic and therapeutic processes.

Non-covalent functionalized SWNTs as delivery agents for novel Bodipy-based potential PDT sensitizers

Pyrenyl-functionalized distyryl-Bodipy sensitizer attached non-covalently to SWNTs was shown to generate singlet oxygen when excited at 660 nm with a red LED array; this work emphasizes the potential of SWNT as a viable alternative carrier of bioactive agents, including photodynamic therapy sensitizers.

Synthesis of tetrasubstituted Zn(II)-phthalocyanines carrying four carboranyl-units as potential BNCT and PDT agents

The synthesis of two tetrasubstituted zinc(II)phthalocyanines carrying four carbon–carbon linked o-carboranyl-units (40 boron atoms, 27.5% boron by weight) is presented. In an in vitro model test the new compounds showed a good photosensitizing efficiency, that encourages further studies for their evaluation as possible BNCT–PDT sensitizers.

Towards PDT sensitizers with internal source of singlet oxygen

Towards PDT sensitizers with internal source of singlet oxygen

Biodistribution of photosensitizing agents

1. 1. The features of neoplasia which predict for drug responsiveness are rapid growth and/or inefficient repair of damage, especially to DNA. 2. 2. PDT has the advantage of yielding responses regardless of the growth fraction of a tumor, and repair appears to play only a minor role. 3. 3. While an entirely different spectrum of tumors can be targeted with PDT, the perhaps unavoidable accompaniment is that a new set of rules for efficacy will need to be established. 4. 4. The selectivity of PDT is based on the need for irradiation which can be directed, along with the short tissue half-life of the cytotoxic product, singlet oxygen. Sensitizers which target specific cellular organelles could promote PDT efficacy, if in vitro data (Woodbum et at., 1992b Photochem. Photobiol. 55, 697–704) can be translated into clinical practice. 5. 5. It remains to be established whether total drug distribution to neoplastic tissues or concentration in specific sub-cellular sites is the more important factor. 6. 6. Questions relating to the role of biodistribution as a factor in efficacy of PDT sensitizers of photosensitizers remain to be explored. Just as the political cartographers are grappling with changes in territorial boundaries of known lands, we continue to clarify the rules relating to PDT boundaries. In this regard, it is clearly important for determinants of pharmacokinetics and biodistribution to be evaluated and understood. 7. 7. Once clinical reports on the “second generation” agents are published, we may get a better picture, although it is not unusual for clinical reports to raise more questions than they answer. 8. 8. It seems safe to conclude that there is nothing “magic” about HPD, and that additional efficacious photosensitizers for PDT can be produced. 9. 9. If we find that a wide variety of different structures are useful in the clinic, a likely conclusion is that there are multiple mechanisms of tumor localization. Since the nature of neoplasia is so diverse, this possibility should not be surprising. 10. 10. In view of the finding, cited above, that liposomes show about the same degree of tumor selectivity as does Photofrin, it may be feasible to target any efficient photosensitizer for neoplastic tissues by development of an appropriate delivery system.

Properties for optimal PDT sensitizers

Properties for optimal PDT sensitizers