The synthesis of novel water-soluble zinc (II) phthalocyanine based photosensitizers and exploring of photodynamic therapy activities on the PC3 cancer cell line.

In this study, Schiff base substituted phthalocyanine complexes (Zn1c, Zn2c) and their quaternized derivatives (Q-Zn1c, Q-Zn2c) were synthesized for the first time. Their structures have been characterized by FT-IR, 1H-NMR, UV-Vis, mass spectrometry and elemental analysis as well as. The photophysicochemical properties (fluorescence, singlet oxygen and photodegradation quantum yield) of these novel complexes were investigated in dimethylsulfoxide (DMSO) for both non-ionic and quaternized cationic phthalocyanine complexes and in aqueous solution for quaternized cationic phthalocyanine complexes. Water soluble cationic phthalocyanine compounds gave good singlet oxygen quantum yield (0.65 for Q-Zn1c, 0.66 for Q-Zn2c in DMSO; 0.65 for Q-Zn2c in aqueous solution). The binding of Q-Zn1c and Q-Zn2c to BSA/DNA was studied by using UV-Vis and fluorescence spectroscopy and these. Studies indicate that the mechanism of BSA quenching by quaternized zinc(II) phthalocyanines was static quenching. Quaternized zinc(II) phthalocyanines interacted with ct-DNA by intercalation. Quaternized zinc(II) phthalocyanines caused a decrease in cell viability and triggered apoptotic cell death after PDT was applied at a concentration that did not have a toxic effect on their own. Q-Zn1c and Q-Zn2c mediated PDT reduced the activity of SOD, CAT, GSH while increased MDA level in the prostate cancer cells. Furthermore, expression of apoptotic proteins after PDT was examined. The results revealed that the synthesized water soluble quaternized zinc(II) phthalocyanine complexes (Q-Zn1c and Q-Zn2c) are promising potential photosensitizers for PDT.

Photosensitizing potential of tailored magnetite hybrid nanoparticles functionalized with levan and zinc (II) phthalocyanine.

Phototherapies, including photodynamic therapy (PDT), have been widely used in the treatment of various diseases, especially for cancer. However, there is still a lack of effective, safe photosensitizers that would be well tolerated by patients. The combination of several methods (like phototherapy and hyperthermia) constitutes a modern therapeutic approach, which demands new materials based on components that are non-toxic without irradiation. Therefore, this study presents the synthesis and properties of novel, advanced nanomaterials in which the advantage features of the magnetic nanoparticles and photoactive compounds were combined. The primary purpose of this work was the synthesis of magnetic nanoparticles coated with biocompatible and antitumor polysaccharide - levan, previously unknown from scientific literature, and the deposition of potent photosensitizer - zinc(II) phthalocyanine on their surface. In order to better characterize the nature of the coating covering the magnetic core, the atomic force microscope analysis, a contact angle measurement, and the mechanical properties of pure levan and its blend with zinc(II) phthalocyanine films were investigated. This magnetic nanomaterial revealed the ability to generate singlet oxygen upon exposure to light. Finally, preliminary toxicity of obtained nanoparticles was tested using the Microtox® test - with and without irradiation.

Controlling Interfacial Charge Transfer and Fill Factors in CuO-based Tandem Dye-Sensitized Solar Cells.

We designed and synthesized a series of novel electron-accepting zinc(II)phthalocyanines (ZnPc) and probed them in p-type dye sensitized solar cells (p-DSSCs) by using CuO as photocathodes. By realizing the right balance between interfacial charge separation and charge recombination, optimized fill factors (FFs) of 0.43 were obtained. With a control over fill factors in p-DSSCs in hand we turned our attemtion to t-DSSCs, in which we combined for the first time CuO-based p-DSSCs with TiO2 -based n-DSSCs using ZnPc and N719. In the resulting t-DSSCs, the VOC of 0.86 V is the sum of those found in p- and n-DSSCs, while the FF remains around 0.63. It is only the smaller Jsc s in t-DSSCs that limits the efficiency to 0.69 %.

Synthesis of asymmetric zinc(II) phthalocyanines with two different functional groups & spectroscopic properties and photodynamic activity for photodynamic therapy.

Zinc(II) phthalocyanine containing [2-(tert-butoxycarbonyl)amino]ethoxy and iodine groups (A and B), as well as their deprotected mono-amino and tri-iodine zinc(II) phthalocyanine (2) were obtained. This structure surrounds by substituents with functional groups. From this perspective it can be used a starting material for many reactions and applications, such as sonogashira coupling, carbodiimide coupling. An example of a first diversification reaction of this compound was obtained with conjugation of a biotin. Asymmetrically biotin conjugated and heavy atom bearing zinc(II) phthalocyanine (3) were synthesized characterized for the first time and photophysical, photochemical and photobiological properties of these phthalocyanines were compared in this study.

Highly positive-charged zinc(II) phthalocyanine as non-aggregated and efficient antifungal photosensitizer.

A new tetra-α-substituted zinc(II) phthalocyanine containing dodeca-amino groups (compound 4) and its quaternized analogue (compound 5) have been prepared and evaluated for their photoactivities against Candida albicans. Compared with the dodeca-amino phthalocyanine 4, the dodeca-cationic phthalocyanine 5 exhibits a higher photodynamic inactivation against C. albicans with an IC90 value down to 1.46 µM, which can be attributed to its non-aggregated nature in aqueous environments and more efficient cellular uptake. More interestingly, 5 shows a higher photodynamic inactivation on C. albicans due to its stronger affinity to C. albicans cells than mammalian cells. These results suggest that the highly positive-charged phthalocyanine 5 is a potential non-aggregated antifungal photosensitizer, which shows some selectivity toward the fungus.

Spectroscopic study on the interaction of bovine serum albumin with zinc(II) phthalocyanine.

The interaction between the photosensitive antitumour drug, 2(3),9(10),16(17),23(24)-tetra-(((2-aminoethylamino)methyl)phenoxy)phthalocyaninato-zinc(II) (ZnPc) and bovine serum albumin (BSA) has been investigated using various spectroscopic methods. This work may provide some useful information for understanding the interaction mechanism of anticancer drug-albumin binding and gain insight into the biological activity and metabolism of the drug in blood. Based on analysis of the fluorescence spectra, ZnPc could quench the intrinsic fluorescence of BSA and the quenching mechanism was static by forming a ground state complex. Meanwhile, the Stern-Volmer quenching constant (KSV), binding constant (Kb), number of binding sites (n) and thermodynamic parameters were obtained. Results showed that the interaction of ZnPc with BSA occurred spontaneously via hydrogen bond and van der Waal's force. According to Foster's non-radioactive energy transfer theory, the energy transfer from BSA to ZnPc occurred with high possibility. Synchronous fluorescence and circular dichroism (CD) spectra also demonstrated that ZnPc induced the secondary structure of and conformation changes in BSA, especially α helix.

Rational design of a zinc phthalocyanine binding protein.

Phthalocyanines have long been used as primary donor molecules in synthetic light-powered devices due to their superior properties when compared to natural light activated molecules such as chlorophylls. Their use in biological contexts, however, has been severely restricted due to their high degree of self-association, and its attendant photoquenching, in aqueous environments. To this end we report the rational redesign of a de novo four helix bundle di-heme binding protein into a heme and Zinc(II) phthalocyanine (ZnPc) dyad in which the ZnPc is electronically and photonically isolated. The redesign required transformation of the homodimeric protein into a single chain four helix bundle and the addition of a negatively charge sulfonate ion to the ZnPc macrocycle. To explore the role of topology on ZnPc binding two constructs were made and the resulting differences in affinity can be explained by steric interference of the newly added connecting loop. Singular binding of ZnPc was verified by absorption, fluorescence, and magnetic circular dichroism spectroscopy. The engineering guidelines determined here, which enable the simple insertion of a monomeric ZnPc binding site into an artificial helical bundle, are a robust starting point for the creation of functional photoactive nanodevices.

Heparosan-based self-assembled nanocarrier for zinc(II) phthalocyanine for use in photodynamic cancer therapy.

Zinc(II) phthalocyanine (ZnPc) is a promising photosensitizer in photodynamic therapy (PDT) for melanoma treatment. However, the poor solubility of ZnPc limits its application. To overcome this limitation, heparosan (HP)-based nanoparticles were prepared by anchoring the l-lysine-linked α-linolenic acid branch to the carboxylic acid group to produce amphiphilic conjugates named heparosan with an l-lysine-linked α-linolenic acid branch (HLA). HLA conjugates could self-assemble into spherical nanoparticles in aqueous media and encapsulate ZnPc to form HLA-ZnPc nanoparticles. The cellular uptake of ZnPc could be improved by HLA carriers. These nanoparticles presented excellent photodynamic-mediated toxicity against mouse melanoma cells (B16) by markedly upregulating the intracellular reactive oxygen species (ROS) levels while showing no cytotoxicity to either B16 or normal cells (L02 and HK-2 cells) in the dark. Furthermore, HLA-ZnPc displayed excellent stability in both powder and Roswell Park Memorial Institute (RPMI) 1640 medium, indicating its promise for application in drug delivery and PDT. These results revealed a strategy for HP-based enhancement of ZnPc in PDT efficacy.

Study of Cytotoxic and Photodynamic Activities of Dyads Composed of a Zinc Phthalocyanine Appended to an Organotin.

The combination of photodynamic therapy and chemotherapy is a promising strategy to enhance cancer therapeutic efficacy and reduce drug resistance. In this study two zinc(II) phthalocyanine-tin(IV) conjugates linked by a triethylene glycol chain were synthesized and characterized. In these complexes, the zinc(II) phthalocyanine was used as a potential photosensitizer for PDT and the tin complex was selected as cytostatic moiety. The two dyads composed of zinc(II) phthalocyanine and tin complexes exhibited high cytotoxicity, in absence of light stimulation, against MCF-7 human breast cancer cells with low LC50 values in the range of 0.016-0.453 µM. In addition, these complexes showed superior cytotoxicity than their mixture of equimolar component, accompanied with a higher activity towards cancer cells compared to human healthy fibroblasts. However, under irradiation of the zinc phthalocyanine unit (at 650 nm) no photodynamic activity could be detected, due to the most likely quenching of zinc(II) phthalocyanine singlet excited state by the nearby tin complex according to a photoinduced electron transfer process. This study demonstrates the potential of heterometallic anticancer chemotherapeutics composed of a zinc phthalocyanine and tin complex, and it highlights that the development of such conjugates requires that the sensitizer preserves its photophysical properties and in particular its singlet oxygen sensitization ability in the conjugate in order to combine the PDT activity with the cytotoxicity of the anticancer drug.

A non-aggregated zinc(II) phthalocyanine with hexadeca cations for antitumor and antibacterial photodynamic therapies.

With a view to developing highly efficient photosensitizers for both antitumor and antimicrobial photodynamic therapies, herein, we reported a super cationic zinc(II) phthalocyanine (Pc4), which was prepared through the quaternization of the N, N-dimethyl-3-aminophenoxyl-hexadeca-substituted precursor Pc3. Meanwhile, two disubstituted analogues (Pc1 and Pc2) were also prepared as controls. The cationic Pc2 and Pc4 had higher photoactivities including fluorescence and singlet oxygen than the neutral counterparts Pc1 and Pc3, probably because of the inhibition of intramolecular charge transfer (ICT) effect of the amino groups. With the bulky steric effect and high hydrophilicity, Pc4 presented non-aggregated behavior in aqueous solutions. Therefore, it exhibited the highest in vitro photodynamic activity toward HepG2 cancer cells with an IC50 value as low as 0.04 µM. Furthermore, Pc4 showed a highly efficient in vivo PDT effect on H22 tumor-bearing mice with 98.7% tumor growth inhibition. In addition, Pc4 also exhibited an excellent in vitro and in vivo photodynamic inactivation against S. aureus. The results indicate that the non-aggregated hexadeca-cationic Pc4 could serve as a promising photosensitizer for both antitumor and antimicrobial photodynamic therapies.

Theranostic micelles combined with multiple strategies to effectively overcome multidrug resistance.

AIM: To develop precise targeting and versatile Fe3O4@SiO2-P123/PTX-ZnPc nanoparticles (FSP-PTX-ZnPc NPs) to reverse paclitaxel (PTX)-induced multidrug resistance in breast cancer. MATERIALS & METHODS: PTX and zinc (II) phthalocyanine (ZnPc) co-loaded FSP-PTX-ZnPc NPs were designed. The resulting multifunctional NPs were evaluated systematically in vitro and in vivo, and the mechanism of drug-resistance reversal was investigated. RESULTS: The NPs enhanced drug uptake in MCF-7/PDR cells by increasing drug solubility and impairing P-glycoprotein efflux. Additionally, magnetic targeting and enhanced permeation and retention (EPR) effect enhanced drug accumulation in tumor, facilitating the chemotherapeutic and photodynamic therapy effects. Moreover, FSP-PTX-ZnPc NPs could penetrate the blood-brain barrier, a desirable trait for brain disease therapy. CONCLUSION: The multifunctional FSP-PTX-ZnPc NPs are an effective tool for overcoming drug resistance in breast cancer.

Disassembly of Hydrophobic Photosensitizer by Biodegradable Zeolitic Imidazolate Framework-8 for Photodynamic Cancer Therapy.

Photodynamic therapy (PDT), an alternative to conventional cancer therapeutics, has gained increasing attention for its noninvasive advantage and simultaneous fluorescence imaging property. PDT is a tripartite process that functions in the simultaneous presence of a photosensitizer (PS), light, and available oxygen molecules. However, many highly efficient PSs are hydrophobic and highly tend to self-aggregate in aqueous solution, leading to quick quenching of the PDT effect. Here we construct zeolitic imidazolate framework-8 (ZIF-8) containing water-insoluble photosensitizer zinc(II) phthalocyanine (ZnPc), a typical hydrophobic PS, by one-step coprecipitation process, named as ZnPc@ZIF-8. The micropores of ZIF-8 act as molecular cages to separate and maintain hydrophobic ZnPc in the monomeric state and protect it against self-aggregation, which enables the encapsulated ZnPc to generate cytotoxic singlet oxygen (1O2) under light irradiation (650 nm) in aqueous condition. The formed nanosystem of ZnPc@ZIF-8 can be endocytosed by cancer cells and exhibits red fluorescent emission with excellent photodynamic activity for cancer treatment in vitro. In addition, ZnPc@ZIF-8 is acid-sensitive and would completely degrade after PDT, which can be monitored by the self-quenching of fluorescence emission of ZnPc. This work paves a facile way for resolving the problem of solubility and bioavailability of hydrophobic PS by utilizing metal-organic frameworks as nanocarriers.

Zinc(II) phthalocyanine fused in peripheral positions octa-substituted with alkyl linked carbazole: Synthesis, electropolymerization and its electro-optic and biosensor applications.

Zinc(II) phthalocyanine fused in peripheral positions octa-substituted with alkyl linked carbazole has been prepared by cyclomerization reaction of 4,5-bis(6-carbazole-9-yl-hexylsulfanil)phthalonitrile in the presence of anhydro Zn(II) acetate and a strong organic base (DBU). Synthesis steps were optimized and higher efficiency synthesis was achieved. The purpose of combining of carbazole moieties with phthalocyanine on the peripheral position is to enhance some properties such as photo and electrochemical properties because of strong electron-donating properties of carbazole group. This molecule has been electrochemically polymerized and the electrical and optical properties of the resulting conductive polymer have been investigated. Amperometric detection was carried out following oxygen consumption at -0.7V vs. the Ag reference electrode in phosphate buffer (50mM, pH 6.0). The novel biosensor showed a linear amperometric response for glucose within a concentration range of 0.05mM to 1.5mM (LOD: 0.024mM). This result shows that modification of the proposed biosensor by copolymerization have provided to give perfect response to different glucose concentrations. Because of its superior spectral and electrochemical properties and contained zinc metal which can act as a mediator during biochemical reactions, this material has been used as a glucose biosensor platform to detection for real samples.

Impact of dose and surface features on plasmatic and liver concentrations of biodegradable polymeric nanocapsules.

The effect of polymeric nanocapsule dose on plasmatic and liver concentrations 20min after intravenous administration in mice was evaluated. Nanocapsules were prepared with different polymers, namely, poly(D,L-lactide) (PLA), polyethylene glycol-block-poly(D,L-lactide) (PLA-PEG), and PLA with chitosan (PLA-Cs) and compared with a nanoemulsion. These formulations were labelled with a phthalocyanine dye for fluorescent detection. The nanostructures had narrow size distributions upon separation by asymmetric flow field flow fractionation with static and dynamic light scattering detection, with average hydrodynamic diameters in the 130-300nm range, negative zeta potentials, except PLA-Cs nanocapsules, which had a positive zeta potential. Flow cytometry revealed uptake mostly by monocytes and neutrophils in mice and human blood. PLA nanocapsules and the nanoemulsion showed dose-dependent plasma concentrations, where the percentage of plasmatic fluorescence increased with increasing administered dose. In contrast, PLA-PEG nanocapsules led to a dose-independent plasmatic profile. PLA-Cs nanocapsules showed the lowest plasmatic and liver levels of fluorescence at all administered doses and significant intravenous toxicity in mice. This work demonstrates the importance of considering the nanocarrier dose when evaluating pharmacokinetic and biodistribution data and emphasizes the role of surface features in determining the plasmatic and liver concentrations of a poorly soluble lipophilic encapsulated compound.

Mono- and tetra-substituted zinc(II) phthalocyanines containing morpholinyl moieties: Synthesis, antifungal photodynamic activities, and structure-activity relationships.

A series of zinc(II) phthalocyanines (ZnPcs) mono-substituted and tetra-substituted with morpholinyl moieties and their quaternized derivatives have been synthesized and evaluated for their antifungal photodynamic activities toward Candida albicans. The α-substituted, quaternized, and mono-substituted ZnPcs are found to have higher antifungal photoactivity than ß-substituted, neutral, and tetra-substituted counterparts. The cationic α-mono-substituted ZnPc (6a) exhibits the highest photocytotoxicity. Moreover, it is more potent than axially di-substituted analogue. The different photocytotoxicities of these compounds have also been rationalized by investigating their spectroscopic and photochemical properties, aggregation trend, partition coefficients, and cellular uptake. The IC90 value of 6a against C. albicans cells is as low as 3.3 µM with a light dose of 27 J cm(-2), meaning that 6a is a promising candidate as the antifungal photosensitizer for future investigations.

Dual Nuclear/Fluorescence Imaging Potantial of Zinc(II) Phthalocyanine in MIA PaCa-2 Cell Line.

BACKGROUND AND OBJECTIVE: Pancreatic cancer is very common and difficult to diagnose in early stage. Imaging systems for diagnosing cancer have many disadvantages. However, combining different imaging modalities offers synergistic advantages. Optical imaging is the most multidirectional and widely used imaging modality in both clinical practice and research. METHODS: In present study, Zinc(II) phthalocyanine [Zn(II)Pc] was synthesized, labeled with iodine- 131 and in vitro study was carried out. The intracellular uptake studies of radiolabeled Zn(II)Pc were performed in WI-38 [ATCC CCL-75™, tissue: human fibroblast lung] and MIA PaCa-2 [ATCC CRL-1420™, tissue: human epithelial pancreas carcinoma] cell lines. RESULTS: The intracellular uptake efficiency of radiolabeled Zn(II)Pc in MIA PaCa-2 cells was determined two times higher than WI-38 cells. Also, fluorescence imaging (FI) efficiency of synthesized Zn(II)Pc was investigated in MIA PaCa-2 cells and significant uptake was observed. CONCLUSION: Zn(II)Pc might be used as a new agent for dual fluorescence/nuclear imaging for pancreatic cancer.

Tetra-triethyleneoxysulfonyl substituted zinc phthalocyanine for photodynamic cancer therapy.

Photodynamic therapy (PDT) has emerged as an effective and minimally invasive treatment option for several diseases, including some forms of cancer. However, several drawbacks of the approved photosensitizers (PS), such as insufficient light absorption at therapeutically relevant wavelengths hampered the clinical effectiveness of PDT. Phthalocyanines (Pc) are interesting PS-candidates with a strong light absorption in the favourable red spectral region and a high quantum yield of cancer cell destroying singlet oxygen generation. Here, we evaluated the suitability of tetra-triethyleneoxysulfonyl substituted zinc phthalocyanine (ZnPc) as novel PS for PDT. ZnPc-induced phototoxicity, induction of apoptosis as well as cell cycle arresting effects was studied in the human gastrointestinal cancer cell lines of different origin. Photoactivation of ZnPc-pretreated (1-10 µM) cancer cells was achieved by illumination with a broad band white light source (400-700 nm) at a power density of 10 J/cm(2). Photoactivation of ZnPc-loaded cells revealed strong phototoxic effects, leading to a dose-dependent decrease of cancer cell proliferation of up to almost 100%, the induction of apoptosis and a G1-phase arrest of the cell cycle, which was associated with decrease in cyclin D1 expression. By contrast, ZnPc-treatment without illumination did not induce any cytotoxicity, apoptosis, cell cycle arrest or decreased cell growth. Antiangiogenic effects of ZnPc-PDT were investigated in vivo by performing CAM assays, which revealed a marked degradation of blood vessels and the capillary plexus of the chorioallantoic membrane of fertilized chicken eggs. Based on our data we think that ZnPc may be a promising novel photosensitizer for innovative PDT.