Synthesis and Encapsulation of a New Zinc Phthalocyanine Photosensitizer into Polymeric Nanoparticles to Enhance Cell Uptake and Phototoxicity (original) (raw)
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…, 2010
Unsymmetrical phthalocyanine derivatives have been widely studied as photosensitizers for photodynamic therapy (PDT), targeting various tumor types. However, the preparation of unsymmetrical phthalocyanines is always a challenge due to the presence of many possible structural isomers. Herein we report a new unsymmetrical zinc phthalocyanine, pentalysine βcarbonylphthalocyanine zinc (ZnPc-(Lys) 5 ), that was prepared in large quantity and high purity. This is a water-soluble cationic photosensitizer and maintains a high quantum yield of singlet oxygen generation similar to that of unsubstituted zinc phthalocyanine (ZnPc). Compared with anionic ZnPc counterparts, ZnPc-(Lys) 5 shows a higher level cellular uptake and 20-fold higher phototoxicity toward tumor cells. Pharmacokinetics and PDT studies of ZnPc-(Lys) 5 in S180 tumor-bearing mice showed a high ratio of tumor versus skin retention and significant tumor inhibition. This new molecular framework will allow synthetic diversity in the number of lysine residues incorporated and will facilitate future QSAR studies.
…, 2010
Unsymmetrical phthalocyanine derivatives have been widely studied as photosensitizers for photodynamic therapy (PDT), targeting various tumor types. However, the preparation of unsymmetrical phthalocyanines is always a challenge due to the presence of many possible structural isomers. Herein we report a new unsymmetrical zinc phthalocyanine, pentalysine βcarbonylphthalocyanine zinc (ZnPc-(Lys) 5 ), that was prepared in large quantity and high purity. This is a water-soluble cationic photosensitizer and maintains a high quantum yield of singlet oxygen generation similar to that of unsubstituted zinc phthalocyanine (ZnPc). Compared with anionic ZnPc counterparts, ZnPc-(Lys) 5 shows a higher level cellular uptake and 20-fold higher phototoxicity toward tumor cells. Pharmacokinetics and PDT studies of ZnPc-(Lys) 5 in S180 tumor-bearing mice showed a high ratio of tumor versus skin retention and significant tumor inhibition. This new molecular framework will allow synthetic diversity in the number of lysine residues incorporated and will facilitate future QSAR studies.
Lasers in Medical Science, 2009
Nanoparticles formulated from the biodegradable copolymer poly(lactic-coglycolic acid) (PLGA) were investigated as a drug delivery system to enhance tissue uptake, permeation, and targeting of zinc(II) phthalocyanine (ZnPc) for photodynamic therapy. Three ZnPc nanoparticle formulations were prepared using a solvent emulsion evaporation method and the influence of sonication time on nanoparticle shape, encapsulation and size distribution, in vitro release, and in vivo photodynamic efficiency in tumor-bearing mice were studied. Sonication time did not affect the process yield or encapsulation efficiency, but did affect significantly the particle size. Sonication for 20 min reduced the mean particle size to 374.3 nm and the in vitro release studies demonstrated a controlled release profile of ZnPc. Tumor-bearing mice injected with ZnPc nanoparticles exhibited significantly smaller mean tumor volume, increased tumor growth delay and longer survival compared with the control group and the group injected with free ZnPc during the time course of the experiment. Histopathological examination of tumor from animals treated with PLGA ZnPc showed regression of tumor cells, in contrast to those obtained from animals treated with free ZnPc. The results indicate that ZnPc encapsulated in PLGA nanoparticles is a successful delivery system for improving photodynamic activity in the target tissue.
Biotinylated-cationic zinc(II) phthalocyanine towards photodynamic therapy
Journal of Porphyrins and Phthalocyanines, 2018
Targeting biotin receptors in cancer cells can improve specifying of photosensitizers (PSs) for cancer treatment by photodynamic therapy (PDT) applications. Consequently, there has been extensive research focusing mainly on the design of PSs with optimized pharmaceutical properties and better targeting toward cancer cells. Herein a tailored mono-biotinylated zinc(II) phthalocyanine (Pc-1) substituted with six phenoxy-bis(triazolyl) substituents has been synthesized. This Pc-1 has been further modified to its cationic version (Pc-2) through quaternizing of the triazole moiety to gain water solubility. Both non-ionic zinc(II) phthalocyanine (Pc-1) and its cationic derivative (Pc-2) were characterized by standard spectroscopic techniques, namely; FT-IR, 1H and [Formula: see text]C NMR, UV-Vis and MALDI-TOF, and by elemental analysis. The photophysical and photochemical properties were evaluated in DMSO for the non-ionic Pc-1 and in both DMSO and water for the cationic Pc-2.
Photodiagnosis and photodynamic therapy, 2018
The aim of the present study was to modify the structural activity of zinc(II)phthalocyanine by combining it with thiophenyl groups then loaded in lipid nano-carriers and evaluates its parameters required for the structure-activity relationship (SAR) for photodynamic therapy (PDT) of cancer. Tetra (4-Thiophenyl) sulphonated phthalocyaninatozinc(II) (PhS.SONa)ZnPc 5 was synthesized and characterized by various spectroscopic methods as a test compound. Liver hepatocellular carcinoma (HepG2) cells were treated with the synthesized (PhS.SONa)ZnPc 5 derivative loaded in lipid nano carriers to understand the effect of combined compound on liver cancer cells. Furthermore, HepG2 cells were irradiated by visible red light at 60 mW/cm for 20 min. The phototoxicity of (PhS.SONa)ZnPc 5 after being formulated in both (L) and transfersomes (T) was investigated. Overall, the results indicate that combination of thiophenyl groups substitution, in particular in the structure of sulphonated zinc phth...
Peripherally and non-peripherally tetra-substituted zinc(II) phthalocyanines bearing 2-(2-{2-[3-(dimethylamino)phenoxy]ethoxy}ethoxy)ethoxy and 2-(2-{2-[3-(diethylamino)phenoxy]ethoxy}ethoxy)ethoxy groups (2a, 5a, 3a and 6a) were synthesized by cyclotetramerization of the corresponding phthalonitriles (2, 5, 3 and 6). Their quaternized ionic derivatives (2b, 5b, 3b and 6b) were also synthesized by the reaction of them with methyl iodide. The novel compounds were characterized by using standard spectroscopic techniques such as FT-IR, 1 H NMR, 13 C NMR, UV-vis, mass and elemental analyses. The obtained quaternized phthalocyanines (2b, 5b, 3b and 6b) showed amphiphilic behaviour with excellent solubility in both organic and aqueous solutions, which makes them potential photosensitizers for use in photodynamic therapy (PDT) of cancer. The photophysical (fluorescence quantum yields and lifetimes) and photochemical (singlet oxygen and photodegradation quantum yields) properties of these novel phthalocyanines were studied in DMSO for both non-ionic and ionic quaternized derivatives. However, these properties were examined in both DMSO and phosphate buffer solution (PBS) for quaternized ionic phthalocyanines. The effects of the positions of substituents ( peripheral or non-peripheral) and the quaternization of the nitrogen atoms on the substituents about their photophysical and photochemical properties were also compared in this study. The bovine serum albumin (BSA) binding behaviours of the studied quaternized ionic zinc(II) phthalocyanines were also described in PBS solutions. The quaternized phthalocyanines (2b, 5b, 3b and 6b) successfully displayed light-dependent photodamage in HeLa and HuH-7 cancer cells in photodynamic therapy treatment. The photosensitivity and the intensity of damage were found directly related to the concentration of the photosensitizers. † Electronic supplementary information (ESI) available. See ; Tel: +90 262 605 3019 9646 | Dalton Trans., 2015, 44, 9646-9658 This journal is
Nanomedicine : nanotechnology, biology, and medicine, 2017
In photodynamic therapy (PDT), the low absorptivity of photosensitizers in an aqueous environment reduces singlet oxygen generation efficiency and thereby decreases photosensitizing efficacy in biological conditions. To circumvent this problem, we designed a phthalocyanine-poly-L-glutamic acid conjugate (1-PG) made from a new phthalocyanine (Pc 1) monofunctionalized to allow adequate conjugation to PGA. The resulting 1-PG conjugate retained high absorptivity in the near-infrared (NIR) region at its λmax 675nm in an aqueous environment. The 1-PG conjugate demonstrated good singlet oxygen generation efficiency, increased uptake by 4 T1 breast cancer cells via clathrin-mediated endocytosis, and enhanced photocytotoxic efficacy. The conjugate also displayed a high light-dark toxicity ratio, approximately 1.5-fold greater than zinc phthalocyanine at higher concentration (10 μM), an important feature for the reduction of dark toxicity and unwanted side effects. These results suggest that ...
Photochemistry and Photobiology, 2012
A major difficulty in photodynamic therapy is the poor solubility of the photosensitizer (PS) under physiological conditions which correlates with low bioavailability. PS aggregation leads to a decrease in the photodynamic efficiency and a more limited activity in vitro and in vivo. To improve the aqueous solubility and reduce the aggregation of 2,9(10),16(17),23(24)-tetrakis[(2-dimethylamino)ethylsulfanyl] phthal-ocyaninatozinc(II) (Pc9), the encapsulation into four poloxamine polymeric micelles (T304, T904, T1107 and T1307) displaying a broad spectrum of molecular weight and hydrophilic-lipophilic balance was investigated. The aqueous solubility of Pc9 was increased up to 30 times. Morphological evaluation showed the formation of Pc9-loaded spherical micelles in the nanosize range. UV/Vis and fluorescence studies indicated that Pc9 is less aggregated upon encapsulation in comparison with Pc9 in water-DMSO 2% and remained photostable. Pc9-loaded micelles generated singlet molecular oxygen in high yields. Photocytotoxicity assays using human nasopharynx KB carcinoma cells confirmed that the encapsulation of Pc9 in T1107 and T1307 increases its photocytotoxicity by 10 times in comparison with the free form in water-DMSO. In addition, Pc9 incorporated into cells was mainly localized in lysosomes.
Organic & Biomolecular Chemistry, 2011
Treatment of 4,5-bis[4-(methoxycarbonyl)phenoxy]phthalonitrile and 4,5-bis[3,5-bis(methoxycarbonyl)phenoxy]phthalonitrile with an excess of 1,3-diiminoisoindoline in the presence of Zn(OAc) 2 •2H 2 O and 1,8-diazabicyclo[5.4.0]undec-7-ene in triethylene glycol monomethyl ether or polyethylene glycol monomethyl ether (with an average molecular weight of 550) led to "3 + 1" mixed cyclisation and transesterification in one pot, affording the corresponding di-b-substituted zinc(II) phthalocyanines in 7-23% yield. As shown by absorption spectroscopy, these compounds were essentially non-aggregated in N,N-dimethylformamide and could generate singlet oxygen effectively. The singlet oxygen quantum yields (U D = 0.53-0.57) were comparable with that of the unsubstituted zinc(II) phthalocyanine (U D = 0.56). These compounds in Cremophor EL emulsions also exhibited photocytotoxicity against HT29 human colorectal adenocarcinoma and HepG2 human hepatocarcinoma cells with IC 50 values in the range of 0.25-3.72 mM. The analogue with four triethylene glycol chains was the most potent photosensitiser and localised preferentially in the mitochondria of HT29 cells. The bis(polyethylene glycol)-counterpart could form surfactant-free nanoparticles both in water and in the culture medium. The hydrodynamic radii, as determined by dynamic laser light scattering, ranged from 6.3 to 79.8 nm depending on the preparation methods and conditions. The photocytotoxicity of these nanoparticles (IC 50 = 0.43-0.56 mM) was comparable with that of the Cremophor EL-formulated system (IC 50 = 0.34 mM).