Pentalysine β-Carbonylphthalocyanine Zinc: An Effective Tumor-Targeting Photosensitizer for Photodynamic Therapy

Graduate University of Chinese Academy of Sciences, 19 Yuquan Road, Shijingshan District, Beijing 100049, China.
ChemMedChem (Impact Factor: 2.97). 06/2010; 5(6):890-8. DOI: 10.1002/cmdc.201000042
Source: PubMed


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 beta-carbonylphthalocyanine 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.

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Available from: Michael Hamblin, Oct 06, 2015
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    • "Our previous work showed that ZnPc has a very low level of distribution in murine brain [8], thus the ligation of ZnPc to GnRH may reduce the penetration of the conjugate through blood-brain barrier, and minimize the side effect of GnRH in brain. Herein we report the synthesis and the physicochemical characterization of this ZnPc-GnRH conjugate, along with the evaluation of its photodynamic activity at cellular level. "
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    ABSTRACT: Photodynamic therapy (PDT) is a promising therapeutic modality which uses a photosensitizer to capture visible light resulting in phototoxicity in the irradiated region. PDT has been used in a number of pathological indications, including tumor. A key desirable feature of the photosensitizer is the high phototoxicity on tumor cells but not on normal cells. In this study, we conjugate a gonadotropin-releasing hormone (GnRH) to a photosensitizer, Zinc phthalocyanine (ZnPc), in order to enhance its specificity to breast cancer, which over-expresses GnRH receptor. ZnPc has unique advantages over other photosensitizers, but is difficult to derivatize and purify as a single isomer. We previously developed a straight-forward way to synthesize mono-substituted β-carboxy-phthalocyanine zinc (ZnPc-COOH). Photophysical and photochemical parameters of this ZnPc-GnRH conjugate including fluorescence quantum yield (Ф(f)), fluorescence decay time (τ(s)) and singlet oxygen quantum yield (Ф(Δ)) were evaluated and found comparable with that of ZnPc, indicating that addition of a GnRH peptide does not significantly alter the generation of singlet oxygen from ZnPc. Cellular uptakes and phototoxicities of this conjugate were tested and found significantly enhanced on human breast cancer cell lines overexpressing GnRH receptors (MDA-MB-231 and MCF-7 cells) compared to cells with low levels of GnRH receptors, such as human embryonic lung fibroblast (HELF) and human liver carcinoma (HepG2) cells. In addition, the cellular uptake of this conjugate toward MCF-7 cells were found clearly alleviated by a GnRH receptor blocker Cetrorelix, suggesting that the cellular uptake of this conjugate was GnRH receptor-mediated. Put together, these findings revealed that coupling ZnPc with GnRH analogue was an effective way to improve the selectivity of ZnPc towards tumors with over-expressed GnRH receptors.
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