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.

Download full-text


Available from: Michael Hamblin
  • Source
    • "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. "
    [Show abstract] [Hide abstract]
    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.
    Full-text · Article · May 2012 · PLoS ONE
  • [Show abstract] [Hide abstract]
    ABSTRACT: A novel photosensitizer, pentalysine beta-carbonyl-phthalocyanine zinc [ZnPc-(Lys)(5)] has tendency to form aggregate in aqueous solution. The observed in vivo Photodynamic therapy (PDT) effect of ZnPc-(Lys)(5) suggests a disaggregation mechanism. In this study, the equilibrium binding constant K-a, the numbers of binding sites n and the distance of Forster radii r between ZnPc-(Lys)(5) and human serum albumin (HSA) are measured by Spectroscopy. A molecular model of HSA-ZnPc-(Lys)(5) complex was generated according to these datum. This molecular model provides rationale that the molecular interaction between HSA and ZnPc-(Lys)(5) facilitates the dissociation of ZnPc aggregates.
    No preview · Conference Paper · Jan 2011
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The in vitro phototoxicity of a photostable, synthetic, water-soluble, halogenated bacteriochlorin, 5,10,15,20-tetrakis(2-chloro-5-sulfophenyl)bacteriochlorin (TCPBSO3H), toward mouse melanoma (S91) cells is ∼60-fold higher than that of the analogous porphyrin, and is associated with very weak toxicity in the dark; 90% of S91 cells were killed in response to a light dose of 0.26 J cm(-2) in the presence of [TCPBSO3H]=5 μM. In vivo toxicity toward DBA mice is very low, even at doses of 20 mg kg(-1). In vivo pharmacokinetics and biodistribution of TCPBSO3H were studied in DBA mice with S91 tumors; 24 h after intraperitoneal injection of 10 mg kg(-1), TCPBSO3H demonstrated preferential accumulation in S91 mouse melanoma, with tumor-to-normal tissue ratios of 3 and 5 for muscle and skin, respectively. Photodynamic therapy (PDT) performed under these conditions, with 90 mW cm(-2) diode laser irradiation at λ 750 nm for 20 min (total light dose of 108 J cm(-2)), resulted in tumor regression. Tumor recurrence was observed only approximately two months after treatment, confirming the efficacy of this PDT against melanoma.
    Full-text · Article · Mar 2011 · ChemMedChem
Show more