Receptor-targeting phthalocyanine photosensitizer for improving antitumor photocytotoxicity.
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.
Danish-Chinese Centre for Proteases and Cancer, State Key Laboratory of Structural Chemistry, Fujian Institute of Research on the Structure of Matter, Chinese Academy of Sciences, Fuzhou, Fujian, China.
Peng
P
Xu
Jincan
J
Chen
Zhuo
Z
Chen
Shanyong
S
Zhou
Ping
P
Hu
Xueyuan
X
Chen
Mingdong
M
Huang
D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D001692:Biological Transport; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects / Q000528:radiation effects; D055598:Chemical Phenomena; D003624:Darkness; D007987:Gonadotropin-Releasing Hormone / Q000037:antagonists & inhibitors / Q000737:chemistry; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D054833:Isoindoles; D058990:Molecular Targeted Therapy; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D009942:Organometallic Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D010778:Photochemotherapy; D017319:Photosensitizing Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D011966:Receptors, LHRH / Q000378:metabolism*; D017967:Zinc Compounds
D000970:Antineoplastic Agents; D007211:Indoles; D054833:Isoindoles; D009942:Organometallic Compounds; D017319:Photosensitizing Agents; D011966:Receptors, LHRH; D017967:Zinc Compounds; C052159:Zn(II)-phthalocyanine; D007987:Gonadotropin-Releasing Hormone