zn(ii)-phthalocyanine and Liver-Neoplasms

Sorafenib, a multitargeted kinase inhibitor, has been reported to elicit a limited therapeutic effect in hepatocellular carcinoma (HCC). Currently, phototherapy, including photodynamic therapy (PDT) and photothermal therapy (PTT), is emerging as a powerful modality for cancer therapy. However, few studies have been reported the effectiveness of the combination of sorafenib with PDT and PTT in HCC. Herein, we designed and synthesized bovine serum albumin (BSA)-coated zinc phthalocyanine (ZnPc) and sorafenib (SFB) nanoparticle (ZnPc/SFB@BSA). The obtained ZnPc/SFB@BSA was able to trigger PDT, PTT, and chemotherapy. After irradiation by a 730 nm light, ZnPc/SFB@BSA significantly suppressed HCC cell proliferation and metastasis while promoted cell apoptosis in vitro. Furthermore, intravenous injection of ZnPc/SFB@BSA led to dramatically reduced tumor growth in an orthotopic xenograft HCC model. More importantly, ZnPc/SFB@BSA presented low toxicity and adequate blood compatibility. Therefore, a combination of ZnPc with sorafenib via BSA-assembled nanoparticle can markedly suppress HCC growth, representing a promising strategy for HCC patients.

Topics: Animals; Antineoplastic Agents; Carcinoma, Hepatocellular; Cell Line, Tumor; Cell Proliferation; Humans; Indoles; Isoindoles; Light; Liver Neoplasms; Male; Mice; Mice, Nude; Nanocapsules; Organometallic Compounds; Photochemotherapy; Photosensitizing Agents; Phototherapy; Reactive Oxygen Species; Serum Albumin, Bovine; Sorafenib; Xenograft Model Antitumor Assays; Zinc Compounds

The palliative treatment options for advanced hepatocellular carcinoma (HCC) are currently not satisfying. The use of photodynamic therapy (PDT) has gained much attention in the treatment of several cancers and has been approved as an alternative approach in treating different forms of cancers. We investigated for the first time the PDT effects of tetra-triethyleneoxysulfonyl zinc phthalocyanine (ZnPc) on HCC cells. Photoactivation of ZnPc loaded HCC cells resulted in a dose- and time- dependent growth inhibitory effect, the production of reactive oxygen species (ROS), induced cytotoxic effects and the induction of apoptosis in the investigated HCC cells (HepG2 and Huh-7). ZnPc-PDT inhibited the proliferation of HCC cells by up to 90% accompanied by a down-regulation of the activity and expression of the proliferation relevant mitogen-activated protein kinase (MAPK)-protein extracellular signal-regulated (ERK ½). Moreover, an up-regulation of proapoptotic BAX and a down-regulation of antiapoptotic B-cell lymphoma 2 (Bcl-2) expressions were observed with both proteins implicated in mitochondria-driven apoptosis. The investigation of the anti-tumor effect of ZnPc-PDT in vivo using the chicken chorioallantoic membrane assays (CAM) revealed a strong reduction in the size of HCC tumor plagues >80% after 4 days of PDT-treatment without affecting the survival of the developing embryo. The pronounced anti-proliferative and anti-tumor effects of ZnPc-PDT both in vitro and in vivo render ZnPc-PDT as a promising palliative treatment option for hepatocellular carcinoma.

Topics: Apoptosis; bcl-2-Associated X Protein; Carcinoma, Hepatocellular; Cell Line, Tumor; Cell Proliferation; Down-Regulation; Humans; Indoles; Isoindoles; Liver Neoplasms; Mitochondria; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Neovascularization, Physiologic; Organometallic Compounds; Photochemotherapy; Photosensitizing Agents; Proto-Oncogene Proteins c-bcl-2; Reactive Oxygen Species; Up-Regulation; Zinc Compounds

A biotinylated glutathione (GSH)-responsive zinc(II) phthalocyanine has been prepared and characterized. With a 2,4-dinitrobenzenesulfonyl moiety, its fluorescence emission and singlet oxygen generation were silenced in its intact state. Upon exposure to high concentration of GSH, its photosensitizing properties were restored in phosphate buffered saline and inside tumor cells. It also showed preferential uptake on HepG2 human hepatocarcinoma cells (with higher biotin receptor expression) rather than Chinese hamster ovary (CHO) cells (with lower biotin receptor expression). Upon irradiation, it caused photocytotoxicity with an IC

Topics: Animals; Biotinylation; Cell Survival; CHO Cells; Cricetinae; Cricetulus; Endoplasmic Reticulum; Endoplasmic Reticulum Chaperone BiP; Glutathione; Heat-Shock Proteins; Hep G2 Cells; Humans; Indoles; Isoindoles; Light; Liver Neoplasms; Organometallic Compounds; Photochemotherapy; Photosensitizing Agents; Transcription Factor CHOP; Zinc Compounds

Targeted photodynamic therapy is a new promising therapeutic strategy to overcome growing problems in contemporary medicine, such as drug toxicity and drug resistance. A series of erlotinib-zinc(II) phthalocyanine conjugates were designed and synthesized. Compared with unsubstituted zinc(II) phthalocyanine, these conjugates can successfully target EGFR-overexpressing cancer cells owing to the presence of the small molecular-target-based anticancer agent erlotinib. All conjugates were found to be essentially non-cytotoxic in the absence of light (up to 50 μM), but upon illumination, they show significantly high photo-cytotoxicity toward HepG2 cells, with IC50 values as low as 9.61-91.77 nM under a rather low light dose (λ=670 nm, 1.5 J cm(-2) ). Structure-activity relationships for these conjugates were assessed by determining their photophysical/photochemical properties, cellular uptake, and in vitro photodynamic activities. The results show that these conjugates are highly promising antitumor agents for molecular-target-based photodynamic therapy.

Topics: Antineoplastic Agents; Apoptosis; Cell Line; Drug Design; ErbB Receptors; Erlotinib Hydrochloride; Hep G2 Cells; Humans; Indoles; Isoindoles; Light; Liver Neoplasms; Microscopy, Confocal; Organometallic Compounds; Photochemotherapy; Photosensitizing Agents; Quinazolines; Structure-Activity Relationship; Zinc Compounds

The combination of photodynamic therapy and chemotherapy is a promising strategy to overcome growing problems in contemporary medicine, such as low therapeutic efficacy and drug resistance. Four zinc(II) phthalocyanine-coumarin conjugates were synthesized and characterized. In these complexes, zinc(II) phthalocyanine was used as the photosensitizing unit, and a coumarin derivative was selected as the cytostatic moiety; the two components were linked via a tri(ethylene glycol) chain. These conjugates exhibit high photocytotoxicity against HepG2 human hepatocarcinoma cells, with low IC50 values in the range of 0.014-0.044 μM. The high photodynamic activities of these conjugates are in accordance with their low aggregation tendency and high cellular uptake. One of these conjugates exhibits high photocytotoxicity and significantly higher chemocytotoxicity. The results clearly show that the two antitumor components in these conjugates work in a cooperative fashion. As shown by confocal microscopy, the conjugates can localize in the mitochondria and lysosomes, and one of the conjugates can also localize in the cell nuclei.

Topics: Antineoplastic Agents; Carcinoma, Hepatocellular; Cell Line, Tumor; Cell Proliferation; Coumarins; Hep G2 Cells; Humans; Indoles; Isoindoles; Light; Liver Neoplasms; Organometallic Compounds; Photochemotherapy; Photosensitizing Agents; Zinc Compounds

To integrate photodynamic therapy (PDT) with photothermal therapy (PTT) and chemotherapy for enhanced antitumor efficiency, we developed a mild and rational route to synthesize novel multifunctional GdOF:Ln@SiO2 (Ln = 10%Yb/1%Er/4%Mn) mesoporous capsules using strong up-conversion luminescent (UCL) GdOF:Ln as cores and mesoporous silica layer as shells, followed by modification with varied functional groups onto the framework. It was found that due to the codoped Yb/Er/Mn in GdOF, the markedly enhanced red emission can efficiently transfer energy to the conjugated PDT agent (ZnPc) which produces high singlet oxygen, and the incorporated carbon dots outside the shell can generate obvious thermal effect under 980 nm laser irradiation and also prevent the premature leaking of ZnPc. Simultaneously, the as-produced thermal effect can obviously enhance the doxorubicin (DOX) release, which greatly improves the chemotherapy, resulting in a synergistic therapeutic effect. The system exhibits drastically enhanced therapeutic efficiency against tumor growth, as demonstrated both in vitro and in vivo. Especially, the doped rare earth ions in the host endow the material with excellent UCL imaging, magnetic resonance imaging (MRI), and computed tomography (CT) imaging properties, thus realizing the target of multimodal imaging guided multiple therapies.

Topics: Animals; Carcinoma, Hepatocellular; Cell Line; Cell Survival; Doxorubicin; Drug Carriers; Drug Liberation; Female; Gadolinium; HeLa Cells; Humans; Indoles; Infrared Rays; Isoindoles; Liver Neoplasms; Materials Testing; Mice; Multimodal Imaging; Nanoparticles; Organometallic Compounds; Photochemotherapy; Porosity; Silicon Dioxide; Theranostic Nanomedicine; Zinc Compounds

A near infrared fluorescence probe, lactose substituted zinc phthalocyanine, [2,9(10),16(17),23(24)-tetrakis((1-(β-d-lactose-2-yl)-1H-1,2,3-triazol-4-yl)methoxyl)phthalocyaninato] zinc(II), was synthesized via click reaction. Structural characterization and optical experiment demonstrated its excellent biocompatibility and fluorescence imaging ability. Near infrared fluorescence imaging in vivo for liver cancer, lung cancer and melanoma cancer with tumor bearing nude mice as models demonstrated that lactose substituted zinc phthalocyanine has specifically targeting ability to liver cancer while no targeting to lung cancer or melanoma, which implied its potential in liver cancer diagnosis as a near infrared optical probe.

Topics: Animals; Cell Survival; Drug Stability; Fluorescent Dyes; Hep G2 Cells; Humans; Indoles; Isoindoles; Lactose; Liver Neoplasms; Melanoma, Experimental; Mice; Mice, Nude; Organometallic Compounds; Radiography; Solubility; Spectroscopy, Near-Infrared; Tissue Distribution; Transplantation, Heterologous; Zinc Compounds

Photodynamic therapy (PDT) is a novel and promising antitumor treatment. Phthalocyanine-mediated PDT has shown antitumor activity in some tumor cells, but the effect of new hydrophilic/lipophilic tetra-α-(4-carboxyphenoxy)phthalocyanine zinc (TαPcZn)-mediated PDT (TαPcZn-PDT) on human hepatocellular carcinoma Bel-7402 cells and underlying mechanisms have not been clarified. In the present study, therefore, the ultraviolet-visible (UV-vis) absorption spectrum and cellular localization of TαPcZn, and effect of TαPcZn-PDT on the proliferation, apoptosis, cell cycle, Bcl-2 and Fas in Bel-7402 cells were investigated by spectrophotometry, inverted microscope, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide (MTT) assay, electron microscopy, annexinV-FITC/propidium iodide double staining, DNA content and immunoblot assay, respectively. We found that an intense absorption in UV-vis absorption spectrum of TαPcZn was in the red visible region at 650-680 nm, where light penetration in tissue is efficient, that green TαPcZn localized to both plasma membrane and nuclear membrane of Bel-7402 cells, signifying that there was a selective uptake of TαPcZn in Bel-7402 cells and TαPcZn-PDT would be expected to directly damage DNA, and that TαPcZn-PDT significantly resulted in the proliferation inhibition, apoptosis induction, S cell cycle arrest, and down-regulation of Bcl-2 and Fas. Taken together, we conclude that TαPcZn-PDT inhibits the proliferation of Bel-7402 cells by triggering apoptosis and arresting the cell cycle.

Topics: Apoptosis; Carcinoma, Hepatocellular; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Fibroblasts; Humans; Indoles; Isoindoles; Light; Liver Neoplasms; Molecular Structure; Organometallic Compounds; Photochemotherapy; Photosensitizing Agents; Zinc Compounds