pH响应两亲嵌段锌酞菁聚合物光敏剂的制备及光活性

将氨基锌酞菁（ZnTAPc）与甲基丙烯酰氯反应制备出含有不饱和双键的取代锌酞菁衍生物（MeZnAPc）,采用ATRP法将聚乙二醇单甲醚大分子引发剂（mPEG110-Br）与甲基丙烯酸（2-异丙胺基）乙酯（DPA）和MeZnAPc共聚,制得一种新型pH响应两亲嵌段锌酞菁聚合物光敏剂（PEG110-b-P（DPAn-co-MeZnAPcm））.用1HNMR,FTIR对MeZnAPc和聚合物光敏剂进行表征.UV-vis测试表明该聚合物光敏剂在pH6.0～6.5具有较好的pH响应性.以1,3-二苯基苯并呋喃（DPBF）为底物研究了该聚合物光敏剂的光催化氧化效率,结果表明其具有较高光活性.利用该聚合物光敏剂在不同pH的水溶液中对L-色氨酸进行光催化氧化实验,结果发现在pH5.5不存在胶束时,锌酞菁可以较好地分散在溶液中,并能维持较高光活性,而在pH7.4形成胶束时可以将锌酞菁很好地包裹在其内部,使其光活性大大降低.因此,这种pH响应两亲嵌段锌酞菁聚合物作为一种新型光敏剂,在光动力学治疗领域有较好的应用前景.     

两亲性酞菁锌对人体肝癌细胞的光灭活作用

采用四甲基偶氮唑蓝比色法(MTT法),考察了两亲性α-四(对-羧基苯氧基)酞菁锌(Ⅱ)光敏剂对Bel-7402人体肝癌细胞的离体光动力学行为,研究了浓度和光照时间对光灭活作用的影响.结果发现:在适宜的浓度下,酞菁锌光敏剂表现出了良好的抑制作用,且此抑制过程遵循一级反应的动力学规律.另外,酞菁在光催化下产生的单重态氧能损坏癌变的细胞膜,导致靶对细胞的死亡.     

β-氢醌-四(对羟基苯基)卟啉的合成及其抗肿瘤活性

合成并初步研究了新型β-取代卟啉光敏剂2-氢醌-5,10,15,20-四(4-羟基苯基)卟啉锌(II)(Zn(II)P)、2-氢醌-5,10,15,20-四(4-羟基苯基)卟啉铜(II)(Cu(II)P)的抗肿瘤活性。结果表明,2-氢醌-5,10,15,20-四(4-羟基苯基)卟啉锌(II)的合成总产率60%,该光敏剂对慢性骨髓性白血病肿瘤细胞(K562)具有很好的光敏毒性,Zn(II)P的浓度为320mmol/L时,就能抑制90%以上的白血病肿瘤细胞的生长。     

温敏性金属酞菁聚合物的制备及光活性

对氨基锌酞菁进行改性,并将其以共价键接枝到聚N-异丙基丙烯酰胺分子链上,制得一种新型的既有温敏性又有光活性的锌酞菁聚合物．与小分子氨基锌酞菁相比,所合成的锌酞菁聚合物能溶解于大多数有机溶剂和水,而且,在水溶液中表现出良好的温敏性,其低临界溶解温度为34．1℃．通过锌酞菁聚合物对单线态氧捕捉剂1,3-二苯基苯并呋喃的光催化降解测试,结果表明在可见光照射下,锌酞菁聚合物无论在溶解状态还是沉淀状态都具有较高的光活性．基于这些特殊性能,这种锌酞菁温敏聚合物作为一种新型光敏剂,有望在光动力学治疗领域得到广泛的应用．     

纳米载体包载锌酞菁及其衍生物用于光动力抗癌的研究进展

锌酞菁(ZnPc)是一种高效的第二代光敏剂,具有良好的光物理和光化学性质,可用于癌症的光动力治疗(PDT)。然而,由于共轭分子间的π-π作用力,锌酞菁溶解性差、结晶趋势强,阻碍了其直接用药。为了克服这个问题,大量纳米载体被研究开发。本文旨在对近五年纳米载体包载锌酞菁及其衍生物用于光动力抗癌的研究进行综述,根据其与锌酞菁及其衍生物的相互作用分为基于聚离子复合的纳米载体、基于物理包封以及化学键合的纳米载体。     

新型不对称酞菁锌的合成和表征

以4-硝基邻苯二甲腈为主要原料,合成了2(3),9(10),16(17),23(24)-四-(正庚酰胺基)-酞菁锌、2(3),9(10),16(17),23(24)-四-(甲氧基)-酞菁锌、2(3),9(10),16(17),23(24)-四-(对叔丁基苯氧基)-酞菁锌和2(3),9(10),16(17),23(24)-四-(苯氧基)-酞菁锌等4种对称型酞菁.在此基础上,选取4-对叔丁基苯氧基邻苯二甲腈为前驱体,采用概率法合成了含有氨基、羧基的2种不对称酞菁锌(A3B).     

新型喹啉-吲哚衍生物的设计、合成及抗肿瘤活性研究（英文）

作为开发新型有效抗癌药物的进一步工作,采用分子杂交策略和路易斯酸催化偶联反应设计合成了一系列新型喹啉-吲哚类化合物.使用噻唑蓝(MTT)法评估了所合成的化合物对人胃癌细胞(MGC-803)、人食管癌细胞(Kyse450)和人结肠癌细胞(HCT-116)的体外抑制活性.其中,2-氯-4-(5-甲氧基-1H-吲哚-3-基)喹啉(9b)展示较好的体外抗肿瘤活性,对MGC-803、Kyse450和HCT-116三种人源癌细胞IC50值分别为0.58, 0.60和0.68μmol·L-1,优于阳性对照药5-氟尿嘧啶(5-Fu)对这三种肿瘤细胞的抑制活性.进一步机制研究表明,化合物9b能够剂量依赖地抑制人胃癌细胞MGC-803和HGC-27的增殖和克隆形成.化合物9b能够诱导人胃癌细胞MGC-803和HGC-27内源性凋亡和下调相关凋亡蛋白的表达,并使细胞周期阻滞在G2/M期.以上结果表明,化合物9b可以作为先导化合物,用于进一步研究开发新型高效抗肿瘤药物.     

芳氧基取代酞菁锌的合成及光物理化学性质

合成得到3-(5-氨基-萘氧基)邻苯二甲腈(C18H11N3O)、4-(5-氨基-萘氧基)邻苯二甲腈(C18H11N3O)、3-联苯氧基邻苯二甲腈(C20H12N2O)及4-联苯氧基邻苯二甲腈(C20H12N2O)4种未见报导的取代邻苯二甲腈,以此为前躯体合成了四[α-(5-氨基-萘氧基)]酞菁锌(C72H44N12O4Zn)、四[β-(5-氨基-萘氧基)]酞菁锌(C72H44N12O4Zn)、四[α-(联苯氧基)]酞菁锌(C80H48N8O4Zn)和四[β-(联苯氧基)]酞菁锌(C80H48N8O4Zn)4种未见报导的芳氧基取代酞菁锌配合物。通过测定它们的紫外-可见吸收光谱、荧光发射光谱,获得其最大吸收波长及其摩尔消光系数、最大发射波长、荧光量子产率(ΦF)、单线态氧量子产率(ΦΔ)及光降解速率常数并与其类似物进行了比较,探讨了它们的光物理光化学性质的构效关系。研究结果表明四[α-(联苯氧基)]酞菁锌在红光区具有大的摩尔消光系数,且具有较高的ΦΔ,有望开发成为光动力治疗用光敏剂。     

四取代羧基酞菁锌与白蛋白共价结合物的制备与光谱性质

通过成酰胺键的方式制备了一系列含羧基酞菁和白蛋白(牛血清白蛋白(BSA),人血清白蛋白(HSA))之间的共价结合物,所涉及到的酞菁分别是α-四(4-羧基苯氧基)酞菁锌(1)和α-四[4-(2-羧基乙基)苯氧基]酞菁锌(3),以及它们相应的β位四取代酞菁锌(化合物2和4).比较了游离酞菁以及它们的白蛋白结合物在磷酸盐缓冲溶液(PBS)中的光谱性质.结果表明,当酞菁被共价固定于白蛋白大分子上之后,展现出比游离酞菁更明显的单体特征吸收,而且结合物中的酞菁光谱特征不受体系pH值变化的影响.羧基在酞菁环上的取代位置,对酞菁与白蛋白结合前后的光谱转变幅度有影响,α位取代比β位取代更有利于光谱的变化.化合物1和3的白蛋白共价结合物在PBS溶液中甚至呈现出单体形式为主的光谱特征,Q带最大吸收波长分别位于697和706nm附近.     

具有Frétchet树枝结构的新型酞菁锌(Ⅱ)配合物:四-{3,5-二-[3,5-二-(4-羧基苯甲氧基)苯甲氧基]-苯甲氧基}酞菁锌(Ⅱ)的合成与表征

报道了一种新型Frétchet树枝配体取代酞菁锌(II)配合物:四-{3,5-二-[3,5-二-(4-羧基苯甲氧基)苯甲氧基]-苯甲氧基}酞菁锌(II)的合成与表征.首先将对氰基苄溴与3,5-二羟基苯甲醇通过Frétchet反应合成3,5-[二-(4-氰基苯甲氧基)]苯甲醇(1),1与四溴化碳和三苯基膦在四氢呋喃中反应合成3,5-二-(4-氰基苯甲氧基)苄溴(2),2与3,5-二羟基苯甲醇反应合成3,5-二-[3,5-二-(4-氰基苯甲氧基)苯甲氧基]苯甲醇(3),接着,3与4-硝基邻苯二甲腈合成"前驱物"四-{3,5-[二-(4-氰基苯甲氧基)]}苯甲氧基邻苯二甲腈(4),然后以1,8-二氮杂双环[5.4.0]十一碳-7-烯(DBU)为催化剂,醋酸锌为模板剂,4通过缩聚反应合成氰基端基的Frétchet树枝配体取代酞菁锌四-{3,5-二-[3,5-二-(4-氰基苯甲氧基)苯甲氧基]-苯甲氧基}锌酞菁配合物5,最后,5的氰基端基在NaOH溶液中水解为相应的以羧基端基Frétchet树枝配体取代酞菁锌:四-{3,5-二-[3,5-二-(4-羧基苯甲氧基)苯甲氧基]-苯甲氧基}酞菁锌(II)(6).采用元素分析,IR,1H NMR,ESI-MS和MALDI-TOF-MS表征所有化合物的结构,通过UV/Vis,稳态和瞬态荧光光谱法研究了5和6的光物理性质.5和6是一类性能较好的树枝状酞菁光敏剂.     

Poly(ethylene glycol) conjugated nano-graphene oxide for photodynamic therapy

A novel methoxy-poly(ethylene glycol) modified nano-graphene oxide (NGO-mPEG) was designed and synthesized as a photosensitizer (PS) carrier for photodynamic therapy of cancer. NGO with a size below 200 nm was prepared using a modified Hummers’ method. NGO was observed by AFM to exhibit a structure with single-layer graphene oxide sheets down to a few nanometers in height. Hydrophilic mPEG conjugation of NGO (NGO-mPEG) was found to enhance solubility in cell culture media. No apparent cytotoxicity of the NGO-mPEG was observed towards MCF-7 carcinoma cell line. Zinc phthalocyanine (ZnPc), a photosensitizer for photodynamic therapy, was loaded in the NGO-PEG through π-π stacking and hydrophobic interactions, with the drug loading efficiency up to 14 wt%. Hydrophobic ZnPc was internalized in MCF-7 cells, exhibiting a pronounced phototoxicity in the cells under Xe light irradiation. The results indicate a great potential of NGO-mPEG for photodynamic therapy of cancer.     

BIOLOGICAL ACTIVITIES OF PHTHALOCYANINES. XIII. THE EFFECTS OF HUMAN SERUM COMPONENTS ON THE in vitro UPTAKE AND PHOTODYNAMIC ACTIVITY OF ZINC PHTHALOCYANINE

Abstract— The effect of human serum components on the photodynamic activity of zinc phthalocyanine (ZnPc) toward Chinese hamster fibroblasts (lineV–79) was studied. Photodynamic activities were correlated with cellular uptake of radiolabeled [⁶⁵Zn]ZnPc, which allowed corrections to be made for the amount of sensitizer present in the cells at the time of irradiation and to express photodynamic efficiences on a cellular dye concentration basis. All serum components, with the exception of high-density lipoproteins, inhibit uptake of ZnPc byV–79 cells, when compared to incubation of ZnPc with the same cells in serum-free medium. High-density lipoproteins increased ZnPc uptake by 23%, but the photodynamic efficiency corrected for the cellular ZnPc concentration was unaffected. Very low-density lipoprotein and globulins decreased ZnPc cell uptake but likewise did not affect the cellular photodynamic efficiency of the dye. In contrast low-density lipoprotein and albumin, while inhibiting ZnPc cell uptake, increased the cellular photodynamic efficiency of ZnPc, suggesting that these proteins facilitate localization of the dye at cellular targers sensitive to photodynamic damage and vital to cell survival. We conclude from these results that association of ZnPc with serum components can have important, and widely differing, effects on both degree of uptake and cellular distribution of the photosensitizer.     

Solvent Induced Conversion of a Self-Assembled Gyrobifastigium to a Barrel and Encapsulation of Zinc-Phthalocyanine within the Barrel for Enhanced Photodynamic Therapy

A rare gyrobifastigium architecture ( GB ) was constructed by self-assembly of a tetradentate donor ( L ) with Pd^II acceptor in DMSO. The GB was converted to its isomeric tetragonal barrel ( MB ) upon treatment with water. The hydrophobic cavity of MB has been explored for the encapsulation of zinc-phthalocyanine ( ZnPc ), which is an excellent photosensitizer for photodynamic therapy (PDT). However, the poor water-solubility and aggregation tendency are the main reasons for the suboptimal PDT performance of free ZnPc in the aqueous medium. Effective solubilization of ZnPc in an aqueous medium was achieved by encapsulating it in the cavity of MB . The inclusion complex ( ZnPc⊂MB ) showed enhanced singlet oxygen generation in water. Higher cellular uptake and anticancer activity of the ZnPc⊂MB compared to free ZnPc on HeLa cells indicate that encapsulation of ZnPc in an aqueous host is a potential strategy for enhancement of its PDT activity in water.     

Photodynamic activity of substituted zinc trisulfophthalocyanines: role of plasma membrane damage

We recently reported that variations in cellular phototoxicity among a series of alkynyl-substituted zinc trisulfophthalocyanines (ZnPcS3Cn) correlates with their hydrophobicity, with the most amphiphilic derivatives showing the highest cell uptake and phototoxicity. In this study we address the role of the plasma membrane in the photodynamic response as it relates to the overall hydrophobicity of the photosensitizer. The membrane tracker dye 1-[4(trimethylamino)phenyl]-6-phenylhexa-1,3,5-triene (TMA-DPH), which is incorporated into plasma membranes by endocytosis, was used to establish plasma membrane uptake by EMT-6 cells of the ZnPcS3C, by colocalization, and TMA-DPH membrane uptake rates after photodynamic therapy were used to quantify membrane damage. TMA-DPH colocalization patterns show plasma membrane uptake of the photosensitizers after short 1 h incubation periods. TMA-DPH plasma membrane uptake rates after illumination of the photosensitizer-treated cells show a parabolic relationship with photosensitizer hydrophobicity that correlates well with the phototoxicity of the ZnPcS3C,. After a 1 h incubation period, overall phototoxicity correlates closely with the postillumination rate of TMA-DPH incorporation into the cell membrane, suggesting a major role of plasma membrane damage in the overall PDT effect. In contrast, after a 24 h incubation, phototoxicity shows a stronger but imperfect correlation with total cellular photosensitizer uptake rather than TMA-DPH membrane uptake, suggesting a partial shift in the cellular damage responsible for photosensitization from the plasma membrane to intracellular targets. We conclude that plasma membrane localization of the amphiphilic ZnPcS3C6-C9 is a major factor in their overall photodynamic activity.     

A new naturally derived photosensitizer and its phototoxicity on head and neck cancer cells

In our screening for photosensitizers from natural resources, 15(1)-hydroxypurpurin-7-lactone ethyl methyl diester (compound 1) was isolated for the first time from an Araceae plant. To evaluate the efficacy of compound 1 as a photosensitizer for head and neck cancers, compound 1 was studied in reference to a known photosensitizer pheophorbide-a (Pha), in terms of photophysical properties, singlet oxygen generation and in in vitro experiments (intracellular uptake and phototoxicity assays) in two oral (HSC2 and HSC3) and two nasopharyngeal (HK1 and C666-1) cancer cell lines. In this study, compound 1 exhibited higher intracellular uptake over 24 h compared with Pha in both HSC3 and HK1 cells. When activated by ≥4.8 J cm(-2) of light, compound 1 was slightly more potent as a photosensitizer than Pha by consistently having marginally lower IC(50) values across different cell lines. In flow cytometry experiments to study the mechanism of photoactivated cell death in HSC3, compound 1 was observed to induce more pronounced apoptosis compared with Pha, which may have been driven by the transient G(2)/M cell cycle block which was also observed. These promising results on compound 1 warrant its further investigation as a clinically useful photodynamic therapy agent for head and neck cancer.     

Ferric Ion Driven Assembly of Catalase-like Supramolecular Photosensitizing Nanozymes for Combating Hypoxic Tumors

A facile approach to assemble catalase-like photosensitizing nanozymes with a self-oxygen-supplying ability was developed. The process involved Fe³⁺-driven self-assembly of fluorenylmethyloxycarbonyl (Fmoc)-protected amino acids. By adding a zinc(II) phthalocyanine-based photosensitizer (ZnPc) and the hypoxia-inducible factor 1 (HIF-1) inhibitor acriflavine (ACF) during the Fe³⁺-promoted self-assembly of Fmoc-protected cysteine (Fmoc-Cys), the nanovesicles Fmoc-Cys/Fe@Pc and Fmoc-Cys/Fe@Pc/ACF were prepared, which could be disassembled intracellularly. The released Fe³⁺ could catalyze the transformation of H₂O₂ enriched in cancer cells to oxygen efficiently, thereby ameliorating the hypoxic condition and promoting the photosensitizing activity of the released ZnPc. With an additional therapeutic component, Fmoc-Cys/Fe@Pc/ACF exhibited higher in vitro and in vivo photodynamic activities than Fmoc-Cys/Fe@Pc, demonstrating the synergistic effect of ZnPc and ACF.     

Photodynamic activities of silicon phthalocyanines against achromic M6 melanoma cells and healthy human melanocytes and keratinocytes

Dichlorosilicon phthalocyanine (Cl2SiPc) and bis(tri-n-hexylsiloxy) silicon phthalocyanine (HexSiPc) have been evaluated in vitro as potential photosensitizers for photodynamic therapy (PDT) against the human amelanotic melanoma cell line M6. Each photosensitizer is dissolved in a solvent-PBS mixture, or entrapped in egg-yolk lecithin liposomes or in Cremophor EL micelles. The cells are incubated for 1 h with the sensitizer and then irradiated for 20 min, 1 h or 2 h (lambda > 480 nm, 10 mW cm-2). The photocytotoxic effect is dependent on the photosensitizer concentration and the light dose. Higher phototoxicity is observed after an irradiation of 2 h: treatment with a solution of photosensitizer (2 x 10(-9) M) leads to 10% (HexSiPc in egg-yolk lecithin liposomes) or 20% (Cl2SiPc in DMF-PBS solution) cell viability. After 1 h incubation and 20 min of light exposure, the photodynamic effect is connected with the type of delivery system used. For HexSiPc, lower cell viability is found when this photosensitizer is entrapped in egg-yolk lecithin instead of solvent-PBS or for Cremophor EL micelles with Cl2SiPc. Liposome-delivered HexSiPc leads to lipid damage in M6 cells, illustrated by an increase of thiobarbituric acid-reacting substances (TBARs), but the change is not significant with Cremophor EL. The same is observed for the antioxidative defences after photodynamic stress. The cells irradiated with HexSiPc entrapped in liposomes display an increase of superoxide dismutase (SOD) activity and a decrease of glutathione (GSH) level, glutathione peroxidase (GSHPx) and catalase (Cat) activities.     

Increased cytotoxicity and phototoxicity in the methylene blue series via chromophore methylation

The cytotoxic and photodynamic activities of the commercially-available biological stains methylene blue (MB), 1,9-dimethyl MB (Taylor's Blue) and a newly synthesised compound, 1-methyl MB, were measured against the murine mammary tumour cell line, EMT-6 Both 1-methyl MB and 1,9-dimethyl MB exhibited increased dark toxicity with concomitant higher phototoxicity compared to MB at a light dose of 7.2 J cm⁻². While increasing the light dose as a function of the fluence rate increased the photocytotoxicity of MB, this had little effect on the methylated derivatives. In vitro chemical testing proved that successive methylation rendered the phenothiazinium chromophore both more resistant to reduction to its inactive leuco form, and also led to increased levels of singlet-oxygen production, thus providing a possible explanation for the increased toxicities of the methylated derivatives. Comparisons are made with the benzo[a]phenothiazinium photosensitizer, EtNBS.     

Polymeric Encapsulation of Novel Homoleptic Bis(dipyrrinato) Zinc(II) Complexes with Long Lifetimes for Applications as Photodynamic Therapy Photosensitisers

The use of photodynamic therapy (PDT) to treat cancer has received increasing attention over the last years. However, the clinically used photosensitisers (PSs) have some limitations that include poor aqueous solubility, hepatotoxicity, photobleaching, aggregation, and slow clearance from the body, so the design of new classes of PSs is of great interest. We present the use of bis(dipyrrinato)zinc(II) complexes with exceptionally long lifetimes as efficient PDT PSs. Based on the heavy‐atom effect, intersystem crossing of these complexes changes the excited state from singlet to a triplet state, thereby enabling singlet oxygen generation. To overcome the limitation of quenching effects in water and improve water solubility, the lead compound 3 was encapsulated in a polymer matrix. It showed impressive phototoxicity upon irradiation at 500 nm in various monolayer cancer cells as well as 3D multicellular tumour spheroids, without observed dark toxicity.     

Synthesis and catalytic performance of a soluble asymmetric zinc phthalocyanine

The soluble asymmetric phthalocyanine (Pc) (ZnPc-OH) was synthesized and used as a photosensitizer to degrade water pollutants. The catalytic ability of zinc Pc was proved by degrading Rhodamine B. In addition, ZnPc-OH, which has good solubility, can be used in photodynamic therapy.