Toward hypericin-derived potential photodynamic therapy agents

To optimize a hypericin derivative as a potential photodynamic therapy agent its light-induced singlet oxygen/superoxide radical formation capability should be enhanced and its long-wavelength absorption band should be bathochromically shifted to better match medicinal lasers. A heavy-atom-substituted derivative was realized by electrophilic iodination of hypericin to yield 2,5-diiodo-hypericin. Using photodestruction of bilirubin IX alpha this derivative was demonstrated to exhibit an enhanced light-induced singlet oxygen/superoxide radical formation capability as compared to hypericin. With respect to a bathochromically shifted derivative styryl residues were attached to the methyl groups of hypericin by de novo ring synthesis. Although the long-wavelength absorption band of this derivative displayed a bathochromic shift of nearly 40 nm it unfortunately immediately underwent an intramolecular [2 + 2] cycloaddition to yield the corresponding cyclobutane derivative in which the added conjugation system became interrupted.     

Functional organic nanoparticles for photodynamic therapy

In recent years, cancer has been one of the leading causes of death in the world. Much effort has been devoted to developing cancer treatments. Photodynamic therapy (PDT) is a noninvasive therapeutic modality by combining the light of a specific wavelength, a photosensitizer (PS) and oxygen, which has been widely applied for the treatment of cancers. However, the application of PDT in clinic is greatly limited due to lack of tumor selectivity and often causing skin photosensitivity. The use of organic nanoparticles (NPs) as an advanced technology in the field of PDT shows a great promise to overcome these shortcomings. Therefore, in this review, we summarize several functional organic NPs as PS carriers that have been developed to enhance the efficacy of PDT against cancers.     

Fullerene C60 derivatives as antimicrobial photodynamic agents

Functionalized fullerenes have shown interesting biomedical applications as potential phototherapeutic agents. The hydrophobic carbon sphere of fullerene C₆₀ can be substituted by cationic groups to obtain amphiphilic structures. These compounds absorb mainly UV light, but absorption in the visible region can be enhanced by anchoring light-harvesting antennas to the C₆₀ core. Upon photoexcitation, fullerenes act as spin converters by effective intersystem crossing. From this excited state, they can react with ground state molecular oxygen and other substrates to form reactive oxygen species. This process leads to the formation of singlet molecular oxygen by energy transfer or superoxide anion radical by electron transfer. Photodynamic inactivation experiments indicate that cationic fullerenes are highly effective photosensitizers with applications as broad-spectrum antimicrobial agents. In these structures, the hydrophobic character of C₆₀ improves membrane penetration, while the presence of positive charges increases the binding of the fullerene derivatives with microbial cells. Herein, we summarize the progress of antimicrobial photodynamic inactivation based on substituted fullerenes specially designed to improve the photodynamic activity.     

Supramolecular agents for combination of photodynamic therapy and other treatments

Photodynamic therapy (PDT) is a promising treatment for cancers such as superficial skin cancers, esophageal cancer, and cervical cancer. Unfortunately, PDT often does not have sufficient therapeutic benefits due to its intrinsic oxygen dependence and the limited permeability of irradiating light. Side effects from “always on” photosensitizers (PSs) can be problematic, and PDT cannot treat tumor metastases or recurrences. In recent years, supramolecular approaches using non-covalent interactions have attracted attention due to their potential in PS development. A supramolecular PS assembly could be built to maximize photodynamic effects and minimize side effects. A combination of two or more therapies can effectively address shortcomings while maximizing the benefits of each treatment regimen. Using the supramolecular assembly, it is possible to design a multifunctional supramolecular PS to exert synergistic effects by combining PDT with other treatment methods. This review provides a summary of important research progress on supramolecular systems that can be used to combine PDT with photothermal therapy, chemotherapy, and immunotherapy to compensate for the shortcomings of PDT, and it provides an overview of the prospects for future cancer treatment advances and clinical applications.

This review provides a summary of important research progress on supramolecular systems that can be used to combine photodynamic therapy (PDT) with photothermal therapy, chemotherapy, and immunotherapy to compensate for the shortcomings of PDT.     

Acetylenic quinoxalinoporphyrazines as photosensitisers for photodynamic therapy

A range of lipo- and hydrophilic derivatives of the new class of octaalkynyl tetra-[6,7]-quinoxalinoporphyrazines (TQuiPors), analogues of the naphthalocyanines, were prepared in two steps starting from functionalised hexa-1,5-diyne-3,4-diones. Divalent zinc and magnesium ions were introduced into the macrocyclic core. Whereas the triisopropylsilyl-, 3,5-di-tert-butylphenyl- and 4-triisopropylsilyloxyphenyl-terminated acetylenic TQuiPors are lipophilic and hence soluble in standard organic solvents, a polyethylene glycol-substituted derivative was found to dissolve in DMSO as well as in ethanol/water mixtures. The new chromophores are characterised by intense UV/Vis/NIR absorptions, most notably by bands at 770 nm with extinction coefficients exceeding 500 000 M(-1) cm(-1). With a view to possible photodynamic therapy applications, the potency of the chromophores to sensitise the formation of singlet oxygen was examined, both qualitatively using a 1,3-diphenylisobenzofuran assay, and quantitatively by the determination of the singlet oxygen quantum yields. It was found that all TQuiPors produce singlet oxygen when irradiated in the presence of air. In particular, the octaalkynyl Zn-TQuiPor generates singlet oxygen with a quantum yield of 56 %, thereby rivalling, and, in conjunction with its absorption profile, even exceeding the standards set by established PDT agents. The photostabilities of the TQuiPors were assessed and generally found to be satisfactory, but dependent on the solvent and the wavelength of the incident light.     

Small organometallic compounds as antibacterial agents

The emergence of bacterial resistance to commercial antibiotics is an issue of global importance. During the last two decades, the number of antibacterial agents that have been discovered and introduced into the market has steadily declined and failed to meet the challenges posed by rapidly increasing resistance of the pathogens against common antibacterial drugs. The development of new classes of compounds to control the virulence of the pathogens is therefore urgently required. This perspective describes the historical development in brief and recent advances on the preparation of small organometallic compounds as new classes of antibacterial agents with potential for clinical development.     

New pyrazolic compounds as cytotoxic agents

The evaluation of the in vitro cytotoxic properties of two pyrazole compounds: 1-(4-nitrophényl)-3,5-diméthylpyrazole (1) and 1,1'-di(4-nitrophényl)-5,5'-diisopropyl-3,3'-bipyrazole (2) was investigated against Hep cell line (Human laryngeal carcinoma). These two compounds showed an important cytotoxic activity on the Hep cell line, with IC(50): 8.25 microg mL(-1) for the compound 1; IC(50): 10.20 microg mL(-1) for the compound 2 while the IC(50) for adriamycine used as positive control was 3.62 microg mL(-1).     

Green organic syntheses: organic carbonates as methylating agents

Dimethylcarbonate (DMC) is a valuable methylating reagent that can replace methyl halides and dimethylsulfate in the methylation of a variety of nucleophiles. It couples tunable reactivity and unprecedented selectivity towards mono-C- and mono-N-methylation. In addition, it is a prototype example of a green reagent, because it is nontoxic, is made by a clean process, is biodegradable, and reacts in the presence of a catalytic amount of base, thereby avoiding the formation of undesirable inorganic salts as by-products. Depending on the reaction conditions, DMC can be reacted under plug-flow, CSTR, or batch conditions. Other remarkable reactions are those where DMC behaves as an oxidant. The reactivity of other carbonates is reported as well.     

Potentiality of vanadium compounds as anti-parasitic agents

Research efforts on the medicinal chemistry of vanadium have been mainly focused whether on improving biodistribution and tolerability of the vanadium insulin-enhancing core or on developing potential anti-tumor compounds. Despite the fact that the World Health Organization statistics show that parasitic diseases are among the most prevalent illnesses worldwide, work on vanadium compounds for the potential treatment of some of these diseases has only recently arisen. This review focuses on recent attempts to develop vanadium-based potential anti-parasitic agents, mainly active against the parasites causing American trypanosomiasis (Chagas disease), leishmaniasis and amoebiasis. In addition, the search for new therapeutic uses of some previously known bioactive vanadium compounds is included.     

Near-infrared absorbing Ru(ii) complexes act as immunoprotective photodynamic therapy (PDT) agents against aggressive melanoma

Mounting evidence over the past 20 years suggests that photodynamic therapy (PDT), an anticancer modality known mostly as a local treatment, has the capacity to invoke a systemic antitumor immune response, leading to protection against tumor recurrence. For aggressive cancers such as melanoma, where chemotherapy and radiotherapy are ineffective, immunomodulating PDT as an adjuvant to surgery is of interest. Towards the development of specialized photosensitizers (PSs) for treating pigmented melanomas, nine new near-infrared (NIR) absorbing PSs based on a Ru(ii) tris-heteroleptic scaffold [Ru(NNN)(NN)(L)]Cl_n, were explored. Compounds 2, 6, and 9 exhibited high potency toward melanoma cells, with visible EC₅₀ values as low as 0.292–0.602 μM and PIs as high as 156–360. Single-micromolar phototoxicity was obtained with NIR-light (733 nm) with PIs up to 71. The common feature of these lead NIR PSs was an accessible low-energy triplet intraligand (³IL) excited state for high singlet oxygen (¹O₂) quantum yields (69–93%), which was only possible when the photosensitizing ³IL states were lower in energy than the lowest triplet metal-to-ligand charge transfer (³MLCT) excited states that typically govern Ru(ii) polypyridyl photophysics. PDT treatment with 2 elicited a pro-inflammatory response alongside immunogenic cell death in mouse B16F10 melanoma cells and proved safe for in vivo administration (maximum tolerated dose = 50 mg kg⁻¹). Female and male mice vaccinated with B16F10 cells that were PDT-treated with 2 and challenged with live B16F10 cells exhibited 80 and 55% protection from tumor growth, respectively, leading to significantly improved survival and excellent hazard ratios of ≤0.2.

Ru(ii) photosensitizers (PSs) destroy aggressive melanoma cells, triggering an immune response that leads to protection against tumor challenge and mouse survival.     

Water soluble distyryl-boradiazaindacenes as efficient photosensitizers for photodynamic therapy

We introduce a novel class of water soluble, extended conjugation boradiazaindacene dyes which are efficient singlet oxygen generators and have spectacular photoinduced cytotoxicity when excited in the "therapeutic window" of the electromagnetic spectrum.     

Metal chelates of porphyrin derivatives as sensitizers in photooxidation processes of sulfur compounds and in photodynamic therapy of cancer

A number of porphyrin derivatives based on hematoporphyrin, 5,10,15,20-tetrasubstituted porphyrins, phthalocyanines, and naphthalocyanines were prepared either as low-molecular compounds or bonded with methoxypoly(ethylene glycol) or attached to silica of low surface area. The low-molecular weight and the polymer-bonded porphyrins exhibit comparable triplet lifetimes and activities in the photosensitized formation of singlet oxygen. For photoninduced processes, the monomeric state of sensitizers is fundamentally important. The porphyrins have been investigated as sensitizers for photooxidation of thiolates and sulfides, which occursvia singlet oxygen, and, therefore, is much more efficient than the corresponding catalytic dark oxidation. Polymer-bonded porphyrins and long-wavelength absorbing naphthalocyanines incorporated in liposomes exhibitin vivo high accumulation in tumor tissues. Under irradiation, singlet oxygen is produced, and efficient phototherapeutic effects are observed, which may be used for photodynamic cancer therapy.Translated fromIzvestiya Akademii Nauk. Seriya Khimicheskaya, No. 12, pp. 2071–2082, December, 1994.D. Wöhrle is very thankful to G. Schulz-Ekloff (Bremen), M. Shopova (Sofia), I. Okura (Tokyo), B. Roeder (Berlin), G. Graschew (Heidelberg), and their coworkers for fruitful cooperation. The research was supported by the German Research Society (Deutsche Forschungsgemeinschaft, 436 BUL 113/51/0, Wo 237/ 12-1), the German Cancer Service (Deutsche Krebshilfe, W 15/89/Sch12), Bremen University (FSP 2/90), and the Federal Department of Scientific Research and Tech nology (Bundesministerium far Forschung und Technotogie, Bonn, 13N6290).     

Novel heparan sulfate mimetic compounds as antitumor agents

Heparan sulfate glycosaminoglycans (HSGAGs) are involved in tumor cell growth, adhesion, invasion, and migration, due to their interactions with various proteins. In this study, novel HSGAG-mimetic compounds (KI compounds) were designed and synthesized. As a result of cell-based assays, KI-105 was found to exert potent inhibitory activities against migration and invasion of human fibrosarcoma HT1080 cells. The present results indicate that a novel invasion/migration inhibitor, KI-105, can increase the adherence of HT1080 cells. It was conceivable that this cellular effect was caused by an increase in the amount of cell-surface HSGAGs and focal adhesions. Although further investigations are needed to decipher the molecular mechanism of KI-105, it is suggested that heparanase and Cdc42 are involved in its biological effects.     

Imidazole-modified porphyrin as a pH-responsive sensitizer for cancer photodynamic therapy

5,10,15,20-Tetrakis(N-(2-(1H-imidazol-4-yl)ethyl)benzamide)porphyrin produced twice as many singlet oxygen ((1)O(2)) molecules at pH 5.0 (quantum yield 0.53 ± 0.01) than at pH 7.4, whereas the (1)O(2) quenching rate was reduced by a factor of 2.5 for a pH change from 7.4 to 5.0.     

Polymeric porphyrins as new photocatalysts in photodynamic therapy of cancer

Photodynamic therapy and diagnosis (PDT) is described as an efficient clinical method for the treatment of cancer patients using hematoporphyrin derivative (Hpd) as sensitizer. Newly developed metal-containing porphyrin type compounds are potential agents for PDT. A concept for covalently bound polymeric metal-containing or metal-free sensitizers is discussed. First results of these polymeric sensitizers are reported from in vivo experiments. High tumor accumulation up to 30% was observed. Results of fluorescence diagnosis are shown.     

Metal phthalocyanine as photosensitizer for photodynamic therapy (PDT)

A series of sulfonated (S) phthalimidomethyl (P) zinc phthalocyanines (Pc) was synthesized in a reaction, in which both kinds of substituents were introduced to ZnPc simultaneously. The products were separated by HPLC. The five different fractions obtained were further purified by a membrane separation method, and then characterized by UV/Vis, IR, element analysis and the abilities to generate singlet oxygen upon irradiation by light as well as a preliminary determination ofin vitro antitumor activities. The results show that one of the five separating parts with formula of ZnPcS₂P₂ exhibited rather good PDT activity. The compound was further characterized by NMR, MS and thermal analysis. Studies onin vivo antitumor activities of ZnPcS₂P₂ as photosensitizer show that its inhibitory rate was up to 89.8% and 90.8% for S₁₈₀ and U₁₄ solid tumors transplanted in mice respectively when the dosage of drug was 2 mg/kg and the dosage of laser light with 670 nm wavelength was 72 J/cm². Several structural factors influenced on the PDT activities were discussed.     

Heterocyclic compounds as organic luminophores (review)

A review of heterocyclic compounds having luminescence properties is given. Methods for the preparation of some of them, the relationship between structure and luminescence, and their areas of application are examined.     

Structures and electronic absorption spectra of a recently synthesised class of photodynamic therapy agents

A theoretical study was performed on a novel class of boron-containing molecules (various substituted tetraarylazadipyrromethenes), which show in vitro activity for application in photodynamic therapy. Geometric optimisation of the structures for the singlet and triplet electronic states was carried out on compounds in vacuo at the density functional level of theory, by employing the PBE0 hybrid functional and the split-valence plus polarisation basis set. The absorbance properties in the UV-visible region were examined by means of time-dependent density functional response theory, using the same functional as mentioned above. To evaluate the influence of the solvent on the excitation energies, the continuum polarisable model was applied. Calculated electronic excitations, such as those regarding the Q-like band, were found to be in good agreement (within 0.01-0.1 eV) with experimental values and experimental trends on changing both the substituents and solvent.     

Intercalated kaolinite as an emerging platform for cancer therapy

An innovative cancer therapy strategy regarding the interface engineering of kaolinite has been designed. The exposed silanol group facilitates more guest species with high dispersion on the supports. Mn_3O_4 magnetic nanoparticles are uniformly distributed on external surfaces of the Kaolin_(C12N)with the Al–O–Mn bond for the detection of the tumor microenvironment by T1-MRI; Doxorubicin(DOX) are loaded in the interlayer space with the electrostatic interaction for chemo-treating; and KI is coated on the outer layer of the nanocomposites based on the electrostatic interaction for thyroid cancer targeting. The synergetic effects and the treatment mechanism enhanced by the interface engineering, KI@DOX-Mn_3O_4-Kaolin_(C12N)can cause remarkably low cell viability(57%, 200 μg/mL), tumor shrinking(75%, 20 μg/kg), and accumulation into the tumor tissues. The novel kaolinite based drug delivery system is expected to incorporate imaging diagnosis, targeted therapy and drug delivery into one single system for postoperative residual thyroid cancer treatment and observation for metastasis of focal area.