Boron and gadolinium neutron capture therapy

The principles of neutron capture therapy of tumor diseases, the types of drugs, and the results of their clinical applications are discussed.Based on the report presented at the International Conference Modern Trends in Organoelement and Polymer Chemistry dedicated to the 50th anniversary of the A. N. Nesmeyanov Institute of Organoelement Compounds of the Russian Academy of Sciences (Moscow, May 30–June 4, 2004).Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 9, pp. 1795–1812, September, 2004.     

3-位长链烷基双(单)取代焦脱镁叶绿酸-a甲酯的合成

以焦脱镁叶绿酸-a甲酯(1)为起始原料, 通过E环保护和3-位乙烯基的氧化反应得到卟吩醛2, 与长链烷基溴化镁的Grignard反应将3-位甲酰基转化为1-羟长链烷基, 选用TPAP和N-甲基吗啉N-氧化物混合氧化剂对卟吩仲醇3的羟基进行氧化, 生成3-位烷酰基焦脱镁叶绿酸-a衍生物4, 再与长链烷基溴化镁进行Grignard反应, 得到亲核加成产物卟吩叔醇5和还原产物3; 以对甲苯磺酸催化, 卟吩醇3和5在干燥苯中回流脱水, 分别给出反式结构的3-位长链烷基单或者双取代的焦脱镁叶绿酸-a甲酯衍生物6和7. 所合成的叶绿酸衍生物均经UV, IR, ¹H NMR及元素分析证明其结构.     

Spectroscopic studies of tin ethyl etiopurpurin in homogeneous and heterogeneous systems

Tin ethyl etiopurpurin is a promising second generation photosensitizer for photodynamic treatment of cancer. This compound is only poorly soluble in aqueous media and, therefore, needs a delivery system for administration to animals. Successful tumor eradication has previously been reported, following light exposure of rats previously administered with the purpurin formulated as a Cremophor El emulsion, in dipalmitoyl—phosphatidyl—choline liposomes or with gamma cyclodextrins. In this paper, we describe some absorbance and fluorescence studies of tin ethyl etiopurpurin in homogeneous and heterogeneous systems. In general, absorption and emission maxima were found to be red shifted as the environment changed from polar to non-polar. The viscosity and dielectric constant of the medium affected the purpurin fluorescence intensity. The liposome preparations were characterized by particle size determination, differential scanning calorimetry and by sensitizer fluorescence quenching studies. Photobleaching studies also showed variation owing to changes in the environment in which the dye was located.     

Does Hypericum perforatum L. extract show any specificity as photosensitizer for HL-60 leukemic cells and cord blood hemopoietic progenitors during photodynamic therapy?

Autologous bone marrow transplantation is a therapeutic modality that increases the survival rates for children with malignancies with poor prognosis but relapse rates are high and attributed partially to the existence of residual malignant cells. Photodynamic treatment (PDT) has been developed among purging strategies. We investigated the effect of the methanolic extract (ME) and its polar methanolic fraction (PMF) of Hypericum perforatum L., as a new photosensitizer for the leukemic cell line HL-60 and cord blood (CB) hemopoietic progenitors as well as the subcellular localization of the photosensitizer.

Methods

ME and PMF were prepared after extraction of the dry herb with methanol (ME), followed by liquid–liquid extraction with petroleum ether (PMF). Cells were incubated with the extracts before irradiation with Nd-Yvo Laser. Various concentrations of PMF or ME as well as irradiation doses were tested. Following irradiation, cell viability was determined by trypan blue in continuous liquid cultures for HL-60 cells and in clonogenic assays for CB cells. The subcellular localization of the photosensitizer was determined by confocal microscopy.

Results

Laser photoirradiation in the presence of both PMF and ME induces the killing of HL-60 cells. This effect is dose dependent. No CFU-GM and BFU-E growth was observed from CB mononuclear cells under the tested experimental conditions. Confocal microscopy revealed that the extracts localize mainly in the cytoplasm of the cells.

Conclusions

PDT with both PMF and ME induces the killing of HL-60 leukemic cells and the optimal conditions of treatment were determined. This effect of PDT/PMF was also exerted on CB progenitor cells indicative of the non-selective uptake of the photosensitizer by malignant cells. Though this suggests that PDT/PMF cannot be helpful in autologous bone marrow purging, these novel extracts can however be beneficial in the PDT treatment of tumors given their photostability, low toxicity and low cost.     

Covalent modification of mushroom tyrosinase with different amphiphic polymers for pharmaceutical and biocatalysis applications

Two different poly(ethylene glycol) derivatives (linear, mol wt 5000 and a branched form, mol wt 10000) and a new polymer (poly [acryloylmorfoline], mol wt 5500) were covalently bound to the enzyme tyrosinase. The polymer-protein conjugates were studied with a view to their potential pharmaceutical application and to their use for the bioconversion of phenolic substrates in organic solvents.V _max andK _m for the dopa-dopaquinone conversion, thermostability, stability toward inactivation by dopa oxidation products, half-life in blood circulation, and behavior in organic solvents for the different adducts were investi gated. Arrhenius plots for the dopa-dopaquinone conversion were also obtained in order to study the effects of temperature on the different enzyme forms. Covalent attachment of the polymers increased enzyme stability in aqueous solution and the solubility in organic solvents. However, organic solvent solubilization brought about loss of enzyme conformation as assessed by CD measurements, which is accompanied by a nonreversible loss of catalytic activity.     

Catechol-Bisphosphonate Conjugates： New Potential Chelating Agents for Metal Intoxication Therapy

In a quest for better chelating therapy drugs for the treatment of intoxication by Fe, A1, or actinides, two new series of mixed catechol-bisphosphonate through amide linkage were synthesized. Benzyl group was used as protecting group to avoid the breakage of amide by acid hydrolysis or imcomplete reaction in silylation-dealkylation using bromotrimethylsilane.     

General method for the synthesis of 2′-O-carboranyl-nucleosides

The carboranyl cage is a new modifying entity for nucleosides, DNA oligonucleotides, and other biomolecules. Herein, the first reliable method for the synthesis of nucleosides modified with a carborane cluster at the 2′-position is described.     

Targeted pH-responsive polyion complex micelle for controlled intracellular drug delivery

Cancer therapy with nanoscale drug formulations has made significant progress in the past few decades. However, the selective accumulation and release of therapeutic agents in the lesion sites are still great challenges. To this end, we developed a cRGD-decorated pH-responsive polyion complex (PIC) micelle for intracellular targeted delivery of doxorubicin (DOX) to upregulate tumor inhibition and reduce toxicity. The PIC micelle was self-assembled via the electrostatic interaction between the positively charged cRGD-modified poly(ethylene glycol)-block-poly(l-lysine) and the anionic acid-sensitive 2,3-dimethylmaleic anhydride-modified doxorubicin (DAD). The decoration of cRGD enhanced the cell internalization of PIC micelle through the specific recognition of α_vβ₃ integrin on the membrane of tumor cells. The active DOX was released under intracellular acidic microenvironment after endocytosis following the decomposition of DAD. Moreover, the targeted PIC micelle exhibited enhanced inhibition efficacies toward hepatoma in vitro and in vivo compared with the insensitive controls. The smart multifunctional micelle provides a promising platform for target intracellular delivery of therapeutic agent in cancer therapy.     

HepG2 human hepatocarcinoma cells: an experimental model for photosensitization by endogenous porphyrins

Endogenous protoporphyurin IX (PpIX) synthesis after δ-aminolaevulinic acid (ALA) administration occurs in cancer cells in vivo; PpIX, which has a short half-life, may thus constitute a good alternative to haematoporphyrin derivative (HPD) (or Photofrin). This study assesses the ability of the human hepatocarcinoma cell line HepG2 to synthesize PpIX in vitro from exogenous ALA, and compares ALA-induced toxicity and phototoxicity with the photodynamic therapy (PDT) effects of HPD on this cell line.

ALA induced a dose-dependent dark toxicity, with 79% and 66% cell survival for 50 and 100 μg ml⁻¹ ALA respectively after 3 h incubation; the same treatment, followed by laser irradiation (λ = 632 nm, 25 J cm⁻²), induced a dose-dependent phototoxicity, with 54% and 19% cell survival 24 h after PDT. Whatever the incubation time with ALA, a 3 h delay before light exposure was found to be optimal to reach a maximum phototoxicity.

HPD induced a slight dose-dependent toxicity in HepG2 cells and a dose- and time-dependent phototoxicity ten times greater than that of ALA-PpIX PDT. After 3 h incubation of 2.5 and 5 μg ml⁻¹ HPD, followed by laser irradiation (λ = 632 nm, 25 J cm⁻²), cell survival was 59% and 24% respectively at 24 h.

Photoproducts induced by light irradiation of porphyrins absorb light in the red spectral region at longer wavelengths than the original porphyrins. The possible enhancement of PDT effects after HepG2 cell incubation with ALA or HPD was investigated by irradiating cells successively with red light (λ = 632 nm) and light (λ = 650 nm). The total fluence was kept constant at 25 J cm⁻². For both HPD and ALA-PpIX PDT, phototoxicity was lower when cells were irradiated for increased periods with λ = 650 nm light than with λ = 632 nm light alone. This suggests that any photoproducts involved either have a short life or are poorly photoreactive.

Not all cell lines can synthesize PpIX after ALA incubation. HepG2 cells, which can synthesize enzymes and precursors of endogenous porphyrin synthesis, represent a good in vitro model for experiments using ALA-PpIX PDT. In addition, ALA-PpIX PDT may represent a new, specific treatment for hepatocarcinomas.     

Photodynamic destruction of Haemophilus parainfluenzae by endogenously produced porphyrins

Bacterial resistance against antibiotic treatment is becoming an increasing problem in medicine. Therefore methods to destroy microorganisms by other means are being investigated, one of which is photodynamic therapy (PDT).

It has already been shown that a variety of Gram-positive and Gram-negative bacteria can be killed in vitro by PDT using exogenous sensitizers. An alternative method of photosensitizing cells is to stimulate the production of endogenous sensitizers. The purpose of this study was to investigate the bactericidal efficacy of PDT for Haemophilus parainfluenzae with endogenously produced porphyrins, synthesized in the presence of δ-aminolaevulinic acid (δ-ALA). H. parainfluenzae incubated with increasing amounts of δ-ALA showed decreased survival after illumination with 630 nm light. No photodynamic effect on the bacterial viability was found when H. parainfluenzae was grown without added δ-ALA. H. influenzae, grown in the presence of δ-ALA, but not capable of synthesizing porphyrins from δ-ALA, was not affected by PDT. Of the range of incident wavelengths, 617 nm appeared to be the most efficient in killing the bacteria. Spectrophotometry of the bacterial porphyrins demonstrated that the maximum fluorescence occurred at approximately 617 nm, with a much lower peak around 680 nm. We conclude that a substantial killing of H. parainfluenzae by PDT in vitro after endogenous sensitization with δ-ALA can be achieved.