A star-shaped porphyrin-arginine functionalized poly(l-lysine) copolymer for photo-enhanced drug and gene co-delivery

The co-delivery of drug and gene has become the primary strategy in cancer and other disease therapy. To co-deliver hydrophobic drug and functional gene efficiently into tumor cells, a star-shaped copolymer (PP-PLLD-Arg) with a photochemical internalization effect consisting of a porphyrin (PP) core and arginine-functionalized poly(l-lysine) dendron (PLLD-Arg) arms has been designed, and used to co-deliver docetaxel (DOC) and MMP-9 shRNA plasmid for nasopharyngeal cancer therapy. It was found that PP-PLLD-Arg/MMP-9 nanocomplex showed the photo-enhanced gene transfection efficiency in vitro, and could mediate a significant reduce of MMP-9 protein expression in HNE-1 cells. For co-delivery analysis, the obtained PP-PLLD-Arg/DOC/MMP-9 complexes could induce a more significant apoptosis than DOC or MMP-9 used only, and decreased invasive capacity of HNE-1 cells. Moreover, the star-shaped copolymer exhibited better blood compatibility and lower cytotoxicity compared to PEI-25k in the hemolysis and MTT assays, and also showed a good biocompatibility in vivo. Therefore, PP-PLLD-Arg with suited irradiation is a promising non-toxic and photo-inducible effective drug and gene delivery strategy, which should be encouraged in tumor therapy.     

排铅后再接铅生物指标的观测

目的：探讨排铅工人再接铅后,某些生物监测指标和卟啉代谢指标的动态变化。方法：110名冶炼厂工人排铅治疗后,回生产岗位2周,7周,24周,分别采样进行血铅（PbB),尿铅（PbU),尿道基酮戊酸（δ－ALA）,血氨基酮戊酸脱水酶 （δ－ALAD）,红细胞游离原卟啉（FEP）,血红蛋白（Hb)的监测,同时进行作业场所空气铅烟的监测。结果：低水平接触组以PbB变化较早和灵敏,其次为δ－ALAD,δ－ALA和FEP的增高出现较晚;中等水平接触组以PbB,PbU和δ－ALAD变化出现最早和敏感,其后变化趋势变缓,但δ－ALA,FEP持续增高;高水平接触组各项指标均出现明显的改变,以δ－ALA变化幅度较大,其次为FEP,PbU,PbB,而δ－ALAD的变化与中等水平组相似,Hb仅在24周出现降低。经相关和聚类分析,PbB,PbU,δ-ALAD活性具有相似变化规律,而EP与δ－ALA具有相似的时间序列变化规律。结论：工人排铅后再接铅,在较短时间内出现铅的毒性效应,应加强一级预防,接铅后各项指标呈现两种不同类型的变化态势。     

铅作业工人尿中γ—谷氨酰移换酶活性的研究

对218名铅作业工人的肾功能和卟啉代谢状况进行了研究,果表明尿γ谷氨酰移换酶(γ-GT)活性下降与尿铅浓度和铅中毒程度无明显相关;尿γ-GT活性下降是反映铅中毒性肾损害的敏感指标。尿γ—GT检测可作为铅中毒性肾损害的监测指标。     

Effect of chemical modification strategy on the characteristics of copper-67-labeled immunoconjugates, Part II: Aggregation

As outlined in the preceding paper, chemical modification strategies can have a profound impact on the immunoreactivity of immunoconjugates synthesized from the anti—renal cell carcinoma monoclonal antibody A6H and synthetic porphyrin chelating agents. Protein aggregation also appeared to be a consequence of the synthetic protocol. To investigate this aggregation, detailed high-performance liquid chromatographic analysis was carried out on immunoconjugates prepared using a polyclonal rabbit antibody, RIgG, as well as A6H. Our investigation suggested that aggregates were formed during the chemical modification steps. The percentage of the aggregated species was found to be a function of the number as well as the metallation status of the porphyrins (for preparations without intermediate linker molecules). Aggregation tendency was observed regardless of antibody type [intact A6H and two of its fragments, half A6H and A6HF(ab')₂], chemical linkage type and site, the presence or absence of intermediate linker molecules, and the nature of the chemical modification steps employed, with a single exception that may be capitalized on for further modification strategy design.     

Influence of UVA and UVB irradiation on hepatic and cutaneous P450 isoenzymes

The influence of UVA and UVB irradiation of the skin for 1, 2 and 4 weeks on the activities of the hepatic and cutaneous P450 isoenzymes was investigated in female Wistar rats before and after systemic administration of hexachlorobenzene (HCB), a well-known porphyrogenic agent, which additionally induces P450 1A1 and P450 1A2 isoenzymes. UVA and UVB irradiation of the skin of the controls and HCB-treated animals did not influence porphyrin metabolism. In the nonporphyric rats hepatic EROD (P450 1A1) activity was induced by UVB, but the activity of ADM (P450 2B) and EMDM (P450 3A) was either minimally or not affected. In the HCB-treated (porphyric) rats UVA and UVB irradiation resulted in a significant depression of HCB-induced EROD in the liver and in the skin. In both the nonporphyric and the porphyric rats UVA and UVB irradiation had no effect on hepatic ADM activity. In the liver of the nonporphyric animals EMDM activity remained unchanged after UVA and UVB irradiation, whereas in the HCB-treated animals the activity of this enzyme was increased. Finally, after UVA and UVB irradiation cutaneous EMDM activity was increased in the controls, whereas the HCB-induced increase of this enzyme in porphyric animals was decreased. In addition long-term (28 days) UVB irradiation decreased hepatic GSH content significantly in normal and porphyric rats. These experimental findings cannot be directly extrapolated to humans; however, they suggest that exposure of human skin to UV radiation may result in alterations in the activity of cutaneous, hepatic and other extracutaneous P450 isoenzymes. Received: 27 June 1996     

卷烟主流烟气中NOx截留的研究

目的 探讨截留卷烟主流烟气中氮氧化物的有效方法。方法 向卷烟滤嘴中以2.0、4.0和8.0μg/支加入卟啉及铁卟啉。采用盐酸萘乙二胺分光光度法分析卟啉及铁卟啉对清除卷烟主流烟气中氮氧化物的效果。结果 卷烟主流烟气中氮氧化物随卷烟滤嘴中卟啉及铁卟啉含量的增加而降低（卟啉:r=-0.994 3,P<0.01;铁卟啉:r=-0.989 2,P<0.01）。结论 卟啉和铁卟啉对卷烟主流烟气中氮氧化物有明显的截留效果。     

Relationship between lead concentration in blood and biological response for porphyrin metabolism in workers occupationally exposed to lead

Summary The biological responses of the heme biosynthesis pathway in male workers moderately exposed to lead are discussed in relation to the concentration of lead in the blood. The level of erythrocyte delta-aminolevulinic acid dehydratase (ALA-D) activity in the group of lead-exposed workers was remarkably reduced while the level of erythrocyte protoporphyrin (Proto) in them was strikingly increased, compared to normal levels. On the other hand, the amounts of hemoglobin (Hb) and urinary delta-aminolevulinic acid (ALA) in the group of lead-exposed workers kept the normal levels.In the workers moderately exposed to lead, the log of erythrocyte Proto level was closely correlated to the blood lead level and the sensitivity of the Proto test was almost equal to that of erythrocyte ALA-D test. It was observed that the erythrocyte Proto was remarkably increased even in lead-exposed workers whose ALA excretion into the urine was in the range of normal level.     

Effects of iron-loading and ethanol treatment on rat porphyrin metabolism

Rats were fed for 50 weeks with a standard diet containing 5.9% ferric ammonium sulphate. Half of these animals drank normal water, and the other half water containing 5% ethanol (groups 1 and 2). Two other groups received normal food, but drank water containing 5 or 10% ethanol (groups 3 and 4) for 40 weeks. Histologic examinations revealed that the iron-loading resulted in only mild hepatic siderosis in groups 1 and 2, the degree of siderosis not differing appreciably in the two groups. The ethanol led to fatty degeneration too in the liver of animals in group 2. Both iron-loading and ethanol treatment, either separately or in combination, increased the porphyrin excretion, but the distribution of the various porphyrins in the urine and faeces showed merely the symptoms of an aspecific poisoning. A significantly elevated uroporphyrin excretion was not observed in any of the groups, and thus the results support the view that dietary iron-loading and ethanol consumption can not be regarded as direct aetiologic factors in the pathomechanism of porphyria cutanea tarda. At the same time, the results suggest that vitamin E therapy, frequently employed effectively in porphyria cutanea tarda, can not be considered a causal intervention as regards the mechanism of action.     

Whole-body Autoradiography of Tumor-bearing Hamsters with a New Tumor Imaging Agent, Indium-111-labeled Porphyrin

We have synthesized a new tumor imaging agent, ¹¹¹In-labeled porphyrin (¹¹¹In-ATN-2). In order to image transplantable pancreatic carcinoma in Syrian golden hamsters, we investigated the biodistribution of ¹¹¹In-ATN-2 72 hr after injecting the agent by means of whole-body autoradiography. The efficacy of the agent was compared with that of ⁶⁷Ga citrate. The images with ¹¹¹In-ATN-2 were found to be clearer than those with ⁶⁷Ga citrate. Tumor-to-tissue radiodistribution ratios of the former were higher than those of the latter. Thus, ¹¹¹In-ATN-2 seems to be more useful for tumor diagnosis.     

The association between genetic polymorphisms of coproporphyrinogen oxidase and an atypical porphyrinogenic response to mercury exposure in humans

Previous studies have demonstrated highly specific urinary porphyrin profile (UPP) changes in response to mercury (Hg) exposure in animals and human subjects and have defined the biochemical etiology of this effect as selective alteration of the heme pathway enzymes, uroporphyrinogen decarboxylase (UROD), and coproporphyrinogen oxidase (CPOX) by Hg in the kidney. Ongoing validation studies in a population of dental practitioners with low-level occupational Hg exposure have demonstrated the predicted UPP change among approximately 85% of subjects. This study focused on the genetic etiology of an atypical porphyrinogenic response (APR) seen among the remaining 15% of Hg-exposed subjects, characterized by excess excretion of 4- and 5-carboxyl porphyrins and also of the atypical ketoisocoproporphyrin (KICP). Automated DNA-sequencing-based assays were developed to examine the 7 exons and flanking intron-exon boundaries of the CPOX gene. Among several polymorphisms identified, an A814C variant in exon 4 encoding a N272H substitution was found to be predominant among subjects with the APR. Studies suggest that this variant CPOX preferentially converts the upstream 5-carboxylporphyrin (5-CP) to KICP. By partially inhibiting the 5- to 4-decarboxylation step of UROD, Hg promotes 5-CP accumulation, accounting for e xcess KICP excretion and the APR in Hg-exposed subjects carrying the variant CPOX gene. This finding represents the first report of a polymorphism in a human gene that modifies the effect of Hg on a biological process. The APR might serve as a biomarker of both Hg exposure and susceptibility to Hg toxicity.