新型光敏抗菌药物的研究
|
摘要
近年来,由于抗生素的滥用导致了“超级细菌”(superbug)的出现和传播。所谓“超级细菌”是指这些细菌对于目前的抗生素具有多重耐药的特性,这对于临床创伤感染的治疗增添了很大的难度。且耐多重抗生素的超级细菌的爆发性流行尽管只是有潜在的可能,但其可怕之处却引起了世界各国的恐慌。因此发展新的抗感染策略迫在眉睫。光动力抗菌治疗方法(photodynamic antimicrobial chemotherapy,PACT)就是其中最具前景的新疗法之一,对于细菌、真菌和病毒引起的感染,特别是对于耐药菌感染均显示很好的疗效。光动力灭菌是基于光、光敏剂和氧三种因素协同作用的氧化损伤机制,不会因为单一用药、光敏剂的浓度、曝光时间不足等因素产生耐药问题。且超级细菌多发生在伤口、肺部以及血液和尿道中,除了血液感染外,其它部位采用PACT还是易于实现的,因而无论从耐药性、杀菌性以及效果和方便考虑,PACT均有很大的优势。PACT的关键是光敏药物。目前,国外利用不同光敏剂对不同细菌的光动力灭活作用进行了大量的探索,旨在发现理想的光敏药物。理想的抗菌光敏剂,应具有高效低毒和好的选择性,对细胞壁的通透性强,高效灭活微生物,而对于正常组织伤害较小。在国内外以往的文献报道中,作为抗菌的光敏药物选择性不够突出,有些对于革兰氏阳性菌有效,有些对革兰氏阴性菌有效,对于上述两类菌群均有效的高效光敏剂尚不多见,因而设计和发现可以有效治疗上述两类细菌的光敏药物,将会大大拓展PACT的应用。基于上述研究目标,我们开展了体内体外光敏抗菌药物的筛选,具体研究内容涵盖以下两部分：
1.高效抗菌光敏剂的设计与筛选
1.1水溶性糖酞菁类光敏剂的光动力抗菌作用研究
酞菁类光敏剂有其特有的优势,但是水溶性差、易聚集的缺点限制了酞菁的使用。考虑到细菌代谢和繁殖较快,我们利用半乳糖作为修饰基团,不仅可以改善酞菁的水溶性、生物相容性,而且可以提高细菌的选择性摄取可使光敏药物优先聚集于细菌内而非周围组织或细胞中,从而实现选择性灭菌。研究结果表明：细菌对四种酞菁类化合物(T1-T4)的吞噬量在30min时达到最大,随着光照时间的延长,菌落数呈下降趋势,在能量密度达到6J/cm2后,灭活率达到最大,且细菌的灭活率不再随激光能量密度的增加而增加。在四种半乳糖取代的酞菁化合物(T1-T4)中,光照T1对革兰氏阳性耐药菌MRSA有很好的灭活作用且暗毒性较低,但对革兰氏阴性菌(绿脓杆菌和大肠杆菌)的灭活效果却很低。激光共聚焦显微成像显示MRSA对T1的吞噬量最多,T1的荧光最强。
1.2卟啉类光敏剂的光动力抗菌作用研究
由于半乳糖酞菁类光敏剂对革兰氏阳性菌有较好的杀菌效果,但对革兰氏阴性菌杀菌效率很低,极大的限制了此类光敏剂的使用。卟啉类化合物是源于天然的另外一类光敏剂,但其母核的光敏效率与选择性均不够理想,考虑到细菌的增长分化需要大量的碳源和氮源。我们选择双乙二胺为对原卟啉化合物进行修饰,得到一类新型的抗菌光敏剂。体外研究表明其对革兰氏阴性菌及革兰氏阳性菌在体外均有高效的抗菌灭活作用,以小鼠急性创伤感染为模型的在体实验表明,双乙二胺的PACT作用可以明显的杀死绿脓杆菌,促进创伤面的愈合。
双乙二胺光敏剂有其特有的抗菌优势,但是不稳定,见光容易分解的缺点限制了其使用。为了进一步研究氨基数目的取代关系对卟啉光敏剂的稳定性、生物活性的影响,本实验室对双乙二胺进一步设计,得到了五种氨基卟啉类化合物,体外实验表明：该五种卟啉类化合物PAl-PA5均具有较缓慢的光漂白率和较强的单线态氧产生能力,其中PA1的单线态氧产生率最高(0.69),高于四苯基卟啉(0.64),其余化合物PA1-PA4单线态氧产率在0.15-0.37之间。细胞吞噬实验表明MRSA,E.coli, P.aeruginosa在30min即对上述五种化合物的吞噬量达到最大。激光共聚焦显微成像显示上述三种菌株对五种化合物的吸收具有选择性,对化合物PAl-PA2吞噬较强,而对PA3-PA5吞噬却较弱。光敏抗菌实验表明PA1产生的灭菌效果较其他四种化合物好,对三种菌的MIC均为16μM,对MRSaA,E.coli的MBC为31μM,对P.aeruginosa的MBC为62.5μM。PAl的暗毒性也低(MBC>500μM)。利用菌落计数法检测了PA1-PA5对三种细菌的光反应、暗反应浓度曲线。结果表明随着浓度的增加,PA1表现出明显的杀菌效果,对MRSA的杀菌效果最强,当浓度为15.6μM时,全部杀死革兰氏阳性菌MRSA.当浓度上升为31.25μM时,PA1几乎能全部杀死E.coli,P.aeruginosa。但在此浓度范围内对3T3成纤维细胞的损伤却很小。
以上结果表明PA1对革兰氏阳性菌及阴性菌均有很好的抗菌性能,可作为一种新型广谱的抗菌光敏剂使用,具有广阔的前景。
2卟啉类抗菌光敏剂在皮肤感染类疾病中的光敏抗菌效果评价
2.1光敏抗菌对创伤感染的效果评价
皮肤破损性疾病是一种临床常见病、多发病,由于多重耐药细菌的出现,临床治疗面临很大的难度。以筛选出的苗头化合物PA1为研究对象,重点探讨PA1对由MRSA,E.coli,P.aeruginosa混合感染的大鼠创面模型的PACT作用,结果表明：PA1介导的PACT能促进大面积创伤感染的大鼠皮肤愈合.其机制可能与诱导bFGF,TGF-β1的高表达,促进创面纤维合成和重新分布有关。造模后4,10及14天,高剂量PACT组的bFGF和TGF-β1的表达最高,模型对照组最低(P<0.01).PACT能显著改善创面感染组织炎症状况,降低组织中炎症相关因子TNF-a和IL-6含量。减少创面组织中细菌的数量,加快创面愈合的速率。PACT的效果与PA1的浓度呈正相关,表现出较好的剂量依赖关系。
大面积创伤发生时,由于屏障系统被破坏,细菌很容易穿透屏障,造成败血症。尽管PACT可以外用,体内却只能靠自身免疫力清除细菌,如果感染程度超过自身免疫力则容易引起败血症。基于这种考虑将PACT和抗生素的优势结合起来,PACT可以清除外表细菌,而体内细菌则由抗生素清除。基于大鼠创伤模型的实验表明：PACT联合抗生素治疗能显著降低大鼠大面积重度感染组织的炎症表达；减少创面组织中细菌数量,促进创面愈合,结果优于PACT治疗组和抗生素治疗组。PACT联合抗生素治疗大鼠大面积重度感染,死亡率为20%,而模型对照组的死亡率是60%,表明PACT联合抗生素治疗的有效性。免疫组化分析表明PACT联合抗生素治疗可显著提高创面组织中bFGF(?)TGF-β1的含量表达,促进创面纤维合成和重新分布,加快创面愈合的速率,同时显著降低创面组织中炎症相关因子TNF-α和IL-6含量,减少创伤组织的炎症反应,有助于创伤组织的修复。
2.2光敏抗菌作用在烧伤感染中的效果评价
烧烫伤(bums/scalds)是皮肤创伤的一种常见形式,为临床常见病和多发病。细菌感染是烧伤患者的主要并发症,发病率高,是造成病人死亡的主要因素,因此抗感染成为治疗烧伤病人的重要环节。PACT联合抗生素治疗大鼠Ⅲ度烧伤感染结果表明,PACT联合抗生素治疗能显著降低烧伤感染组织的炎症表达；减少创面组织中细菌数量,促进创面愈合,结果优于PACT治疗组和抗生素治疗组。(?)PACT联合抗生素治疗大鼠Ⅲ度烧伤感染,死亡率为0%,而模型对照组的死亡率是50%。免疫组合分析表明PACT联合抗生素治疗可显著提高创面组织中bFGF和新生血管数CD31的含量表达,促进血管新生和成纤维细胞的增殖,促进了创面肉芽组织的生长,从而促进创面愈合,同时可以提高机体的自身免疫能力显著降低烧伤创面组织中炎症相关因子TNF-α和IL-6含量,减少创伤组织的炎症反应,有助于创伤组织的修复。
综上所述,PA1是一种具有良好抗菌效果的广谱光敏剂,体内、体外实验表明,该光敏剂具有高效、低毒的性质,可作为一种新型广谱的抗菌光敏剂使用,具有广阔的前景。
In recent years, the overuse of antibiotics has led to the emergence and spread of superbug. The so-called superbugs refer to the bacteria which are multidrug-resistant to present antibiotics. This has added to a lot of difficulties for the treatment of wound infection in clinic. Although there is only a potential likelihood for the explosive prevalence of multiantibiotics-resistant superbugs, what terror it will cause has brought great panics in many countries around the world. Therefore, the development of new anti-infection strategy is urgent. Photodynamic antimicrobial chemotherapy (PACT) is one of the most promising new antimicrobial therapies in treating infections caused by bacteria, Fungi and viruses, especially in treating infections by multidrug-resistant bacteria Photodynamic antimicrobial therapy is an oxidative damage mechanism relying on a combined action of three factors----light, photosensitizer and oxygen, which will not bring some drug-resistant problems related with such factors as single-drug administration, the concentration of photosensitizer, inadequate exposure time etc.
Additionally, superbugs are most likely to be found in the infection site of the wound, in the infection of the lungs, the blood and the urinary tract. Except for blood infection, PACT is relatively easy to implement in the other parts' infections. Hence, in terms of drug-resistance, bactericidal effect and convenience, PACT has its great advantages. Currently, a lot of research in foreign countries has been done into the photodynamic inactivation of different bacteria with different photosensitizers, which aims at discovering a desired photosensitizer. A desired antimicrobial photosensitizer should have the following characteristics-----high efficacy yet low toxicity, good selectivity, strong permeability of the cell wall and high effectiveness in microorganism inactivation while doing little harm to the normal tissues. In previous reports, photosensitive drugs as antibacterial agents have no highlighted selectivity, with some effective to Gram-positive bacteria and some effective to Gram-negative bacteria We expect that the desired photosensitive drugs can be effective in treating the above two bacteria and the potential bacteria Therefore, it is of great practical significance to achieve the promotion of PACT. Based on the above objectives, we were screened antibacterial sensitive drugs in vitro and in vivo, the major contents of paper includes the following two parts:
1. The design and screening of high efficacy antimicrobial photosensitizer
1.1The photodynamic antibacterial effect of a-D-galactopyranosyl Zinc Phthalocyanines
Phthalocyanines photosensitizers have its own advantages but there is limitation to the use of Phthalocyanines because of its poor water solubility and easily gathering. Considering the rapid metabolism and reproduction of bacteria, galactose is used as modification to increase its water solubility and its biocompatibility. So,drugs that bacteria selectively take in are well designed so that photosensitive drugs are preferentially concentrated in bacteria rather than in the surrounding tissues or cells so as to achieve selective sterilization. The novel a-D-galactopyranosyl zinc phthalocyanines (T1, T2, T3, T4) have been synthesized to study the biological properties and antibacterial properties. The study showed that the bacterial uptake to four phthalocyanine compounds (T1-T4) reached maximum in30minutes. With increased irradiation time, the number of colonies decreased and when the energy density reached6J/cm2, the inactivation rate of bacteria reached maximum, which no longer increased with increased laser energy density. Of the four a-D-galactopyranosyl zinc phthalocyanines compounds (T1-T4), the irradiation of T1had effective inactivation to Gram-positive drug-resistant bacteria MRSA with low dark toxicity, but the inactivation effect to Gram-negative bacteria (Escherichia coli and Pseudomonas aeruginosa) was very poor. The laser confocal showed that MRSA had maximum uptake of T1and T1had the strongest fluorescent.
1.2The antibacterial effect of Porphyrin compounds
Phthalocyanines photosensitizers are effective in fighting against Gram-positive bacteria but ineffective to Gram-negative bacteria, which greatly limit the use of such photosensitizers. Porphyrins is another kind of natural photosensitizer, But its parent nucleus of photosensitive efficiency and selectivity are not ideal. Considering the reproduction of bacteria need huge amounts of carbon and nitrogen sources, double ethylenediamine is used as the modification of the original porphyrin compounds, and obtained a new type of antibacterial photosensitizer. Amino heme was taken as an example and a study of PACT was conducted against Gram-negative and Gram-positive bacteria, showing that it had good antibacterial effect in vitro. Experiments on rats with acute trauma infection in vivo indicated that PACT with Amino heme could obviously kill P. aeruginosa and promote the wound healing.
Amino heme photosensitizer has its unique antibacterial advantages, but its limitation is unstability and easy decomposition to light, which greatly limits its use. To further study the effect of the amino-substituted porphyrins on the stability and the biological activity of photosensitizers, Amino heme was further designed and five amino porphyrin compounds were obtained. The experiments in vitro showed that the five compounds PA1-PA5were all slower in photobleaching and a strong ability to generate singlet oxygen, of which PA1had the highest rate of generating singlet oxygen (0.69), higher than that of the tetraphenyl porphyrin (0.64), and the singlet oxygen yield of PA2-PA4was0.15-0.37. The uptake of PA1-PA5by MRS A, E.coli, P.aeruginosa showed that the uptake reached maximum in30minutes incubation. The laser confocal microscopy revealed that three strains were selective in taking in5compounds. The uptake of PA1-PA2by three strains was higher whereas the uptake of PA3-PA5was relatively low. The irradiation bacterial effect of PA1was better than the other four compounds. The MIC of the three strains was16μM, the MBC for MRS A, E.coli's was31μM and the MBC for P.aeruginosa was62.5uM. The dark toxicity of PA1was very low (MBC>500μM). The colony counting method was used to detect the concentration curves of PA1-PA5in the light and dark reactions to three strains. The results showed that with increasing concentration, PA1had significant bactericidal effect and the greatest bactericidal effect against MRSA happened in the concentration of15.6uM. When the concentration reached31.25μM, PA1almost completely killed MRSA. However, within this concentration range, PA1had minor inactivation to3T3fibroblasts.
These results indicate that PA1has good antibacterial properties against Gram-positive and negative bacteria, and it can be used as a novel broad-spectrum antimicrobial photosensitizers, which will have a broad and bright prospects.
2Antibacterial effect evaluation of porphyrin photosensitizers in the skin-infection diseases
2.1Effects of Photodynamic antimicrobial therapy of porphyrin photosensitizer on wound infection
Skin trauma is a common disease, and it is more difficult to treat in clinic. The PA1compounds is taken as the study object, mainly focusing on the effect of PA1on the trauma model in rats with mixed wound infection of MRSA, E.coli, P.aeruginosa. The results showed that PACT could greatly promote the skin healing in rats with large areas of wound infections. Its mechanism lay in inducing the high expression of BFGF, TGF-β1and promoting the synthesis and redistribution of fibrolos in the wounds. The expression of BFGF and TGF-β1in the PACT group is the highest while the expression of the control group is the lowest.(p<0.01). PACT could significantly downregulate inflammation condition of the infected tissues in the burns, reducing the amount of TNF-and IL-6and the number of bacteria and promoting the healing speed of the wounds. The concentration change of PA1was positively correlated with PACT effect, showing good dose-dependent relation.
Trauma tend to damage the barrier system of the body, which makes it easy for bacteria to penetrate the barrier and cause sepsis. While PACT can be used in vitro, bacteria in vivo can only be removed by immunity in itself. The combined advantage of PACT and antibiotics is that PACT can remove bacteria in vitro while bacteria in vivo can be cleaned through antibiotics, small amount of which can work. Therefore, the combined therapy of PACT and antibiotics has been used to treat trauma models in seriously-infected rats. The results showed that PACT combined with antibiotics could significantly reduce the inflammation expression of the seriously-infected tissues in rats with severe wounds, greatly reducing the number of bacteria in the wound tissues and promoting the wound healing. The result was far better than that of the PACT group and the antibiotics group. The combined therapy of PACT and antibiotics was used to treat rats with a large area of severe infections, with the mortality20%, whereas the mortality of the control group was60%, which indicated the effectiveness of the combined therapy. The explanation to the treatment of a large area of trauma infections with the combined therapy of PACT and antibiotics was as follows:It could significantly improve the amount of BFGF and TGF-β1, promoting the fiber composition and redistribution of the wound and thus accelerating the healing speed. At the same time, it could greatly reduce the secretion of inflammation-related factors TNF-a and IL-6, reducing the inflammation of the infected tissues in trauma, thus contributing to the healing of the skin lesion.
2.2Effects of photodynamic antimicrobial chemotherapy on burn infection model.
Scalds/Burns is a common form of skin wounds and frequently-occurring disease in clinical. Bacterial infection, the main complications of burn patients, is the dominating factor of death. So, Anti-infection treatment is the important link for burn patients. The results showed that PACT combined with antibiotics could significantly reduce the inflammation expression of the burned tissues in rats with severe burns, greatly reducing the number of bacteria in the wound tissues and promoting the wound healing. The result was far better than that of the PACT group and the antibiotics group. The combined therapy of PACT and antibiotics was used to treat rats with burned severe infections, with the mortality0%, whereas the mortality of the control group was50%, which indicated the effectiveness of the combined therapy. The explanation to the treatment of degree Ⅲ burns infection in rats with the combined therapy of PACT and antibiotics was as follows: It could significantly improve the expression of bFGF and CD31in trauma, facilitating the proliferation of new capillaries and fibroblast cells in the early stage and the growth of wound granulation tissues, and enhancing the wound healing. It could greatly improve the rats'immunity system, regulating the secretion of inflammation-related factors TNF-a and IL-6and reducing the inflammation of burn tissues, thus contributing to the healing of the skin lesion.
In summary, PA1is a broad-spectrum photosensitizer with good antimicrobial effect. The experiments in vitro and in vivo reveal that the photosensitizer has the naure of high efficiency and low toxicity. Therefore, it can be used as a novel broad-spectrum photosensitizer against bacteria, with broad prospects.
1.高效抗菌光敏剂的设计与筛选
1.1水溶性糖酞菁类光敏剂的光动力抗菌作用研究
酞菁类光敏剂有其特有的优势,但是水溶性差、易聚集的缺点限制了酞菁的使用。考虑到细菌代谢和繁殖较快,我们利用半乳糖作为修饰基团,不仅可以改善酞菁的水溶性、生物相容性,而且可以提高细菌的选择性摄取可使光敏药物优先聚集于细菌内而非周围组织或细胞中,从而实现选择性灭菌。研究结果表明：细菌对四种酞菁类化合物(T1-T4)的吞噬量在30min时达到最大,随着光照时间的延长,菌落数呈下降趋势,在能量密度达到6J/cm2后,灭活率达到最大,且细菌的灭活率不再随激光能量密度的增加而增加。在四种半乳糖取代的酞菁化合物(T1-T4)中,光照T1对革兰氏阳性耐药菌MRSA有很好的灭活作用且暗毒性较低,但对革兰氏阴性菌(绿脓杆菌和大肠杆菌)的灭活效果却很低。激光共聚焦显微成像显示MRSA对T1的吞噬量最多,T1的荧光最强。
1.2卟啉类光敏剂的光动力抗菌作用研究
由于半乳糖酞菁类光敏剂对革兰氏阳性菌有较好的杀菌效果,但对革兰氏阴性菌杀菌效率很低,极大的限制了此类光敏剂的使用。卟啉类化合物是源于天然的另外一类光敏剂,但其母核的光敏效率与选择性均不够理想,考虑到细菌的增长分化需要大量的碳源和氮源。我们选择双乙二胺为对原卟啉化合物进行修饰,得到一类新型的抗菌光敏剂。体外研究表明其对革兰氏阴性菌及革兰氏阳性菌在体外均有高效的抗菌灭活作用,以小鼠急性创伤感染为模型的在体实验表明,双乙二胺的PACT作用可以明显的杀死绿脓杆菌,促进创伤面的愈合。
双乙二胺光敏剂有其特有的抗菌优势,但是不稳定,见光容易分解的缺点限制了其使用。为了进一步研究氨基数目的取代关系对卟啉光敏剂的稳定性、生物活性的影响,本实验室对双乙二胺进一步设计,得到了五种氨基卟啉类化合物,体外实验表明：该五种卟啉类化合物PAl-PA5均具有较缓慢的光漂白率和较强的单线态氧产生能力,其中PA1的单线态氧产生率最高(0.69),高于四苯基卟啉(0.64),其余化合物PA1-PA4单线态氧产率在0.15-0.37之间。细胞吞噬实验表明MRSA,E.coli, P.aeruginosa在30min即对上述五种化合物的吞噬量达到最大。激光共聚焦显微成像显示上述三种菌株对五种化合物的吸收具有选择性,对化合物PAl-PA2吞噬较强,而对PA3-PA5吞噬却较弱。光敏抗菌实验表明PA1产生的灭菌效果较其他四种化合物好,对三种菌的MIC均为16μM,对MRSaA,E.coli的MBC为31μM,对P.aeruginosa的MBC为62.5μM。PAl的暗毒性也低(MBC>500μM)。利用菌落计数法检测了PA1-PA5对三种细菌的光反应、暗反应浓度曲线。结果表明随着浓度的增加,PA1表现出明显的杀菌效果,对MRSA的杀菌效果最强,当浓度为15.6μM时,全部杀死革兰氏阳性菌MRSA.当浓度上升为31.25μM时,PA1几乎能全部杀死E.coli,P.aeruginosa。但在此浓度范围内对3T3成纤维细胞的损伤却很小。
以上结果表明PA1对革兰氏阳性菌及阴性菌均有很好的抗菌性能,可作为一种新型广谱的抗菌光敏剂使用,具有广阔的前景。
2卟啉类抗菌光敏剂在皮肤感染类疾病中的光敏抗菌效果评价
2.1光敏抗菌对创伤感染的效果评价
皮肤破损性疾病是一种临床常见病、多发病,由于多重耐药细菌的出现,临床治疗面临很大的难度。以筛选出的苗头化合物PA1为研究对象,重点探讨PA1对由MRSA,E.coli,P.aeruginosa混合感染的大鼠创面模型的PACT作用,结果表明：PA1介导的PACT能促进大面积创伤感染的大鼠皮肤愈合.其机制可能与诱导bFGF,TGF-β1的高表达,促进创面纤维合成和重新分布有关。造模后4,10及14天,高剂量PACT组的bFGF和TGF-β1的表达最高,模型对照组最低(P<0.01).PACT能显著改善创面感染组织炎症状况,降低组织中炎症相关因子TNF-a和IL-6含量。减少创面组织中细菌的数量,加快创面愈合的速率。PACT的效果与PA1的浓度呈正相关,表现出较好的剂量依赖关系。
大面积创伤发生时,由于屏障系统被破坏,细菌很容易穿透屏障,造成败血症。尽管PACT可以外用,体内却只能靠自身免疫力清除细菌,如果感染程度超过自身免疫力则容易引起败血症。基于这种考虑将PACT和抗生素的优势结合起来,PACT可以清除外表细菌,而体内细菌则由抗生素清除。基于大鼠创伤模型的实验表明：PACT联合抗生素治疗能显著降低大鼠大面积重度感染组织的炎症表达；减少创面组织中细菌数量,促进创面愈合,结果优于PACT治疗组和抗生素治疗组。PACT联合抗生素治疗大鼠大面积重度感染,死亡率为20%,而模型对照组的死亡率是60%,表明PACT联合抗生素治疗的有效性。免疫组化分析表明PACT联合抗生素治疗可显著提高创面组织中bFGF(?)TGF-β1的含量表达,促进创面纤维合成和重新分布,加快创面愈合的速率,同时显著降低创面组织中炎症相关因子TNF-α和IL-6含量,减少创伤组织的炎症反应,有助于创伤组织的修复。
2.2光敏抗菌作用在烧伤感染中的效果评价
烧烫伤(bums/scalds)是皮肤创伤的一种常见形式,为临床常见病和多发病。细菌感染是烧伤患者的主要并发症,发病率高,是造成病人死亡的主要因素,因此抗感染成为治疗烧伤病人的重要环节。PACT联合抗生素治疗大鼠Ⅲ度烧伤感染结果表明,PACT联合抗生素治疗能显著降低烧伤感染组织的炎症表达；减少创面组织中细菌数量,促进创面愈合,结果优于PACT治疗组和抗生素治疗组。(?)PACT联合抗生素治疗大鼠Ⅲ度烧伤感染,死亡率为0%,而模型对照组的死亡率是50%。免疫组合分析表明PACT联合抗生素治疗可显著提高创面组织中bFGF和新生血管数CD31的含量表达,促进血管新生和成纤维细胞的增殖,促进了创面肉芽组织的生长,从而促进创面愈合,同时可以提高机体的自身免疫能力显著降低烧伤创面组织中炎症相关因子TNF-α和IL-6含量,减少创伤组织的炎症反应,有助于创伤组织的修复。
综上所述,PA1是一种具有良好抗菌效果的广谱光敏剂,体内、体外实验表明,该光敏剂具有高效、低毒的性质,可作为一种新型广谱的抗菌光敏剂使用,具有广阔的前景。
In recent years, the overuse of antibiotics has led to the emergence and spread of superbug. The so-called superbugs refer to the bacteria which are multidrug-resistant to present antibiotics. This has added to a lot of difficulties for the treatment of wound infection in clinic. Although there is only a potential likelihood for the explosive prevalence of multiantibiotics-resistant superbugs, what terror it will cause has brought great panics in many countries around the world. Therefore, the development of new anti-infection strategy is urgent. Photodynamic antimicrobial chemotherapy (PACT) is one of the most promising new antimicrobial therapies in treating infections caused by bacteria, Fungi and viruses, especially in treating infections by multidrug-resistant bacteria Photodynamic antimicrobial therapy is an oxidative damage mechanism relying on a combined action of three factors----light, photosensitizer and oxygen, which will not bring some drug-resistant problems related with such factors as single-drug administration, the concentration of photosensitizer, inadequate exposure time etc.
Additionally, superbugs are most likely to be found in the infection site of the wound, in the infection of the lungs, the blood and the urinary tract. Except for blood infection, PACT is relatively easy to implement in the other parts' infections. Hence, in terms of drug-resistance, bactericidal effect and convenience, PACT has its great advantages. Currently, a lot of research in foreign countries has been done into the photodynamic inactivation of different bacteria with different photosensitizers, which aims at discovering a desired photosensitizer. A desired antimicrobial photosensitizer should have the following characteristics-----high efficacy yet low toxicity, good selectivity, strong permeability of the cell wall and high effectiveness in microorganism inactivation while doing little harm to the normal tissues. In previous reports, photosensitive drugs as antibacterial agents have no highlighted selectivity, with some effective to Gram-positive bacteria and some effective to Gram-negative bacteria We expect that the desired photosensitive drugs can be effective in treating the above two bacteria and the potential bacteria Therefore, it is of great practical significance to achieve the promotion of PACT. Based on the above objectives, we were screened antibacterial sensitive drugs in vitro and in vivo, the major contents of paper includes the following two parts:
1. The design and screening of high efficacy antimicrobial photosensitizer
1.1The photodynamic antibacterial effect of a-D-galactopyranosyl Zinc Phthalocyanines
Phthalocyanines photosensitizers have its own advantages but there is limitation to the use of Phthalocyanines because of its poor water solubility and easily gathering. Considering the rapid metabolism and reproduction of bacteria, galactose is used as modification to increase its water solubility and its biocompatibility. So,drugs that bacteria selectively take in are well designed so that photosensitive drugs are preferentially concentrated in bacteria rather than in the surrounding tissues or cells so as to achieve selective sterilization. The novel a-D-galactopyranosyl zinc phthalocyanines (T1, T2, T3, T4) have been synthesized to study the biological properties and antibacterial properties. The study showed that the bacterial uptake to four phthalocyanine compounds (T1-T4) reached maximum in30minutes. With increased irradiation time, the number of colonies decreased and when the energy density reached6J/cm2, the inactivation rate of bacteria reached maximum, which no longer increased with increased laser energy density. Of the four a-D-galactopyranosyl zinc phthalocyanines compounds (T1-T4), the irradiation of T1had effective inactivation to Gram-positive drug-resistant bacteria MRSA with low dark toxicity, but the inactivation effect to Gram-negative bacteria (Escherichia coli and Pseudomonas aeruginosa) was very poor. The laser confocal showed that MRSA had maximum uptake of T1and T1had the strongest fluorescent.
1.2The antibacterial effect of Porphyrin compounds
Phthalocyanines photosensitizers are effective in fighting against Gram-positive bacteria but ineffective to Gram-negative bacteria, which greatly limit the use of such photosensitizers. Porphyrins is another kind of natural photosensitizer, But its parent nucleus of photosensitive efficiency and selectivity are not ideal. Considering the reproduction of bacteria need huge amounts of carbon and nitrogen sources, double ethylenediamine is used as the modification of the original porphyrin compounds, and obtained a new type of antibacterial photosensitizer. Amino heme was taken as an example and a study of PACT was conducted against Gram-negative and Gram-positive bacteria, showing that it had good antibacterial effect in vitro. Experiments on rats with acute trauma infection in vivo indicated that PACT with Amino heme could obviously kill P. aeruginosa and promote the wound healing.
Amino heme photosensitizer has its unique antibacterial advantages, but its limitation is unstability and easy decomposition to light, which greatly limits its use. To further study the effect of the amino-substituted porphyrins on the stability and the biological activity of photosensitizers, Amino heme was further designed and five amino porphyrin compounds were obtained. The experiments in vitro showed that the five compounds PA1-PA5were all slower in photobleaching and a strong ability to generate singlet oxygen, of which PA1had the highest rate of generating singlet oxygen (0.69), higher than that of the tetraphenyl porphyrin (0.64), and the singlet oxygen yield of PA2-PA4was0.15-0.37. The uptake of PA1-PA5by MRS A, E.coli, P.aeruginosa showed that the uptake reached maximum in30minutes incubation. The laser confocal microscopy revealed that three strains were selective in taking in5compounds. The uptake of PA1-PA2by three strains was higher whereas the uptake of PA3-PA5was relatively low. The irradiation bacterial effect of PA1was better than the other four compounds. The MIC of the three strains was16μM, the MBC for MRS A, E.coli's was31μM and the MBC for P.aeruginosa was62.5uM. The dark toxicity of PA1was very low (MBC>500μM). The colony counting method was used to detect the concentration curves of PA1-PA5in the light and dark reactions to three strains. The results showed that with increasing concentration, PA1had significant bactericidal effect and the greatest bactericidal effect against MRSA happened in the concentration of15.6uM. When the concentration reached31.25μM, PA1almost completely killed MRSA. However, within this concentration range, PA1had minor inactivation to3T3fibroblasts.
These results indicate that PA1has good antibacterial properties against Gram-positive and negative bacteria, and it can be used as a novel broad-spectrum antimicrobial photosensitizers, which will have a broad and bright prospects.
2Antibacterial effect evaluation of porphyrin photosensitizers in the skin-infection diseases
2.1Effects of Photodynamic antimicrobial therapy of porphyrin photosensitizer on wound infection
Skin trauma is a common disease, and it is more difficult to treat in clinic. The PA1compounds is taken as the study object, mainly focusing on the effect of PA1on the trauma model in rats with mixed wound infection of MRSA, E.coli, P.aeruginosa. The results showed that PACT could greatly promote the skin healing in rats with large areas of wound infections. Its mechanism lay in inducing the high expression of BFGF, TGF-β1and promoting the synthesis and redistribution of fibrolos in the wounds. The expression of BFGF and TGF-β1in the PACT group is the highest while the expression of the control group is the lowest.(p<0.01). PACT could significantly downregulate inflammation condition of the infected tissues in the burns, reducing the amount of TNF-and IL-6and the number of bacteria and promoting the healing speed of the wounds. The concentration change of PA1was positively correlated with PACT effect, showing good dose-dependent relation.
Trauma tend to damage the barrier system of the body, which makes it easy for bacteria to penetrate the barrier and cause sepsis. While PACT can be used in vitro, bacteria in vivo can only be removed by immunity in itself. The combined advantage of PACT and antibiotics is that PACT can remove bacteria in vitro while bacteria in vivo can be cleaned through antibiotics, small amount of which can work. Therefore, the combined therapy of PACT and antibiotics has been used to treat trauma models in seriously-infected rats. The results showed that PACT combined with antibiotics could significantly reduce the inflammation expression of the seriously-infected tissues in rats with severe wounds, greatly reducing the number of bacteria in the wound tissues and promoting the wound healing. The result was far better than that of the PACT group and the antibiotics group. The combined therapy of PACT and antibiotics was used to treat rats with a large area of severe infections, with the mortality20%, whereas the mortality of the control group was60%, which indicated the effectiveness of the combined therapy. The explanation to the treatment of a large area of trauma infections with the combined therapy of PACT and antibiotics was as follows:It could significantly improve the amount of BFGF and TGF-β1, promoting the fiber composition and redistribution of the wound and thus accelerating the healing speed. At the same time, it could greatly reduce the secretion of inflammation-related factors TNF-a and IL-6, reducing the inflammation of the infected tissues in trauma, thus contributing to the healing of the skin lesion.
2.2Effects of photodynamic antimicrobial chemotherapy on burn infection model.
Scalds/Burns is a common form of skin wounds and frequently-occurring disease in clinical. Bacterial infection, the main complications of burn patients, is the dominating factor of death. So, Anti-infection treatment is the important link for burn patients. The results showed that PACT combined with antibiotics could significantly reduce the inflammation expression of the burned tissues in rats with severe burns, greatly reducing the number of bacteria in the wound tissues and promoting the wound healing. The result was far better than that of the PACT group and the antibiotics group. The combined therapy of PACT and antibiotics was used to treat rats with burned severe infections, with the mortality0%, whereas the mortality of the control group was50%, which indicated the effectiveness of the combined therapy. The explanation to the treatment of degree Ⅲ burns infection in rats with the combined therapy of PACT and antibiotics was as follows: It could significantly improve the expression of bFGF and CD31in trauma, facilitating the proliferation of new capillaries and fibroblast cells in the early stage and the growth of wound granulation tissues, and enhancing the wound healing. It could greatly improve the rats'immunity system, regulating the secretion of inflammation-related factors TNF-a and IL-6and reducing the inflammation of burn tissues, thus contributing to the healing of the skin lesion.
In summary, PA1is a broad-spectrum photosensitizer with good antimicrobial effect. The experiments in vitro and in vivo reveal that the photosensitizer has the naure of high efficiency and low toxicity. Therefore, it can be used as a novel broad-spectrum photosensitizer against bacteria, with broad prospects.
引文
1. Williams R, Lewis K, Salyers A A, et al. Resistance as a worldwide problem[J]. Bacterial Resistance to Antimicrobials,2002:223-238.
2. Plowman R, Graves N, Griffin M A S, et al. The rate and cost of hospital-acquired infections occurring in patients admitted to selected specialties of a district general hospital in England and the national burden imposed[J]. Journal of Hospital Infection,2001,47(3):198-209.
3. Chen J, Jin M, Qiu Z G, et al. A survey of drug resistance bla genes originating from synthetic plasmid vectors in six Chinese rivers[J]. Environmental science & technology,2012,46(24): 13448-13454.
4. Wainwright M, Phoenix D A, Gaskell M, et al. Photobactericidal activity of methylene blue derivatives against vancomycin-resistant Enterococcus spp[J]. Journal of Antimicrobial Chemotherapy,1999,44(6):823-825.
5. Tavares A, Carvalho C, Faustino M A, et al. Antimicrobial photodynamic therapy:study of bacterial recovery viability and potential development of resistance after treatment[J]. Marine drugs, 2010,8(1):91-105.
6. Dai T, Huang Y Y, Hamblin M R. Photodynamic therapy for localized infections-state of the art[J]. Photodiagnosis and photodynamic therapy,2009,6(3):170-188.
7. MOAN J, Peng Q. An outline of the hundred-year history of PDT[J]. Anticancer research,2003, 23(5A):3591-3600.
8. Ochsner M. Photophysical and photobiological processes in the photodynamic therapy of tumours[J]. Journal of Photochemistry and Photobiology B:Biology,1997,39(1):1-18.
9. Lavi A, Weitman H, Holmes R T, et al. The depth of porphyrin in a membrane and the membrane's physical properties affect the photosensitizing efficiency[J]. Biophysical journal,2002,82(4): 2101-2110.
10. Soukos N S, Wilson M, Burns T, et al. Photodynamic effects of toluidine blue on human oral keratinocytes and fibroblasts and Streptococcus sanguis evaluated in vitro[J]. Lasers in surgery and medicine,1996,18(3):253-259.
11. Salmon-Divon M, Nitzan Y, Malik Z. Mechanistic aspects of Escherichia coli photodynamic inactivation by cationic tetra-meso (N-methylpyridyl) porphine[J]. Photochemical & Photobiological Sciences,2004,3(5):423-429.
12. Shih M H, Huang F C. Repetitive methylene blue-mediated photoantimicrobial chemotherapy changes the susceptibility and expression of the outer membrane proteins of< i> Pseudomonas aeruginosa[J]. Photodiagnosis and photodynamic therapy,2013,10(4):664-671.
13. Rosseti I B, Chagas L R, Costa M S. Photodynamic antimicrobial chemotherapy (PACT) inhibits biofilm formation by Candida albicans, increasing both ROS production and membrane permeability[J]. Lasers in medical science,2013:1-6.
14. Hancock R E W. The bacterial outer membrane as a drug barrier[J]. Trends in microbiology,1997, 5(1):37-42.
15. Soukos N S, Ximenez-Fyvie L A, Hamblin M R, et al. Targeted antimicrobial photochemotherapy[J]. Antimicrobial agents and chemotherapy,1998,42(10):2595-2601.
16. Hamblin M R, O'Donnell D A, Murthy N, et al. Polycationic photosensitizer conjugates:effects of chain length and Gram classification on the photodynamic inactivation of bacteria[J]. Journal of Antimicrobial Chemotherapy,2002,49(6):941-951.
17. Nitzan Y, Ashkenazi H. Photoinactivation of Acinetobacter baumannii and Escherichia coli B by a cationic hydrophilic porphyrin at various light wavelengths[J]. Current microbiology,2001,42(6): 408-414.
18. Valduga G, Breda B, Giacometti G M, et al. Photosensitization of Wild and Mutant Strains of< i> Escherichia coli by< i> meso-Tetra (< i> N-methyl-4-pyridyl) porphine[J]. Biochemical and biophysical research communications,1999,256(1):84-88.
19. Je J Y, Kim S K. Antimicrobial action of novel chitin derivative[J]. Biochimica et Biophysica Acta(BBA)-General Subjects,2006,1760(1):104-109.
20. Jori G, Brown S B. Photosensitized inactivation of microorganisms[J]. Photochemical & Photobiological Sciences,2004,3(5):403-405.
21. Soncin M, Fabris C, Busetti A, et al. Approaches to selectivity in the Zn (Ⅱ)-phthalocyanine-photosensitized inactivation of wild-type and antibiotic-resistant Staphylococcus aureus[J]. Photochemical & Photobiological Sciences,2002,1(10):815-819.
22. Bertoloni G, Lauro F M, Cortella G, et al. Photosensitizing activity of hematoporphyrin on< i> Staphylococcus aureus cells[J]. Biochimica et Biophysica Acta (BBA)-General Subjects,2000, 1475(2):169-174.
23. Bertolini G, Rossi F, Valduga G, et al. Photosensitizing activity of water-and lipid-soluble phthalocyanines on< i> Escherichia coli[J]. FEMS microbiology letters,1990,71(1):149-155.
24. Asadi M, Safaei E, Ranjbar B, et al. Thermodynamic and spectroscopic study on the binding of cationic Zn (Ⅱ) and Co (Ⅱ) tetrapyridinoporphyrazines to calf thymus DNA:the role of the central metal in binding parameters[J]. New journal of chemistry,2004,28(10):1227-1234.
25. Ravanat J L, Berger M, Benard F, et al. Phthalocyanine and naphthalocyanine photosensitized oxidation of 2'-deoxyguanosine:distinct type Ⅰ and type Ⅱ products[J]. Photochemistry and photobiology,1984,39(6):809-814.
26. Sheu C, Foote C S. Endoperoxide formation in a guanosine derivative[J]. Journal of the American Chemical Society,1993,115(22):10446-10447.
27. Cadet J, Douki T, Gasparutto D, et al. Oxidative damage to DNA:formation, measurement and biochemical features[J]. Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis, 2003,531(1):5-23.
28. Cadet J, Ravanat J L, Martinez G R, et al. Singlet oxygen oxidation of isolated and cellular DNA: product formation and mechanistic insights[J]. Photochemistry and photobiology,2006,82(5): 1219-1225.
29. Spesia M B, Caminos D A, Pons P, et al. Mechanistic insight of the photodynamic inactivation of< i> Escherichia coli by a tetracationic zinc (Ⅱ) phthalocyanine derivative[J]. Photodiagnosis and photodynamic therapy,2009,6(1):52-61.
30. Hamblin M R, Hasan T. Photodynamic therapy:a new antimicrobial approach to infectious disease?[J]. Photochemical & Photobiological Sciences,2004,3(5):436-450.
31. Imray F P, MacPhee D G. The role of DNA polymerase I and the rec system in survival of bacteria and bacteriophages damaged by the photodynamic action of acridine orange[J]. Molecular and General Genetics MGG,1973,123(4):289-298.
32. John D C A, Rosamund J, Douglas K T. Tight binding of a copper (Ⅱ) phthalocyanine (Cuprolinic Blue) to DNA[J]. Biochemical and biophysical research communications,1989,159(3):1256-1262.
33. Maclean M, Macgregor S J, Anderson J G, et al. The role of oxygen in the visible-light inactivation of< i> Staphylococcus aureus[J]. Journal of Photochemistry and Photobiology B: Biology,2008,92(3):180-184.
34. Nitzan Y, Gutterman M, Malik Z, et al. INACTIVATION OF GRAM-NEGATIVE BACTERIA BY PHOTOSENSITIZED PORPHYRINS[J]. Photochemistry and photobiology,1992,55(1):89-96.
35. Wainwright M. 'Safe' photoantimicrobials for skin and soft-tissue infections[J]. International journal of antimicrobial agents,2010,36(1):14-18.
36. Wilson M, Yianni C. Killing of methicillin-resistant Staphylococcus aureus by low-power laser light[J]. Journal of medical microbiology,1995,42(1):62-66.
37. Usacheva M N, Teichert M C, Biel M A. Comparison of the methylene blue and toluidine blue photobactericidal efficacy against gram-positive and gram-negative microorganisms[J]. Lasers in surgery and medicine,2001,29(2):165-173.
38. Wainwright M, Phoenix D A, Laycock S L, et al. Photobactericidal activity of phenothiazinium dyes against methicillin-resistant strains of Staphylococcus aureus[J]. FEMS microbiology letters, 1998,160(2):177-181.
39. Phoenix D A, Sayed Z, Hussain S, et al. The phototoxicity of phenothiazinium derivatives against Escherichia coli and Staphylococcus aureus[J]. FEMS Immunology & Medical Microbiology,2003, 39(1):17-22.
40. Kubin A, Wierrani F, Jindra R H, et al. Antagonistic effects of combination photosensitization by hypericin, meso-tetrahydroxyphenylchlorin (mTHPC) and photofrin Ⅱ on Staphylococcus aureus[J]. Drugs under experimental and clinical research,1998,25(1):13-21.
41. Wierrani F. [Experimental investigations and clinical use of photodynamic therapy (PDT) in the Rudolf Foundation Hospital][J]. Gynakologisch-geburtshilfliche Rundschau,1998,39(4):217-225.
42. Segalla A, Borsarelli C D, Braslavsky S E, et al. Photophysical, photochemical and antibacterial photosensitizing properties of a novel octacationic Zn (Ⅱ)-phthalocyanine[J]. Photochemical & Photobiological Sciences,2002,1(9):641-648.
43. Szpakowska M, Lasocki K, Grzybowski J, et al. Photodynamic activity of the haematoporphyrin derivative with rutin and arginine substituents (HpD-Rut< sub> 2-Arg< sub> 2) against staphylococcus aureus and pseudomonas aeruginosa[J]. Pharmacological Research,2001,44(3): 243-246.
44. Nitzan Y, Salmon-Divon M, Shporen E, et al. ALA induced photodynamic effects on gram positive and negative bacteria[J]. Photochemical & Photobiological Sciences,2004,3(5):430-435.
45. Gross S, Brandis A, Chen L, et al. Protein-A-mediated Targeting of Bacteriochlorophyll-IgG to Staphylococcus aureus:A Model for Enhanced Site-Specific Photocytotoxicity[J]. Photochemistry and photobiology,1997,66(6):872-878.
46. Embleton M L, Nair S P, Cookson B D, et al. Selective lethal photosensitization of methicillin-resistant Staphylococcus aureus using an IgG-tin (IV) chlorin e6 conjugate[J]. Journal of Antimicrobial Chemotherapy,2002,50(6):857-864.
47 Embleton M L, Nair S P, Cookson B D, et al. Antibody-directed photodynamic therapy of methicillinresistant Staphylococcus aureus [J]. Microbial Drug Resistance,2004,10(2):92-97.
48. Gad F, Zahra T, Hasan T, et al. Effects of growth phase and extracellular slime on photodynamic inactivation of gram-positive pathogenic bacteria[J]. Antimicrobial agents and chemotherapy,2004, 48(6):2173-2178.
49. Van der Meulen F W, Ibrahim K, Sterenborg H, et al. Photodynamic destruction of< i> Haemophilus parainfluenzae by endogenously produced porphyrins[J]. Journal of Photochemistry and Photobiology B:Biology,1997,40(3):204-208.
50. Wilson M. Lethal photosensitisation of oral bacteria and its potential application in the photodynamic therapy of oral infections[J]. Photochemical & Photobiological Sciences,2004,3(5): 412-418.
51. Henry C A, Dyer B, Wagner M, et al. Phototoxicity of argon laser irradiation on biofilms of< i> Porphyromonas and< i> Prevotella species[J]. Journal of Photochemistry and Photobiology B: Biology,1996,34(2):123-128.
52. Henry C A, Judy M, Dyer B, et al. Sensitivity of Porphyromonas and Prevotella species in liquid media to argon laser[J]. Photochemistry and photobiology,1995,61(4):410-413.
53. Matevski D, Weersink R, Tenenbaum H C, et al. Lethal photosensitization of periodontal pathogens by a red-filtered Xenon lamp in vitro[J]. Journal of periodontal research,2003,38(4): 428-435.
54. Ashkenazi H, Nitzan Y, Gal D. Photodynamic Effects of Antioxidant Substituted Porphyrin Photosensitizers on Gram-positive and-negative Bacteria[J]. Photochemistry and photobiology, 2003,77(2):186-191.
55. Usacheva M N, Teichert M C, Biel M A. The interaction of lipopolysaccharides with phenothiazine dyes[J]. Lasers in surgery and medicine,2003,33(5):311-319.
56. Komerik N, Wilson M, Poole S. The Effect of Photodynamic Action on Two Virulence Factors of Gram-negative Bacteria[J]. Photochemistry and photobiology,2000,72(5):676-680.
57. Szpakowska M, Reiss J, Graczyk A, et al. Susceptibility of< i> Pseudomonas aeruginosa to a photodynamic effect of the arginine hematoporphyrin derivative[J]. International journal of antimicrobial agents,1997,8(1):23-27.
58. Sol V, Branland P, Chaleix V, et al. Amino porphyrins as photoinhibitors of Gram-positive and-negative bacteria[J]. Bioorganic & medicinal chemistry letters,2004,14(16):4207-4211.
59. Tegos G P, Demidova T N, Arcila-Lopez D, et al. Cationic fullerenes are effective and selective antimicrobial photosensitizers[J]. Chemistry & biology,2005,12(10):1127-1135.
60. Spesia M B, Milanesio M E, Durantini E N. Synthesis, properties and photodynamic inactivation of< i> Escherichia coli by novel cationic tullerene C< sub> 60 derivatives[J]. European journal of medicinal chemistry,2008,43(4):853-861.
61. Lee C F, Lee C J, Chen C T, et al.8-Aminolaevulinic acid mediated photodynamic antimicrobial chemotherapy on< i> Pseudomonas aeruginosa planktonic and biofilm cultures[J]. Journal of Photochemistry and Photobiology B:Biology,2004,75(1):21-25.
62. Hashimoto M C E, Prates R A, Kato I T, et al. Antimicrobial Photodynamic Therapy on Drug-resistant Pseudomonas aeruginosa-induced Infection. An In Vivo Study[J]. Photochemistry and photobiology,2012,88(3):590-595.
63. Donnelly R F, Cassidy C M, Loughlin R G, et al. Delivery of Methylene Blue and meso-tetra (N-methyl-4-pyridyl) porphine tetra tosylate from cross-linked poly (vinyl alcohol) hydrogels:a potential means of photodynamic therapy of infected wounds[J]. Journal of Photochemistry and Photobiology B:Biology,2009,96(3):223-231.
64. Demidova T N, Gad F, Zahra T, et al. Monitoring photodynamic therapy of localized infections by bioluminescence imaging of genetically engineered bacteria[J]. Journal of Photochemistry and Photobiology B:Biology,2005,81(1):15-25.
65. Hamblin M R, O'Donnell D A, Murthy N, et al. Rapid Control of Wound Infections by Targeted Photodynamic Therapy Monitored by In Vivo Bioluminescence Imaging[J]. Photochemistry and photobiology,2002,75(1):51-57.
66. Hamblin M R, Zahra T, Contag C H, et al. Optical monitoring and treatment of potentially lethal wound infections in vivo[J]. Journal of Infectious Diseases,2003,187(11):1717-1726.
67. Wong T W, Wang Y Y, Sheu H M, et al. Bactericidal effects of toluidine blue-mediated photodynamic action on Vibrio vulnificus[J]. Antimicrobial agents and chemotherapy,2005,49(3): 895-902.
68. Zolfaghari P S, Packer S, Singer M, et al. In vivo killing of Staphylococcus aureus using a light-activated antimicrobial agent[J]. BMC microbiology,2009,9(1):27.
69. Dai T, Tegos G P, Zhiyentayev T, et al. Photodynamic therapy for methicillin-resistant Staphylococcus aureus infection in a mouse skin abrasion model[J]. Lasers in surgery and medicine, 2010,42(1):38-44.
70. Simonetti O, Cirioni O, Orlando F, et al. Effectiveness of antimicrobial photodynamic therapy with a single treatment of RLP068/C1 in an experimental model of Staphylococcus aureus wound infection[J]. British Journal of Dermatology,2011,164(5):987-995.
71. Orenstein A, Klein D, Kopolovic J, et al. The use of porphyrins for eradication of Staphylococcus aureus in bum wound infections[J]. FEMS Immunology & Medical Microbiology,1997,19(4): 307-314.
72. Lambrechts S A G, Demidova T N, Aalders M C G, et al. Photodynamic therapy for Staphylococcus aureus infected burn wounds in mice[J]. Photochemical & Photobiological Sciences, 2005,4(7):503-509.
73. Dai T, Tegos G P, Lu Z, et al. Photodynamic therapy for Acinetobacter baumannii burn infections in mice[J]. Antimicrobial agents and chemotherapy,2009,53(9):3929-3934.
74. Bisland S K, Chien C, Wilson B C, et al. Pre-clinical in vitro and in vivo studies to examine the potential use of photodynamic therapy in the treatment of osteomyelitis[J]. Photochemical & Photobiological Sciences,2006,5(1):31-38.
75. Berthiaume F, Reiken S R, Toner M, et al. Antibody-targeted photolysis of bacteria in vivo[J]. Nature Biotechnology,1994,12(7):703-706.
76. Gad F, Zahra T, Francis K P, et al. Targeted photodynamic therapy of established soft-tissue infections in mice[J]. Photochemical & Photobiological Sciences,2004,3(5):451-458.
77. Tardivo J P, Baptista M S. Treatment of osteomyelitis in the feet of diabetic patients by photodynamic antimicrobial chemotherapy[J]. Photomedicine and laser surgery,2009,27(1): 145-150.
78. Teichert M C, Jones J W, Usacheva M N, et al. Treatment of oral candidiasis with methylene blue-mediated photodynamic therapy in an immunodeficient murine model[J]. Oral Surgery, Oral Medicine, Oral Pathology, Oral Radiology, and Endodontology,2002,93(2):155-160.
79. de Souza S C, Junqueira J C, Balducci I, et al. Photosensitization of different< i> Candida species by low power laser light[J]. Journal of Photochemistry and Photobiology B:Biology,2006, 83(1):34-38.
80. Donnelly R F, McCarron P A, Tunney M M, et al. Potential of photodynamic therapy in treatment of fungal infections of the mouth. Design and characterisation of a mucoadhesive patch containing toluidine blue O[J]. Journal of Photochemistry and Photobiology B:Biology,2007,86(1):59-69.
81. Rodrigues G B, Dias-Baruffi M, Holman N, et al.< i> In vitro photodynamic inactivation of< i> Candida species and mouse fibroblasts with phenothiazinium photosensitisers and red light[J]. Photodiagnosis and photodynamic therapy,2013,10(2):141-149.
82. Maisch T, Szeimies R M, Jori G, et al. Antibacterial photodynamic therapy in dermatology[J]. Photochemical & Photobiological Sciences,2004,3(10):907-917.
83. Bliss J M, Bigelow C E, Foster T H, et al. Susceptibility of Candida species to photodynamic effects of photofrin[J]. Antimicrobial agents and chemotherapy,2004,48(6):2000-2006.
84. Zofadek T, Nhi N B, Jagietto I, et al. Diamino acid derivatives of porphyrins penetrate into yeast cells, induce photodamage, but have no mutagenic effect[J]. Photochemistry and photobiology,1997, 66(2):253-259.
85. Donnelly R F, McCarron P A, Tunney M M, et al. Potential of photodynamic therapy in treatment of fungal infections of the mouth. Design and characterisation of a mucoadhesive patch containing toluidine blue O[J]. Journal of Photochemistry and Photobiology B:Biology,2007,86(1):59-69.
86. Lambrechts SAG, Schwartz K R, Aalders M C G, et al. Photodynamic inactivation of fibroblasts by a cationic porphyrin[J]. Lasers in medical science,2005,20(2):62-67.
87. Chabrier-Rosello Y, Foster T H, Perez-Nazario N, et al. Sensitivity of Candida albicans germ tubes and biofilms to photofrin-mediated phototoxicity[J]. Antimicrobial agents and chemotherapy,2005, 49(10):4288-4295.
88. Moretti M B, Garcia S C, Batlle A. Porphyrin Biosynthesis Intermediates Are Not Regulating δ-Aminolevulinic Acid Transport in< i> Saccharomyces cerevisiae[J]. Biochemical and biophysical research communications,2000,272(3):946-950.
89. Donnelly R F, McCarron P A, Lightowler J M, et al. Bioadhesive patch-based delivery of 5-aminolevulinic acid to the nail for photodynamic therapy of onychomycosis[J]. Journal of controlled release,2005,103(2):381-392.
90. Piraccini B M, Rech G, Tosti A. Photodynamic therapy of onychomycosis caused by< i> Trichophyton rubrum[J]. Journal of the American Academy of Dermatology,2008,59(5): S75-S76.
91. Bertoloni G, Rossi F, Valduga G, et al. Photosensitizing activity of water-and lipid-soluble phthalocyanines on prokaryotic and eukaryotic microbial cells[J]. Microbios,1991,71(286):33-46.
92. Mantareva V, Kussovski V, Angelov I, et al. Photodynamic activity of water-soluble phthalocyanine zinc (Ⅱ) complexes against pathogenic microorganisms[J]. Bioorganic & medicinal chemistry,2007,15(14):4829-4835.
93. Segalla A, Borsarelli C D, Braslavsky S E, et al. Photophysical, photochemical and antibacterial photosensitizing properties of a novel octacationic Zn (Ⅱ)-phthalocyanine[J]. Photochemical & Photobiological Sciences,2002,1(9):641-648.
94. Lyon J P, Moreira L M, de Moraes P C G, et al. Photodynamic therapy for pathogenic fungi[J]. Mycoses,2011,54(5):e265-e271.
95. Mohr H, Bachmann B, Klein-Struckmeier A, et al. Virus inactivation of blood products by phenothiazine dyes and light[J]. Photochemistry and photobiology,1997,65(3):441-445.
96. Mohr H, Knilver-Hopf J, Gravemann U, et al. West Nile virus in plasma is highly sensitive to methylene blue-light treatment[J]. Transfusion,2004,44(6):886-890.
97. Ben-Hur E, Geacintov N E, Studamire B, et al. The effect of irradiance on virus sterilization and photodynamic damage in red blood cells sensitized by phthalocyanines[J]. Photochemistry and photobiology,1995,61(2):190-195.
98. Ben-Hur E, Barshtein G, Chen S, et al. Photodynamic treatment of red blood cell concentrates for virus inactivation enhances red blood cell aggregation:protection with antioxidants[J]. Photochemistry and photobiology,1997,66(4):509-512.
99. Lambrechts S A G, Aalders M C G, Verbraak F D, et al. Effect of albumin on the photodynamic inactivation of microorganisms by a cationic porphyrin[J. Journal of Photochemistry and Photobiology B:Biology,2005,79(1):51-57.
100. Zanin I C J, Lobo M M, Rodrigues L K A, et al. Photosensitization of in vitro biofilms by toluidine blue O combined with a light-emitting diode[J]. European journal of oral sciences,2006, 114(1):64-69.
101. Bonsor S J, Nichol R, Reid T M S, et al. Microbiological evaluation of photo-activated disinfection in endodontics (an in vivo study)[J]. British dental journal,2006,200(6):337-341.
102. Silva Garcez A, Nunez S C, Lage-Marques J L, et al. Efficiency of NaOCl and laser-assisted photosensitization on the reduction of< i> Enterococcus faecalis in vitro[J]. Oral Surgery, Oral Medicine, Oral Pathology, Oral Radiology, and Endodontology,2006,102(4):e93-e98.
103. Konopka K, Goslinski T. Photodynamic therapy in dentistry [J]. Journal of Dental Research,2007, 86(8):694-707.
104. Millson C E, Wilson M, MacRobert A J, et al. Ex-vivo treatment of gastric< i> Helicobacter infection by photodynamic therapy[J]. Journal of Photochemistry and Photobiology B:Biology,1996, 32(1):59-65.
105. Lembo A J, Ganz R A, Sheth S, et al. Treatment of Helicobacter pylori infection with intra-gastric violet light phototherapy:A pilot clinical trial[J]. Lasers in surgery and medicine,2009,41(5): 337-344.
106. O' Riordan K, Akilov O E, Chang S K, et al. Real-time fluorescence monitoring of phenothiazinium photosensitizers and their anti-mycobacterial photodynamic activity against Mycobacterium bovis BCG in in vitro and in vivo models of localized infection[J]. Photochemical & Photobiological Sciences,2007,6(10):1117-1123.
107. O'Riordan K, Sharlin D S, Gross J, et al. Photoinactivation of Mycobacteria in vitro and in a new murine model of localized Mycobacterium bovis BCG-induced granulomatous infection[J]. Antimicrobial agents and chemotherapy,2006,50(5):1828-1834.
108. Imlay J A. The molecular mechanisms and physiological consequences of oxidative stress: lessons from a model bacterium[J]. Nature Reviews Microbiology,2013,11(7):443-454.
1. Hamblin, M. R.; Hasan, T., Photodynamic therapy:a new antimicrobial approach to infectious disease? [J]. Photochemical& Photobiological Sciences 2004,3(5),436-450.
2. Gould, I. M., Community-acquired MRSA:can we control it? [J]. Lancet 2006,368 (9538), 824-6.
3. Wainwright, M, Photodynamic antimicrobial chemotherapy (PACT) [J]. Journal of Antimicrobial Chemotherapy 1998,42 (1),13-28.
4. Donnelly, R. F.; McCarron, P. A.; Tunney, M. M., Antifungal photodynamic therapy[J]. Microbiological Research 2008,163 (1),1-12.
5. Bagchi, B.; Basu, S., ROLE OF DYE MOLECULES REMAINING OUTSIDE THE CELL DURING PHOTODYNAMIC INACTIVATION OF ESCHERICHIA COLI IN THE PRESENCE OF ACRIFLAVINE[J]. Photochemistry and Photobiology 1979,29 (2),403-405.
6. Bhatti, M.; MacRobert, A.; Meghji, S.; Henderson, B.; Wilson, M., A Study of the Uptake of Toluidine Blue O by Porphyromonas gingivalis and the Mechanism of Lethal Photosensitization[JJ. Photochemistry and Photobiology 1998,68 (3),370-376.
7. Tavares, A.; Carvalho, C. M.; Faustino, M. A.; Neves, M. G.; Tome, J. P.; Tome, A. C.; Cavaleiro, J. A.; Cunha, A.; Gomes, N. C.; Alves, E.; Almeida, A., Antimicrobial photodynamic therapy:study of bacterial recovery viability and potential development of resistance after treatment[J]. Mar Drugs 2010,8(1),91-105.
8. Wainwright, M.,'Safe'photoantimicrobials for skin and soft-tissue infections[J]. International Journal of Antimicrobial Agents 2010,36 (1),14-18.
9. Tegos, G. P.; Demidova, T. N.; Arcila-Lopez, D.; Lee, H.; Wharton, T.; Gali, H.; Hamblin, M. R., Cationic Fullerenes Are Effective and Selective Antimicrobial Photosensitizers[J]. Chemistry & Biology 2005,12 (10),1127-1135.
10. Mohr, H.; Bachmann, B.; Klein-Struckmeier, A.; Lambrecht, B., Virus Inactivation of Blood Products by Phenothiazine Dyes and Light[J]. Photochemistry and Photobiology 1997,65 (3), 441-445.
11. Mohr, H.; Kniiver-Hopf, J.; Gravemann, U.; Redecker-Klein, A.; Muller, T. H., West Nile virus in plasma is highly sensitive to methylene blue-light treatment[J]. Transfusion 2004,44 (6),886-890.
12. Lambrechts, S. A. G.; Aalders, M. C. G.; Verbraak, F. D.; Lagerberg, J. W. M.; Dankert, J. B.; Schuitmaker, J. J., Effect of albumin on the photodynamic inactivation of microorganisms by a cationic porphyrin[J]. Journal of Photochemistry and Photobiology B:Biology 2005,79 (1),51-57.
13. Wainwright, M.; Phoenix, D. A.; Laycock, S. L.; Wareing, D. R. A.; Wright, P. A., Photobactericidal activity of phenothiazinium dyes against methicillin-resistant strains of Staphylococcus aureus[J]. FEMS Microbiology Letters 1998,160 (2),177-181.
14. Wilson, M.; Yianni, C., Killing of methicillin-resistant Staphylococcus aureus by low-power laser light[J]. Journal of Medical Microbiology 1995,42 (1),62-66.
15. Ashkenazi, H.; Nitzan, Y.; Gal, D., Photodynamic Effects of Antioxidant Substituted Porphyrin Photosensitizers on Gram-positive and -negative Bacteriai[J]. Photochemistry and Photobiology 2003, 77(2),186-191.
16. Spesia, M. B.; Caminos, D. A.; Pons, P.; Durantini, E. N., Mechanistic insight of the photodynamic inactivation of Escherichia coli by a tetracationic zinc(Ⅱ) phthalocyanine derivative [J]. Photodiagnosis and photodynamic therapy 2009, 6(1),52-61.
17. Foley, J. W.; Song, X.; Demidova, T. N.; Jilal, F.; Hamblin, M. R., Synthesis and Properties of Benzo[a]phenoxazinium Chalcogen Analogues as Novel Broad-Spectrum Antimicrobial Photosensitizers[J]. Journal of medicinal chemistry 2006,49 (17),5291-5299.
18. Grinholc, M.; Szramka, B.; Kurlenda, J.; Graczyk, A.; Bielawski, K. P., Bactericidal effect of photodynamic inactivation against methicillin-resistant and methicillin-susceptible Staphylococcus aureus is strain-dependent[J]. Journal of Photochemistry and Photobiology B:Biology 2008,90 (1), 57-63.
19. Lilburn, T. G; Gu, J.; Cai, H.; Wang, Y, Comparative genomics of the family Vibrionaceae reveals the wide distribution of genes encoding virulence-associated proteins[J]. BMC genomics 2010, 11,369.
20. Sun, A.; Zhang, G.; Xu, Y, Photobleaching of metal phthalocyanine sulfonates under UV and visible light irradiation over TiO2 semiconductor[J]. Materials Letters 2005,59 (29-30),4016-4019.
21. Karmakova, T.; Feofanov, A.; Nazarova, A.; Grichine, A.; Yakubovskaya, R.; Luk'yanets,E.; Maurizot, J.-C.; Vigny, P., Distribution of metal-free sulfonated phthalocyanine in subcutaneously transplanted murine tumors[J]. Journal of Photochemistry and Photobiology B:Biology 2004,75 (1-2),81-87.
22. Ceyhan, T.; Altndal, A.; Ozkaya, A. R.; Salih, B.; Bekaroglu, O., Novel ball-type four dithioerythritol bridged metallophthalocyanines and their water-soluble derivatives:Synthesis and characterization, and electrochemical, electrocatalytic, electrical and gas sensing properties[J]. Dalton Transactions 2010,39 (41),9801-9814.
23. Drechsler, U.; Pfaff, M.; Hanack, M., Synthesis of Novel Functionalised Zinc Phthalocyanines Applicable in Photodynamic Therapy[J]. European Journal of Organic Chemistry 1999,1999 (12), 3441-3453.
24. Eisenberg, C.; Seta, N.; Appel, M.; Feldmann, G.; Durand, G.; Feger, J., Asialoglycoprotein receptor in human isolated hepatocytes from normal liver and its apparent increase in liver with histological alterations[J]. Journal ofHepatology 1991,13 (3),305-309.
25.曹波.新型水溶性光敏剂的评价和机制研究[D].北京：北京协和医学院,2012：20-50.
26. Gois, M. M.; Kurachi, C.; Santana, E. J.; Mima, E. G.; Spolidorio, D. M.; Pelino, J. E.; Salvador Bagnato, V., Susceptibility of Staphylococcus aureus to porphyrin-mediated photodynamic antimicrobial chemotherapy:an in vitro study[J]. Lasers in medical science 2010,25 (3),391-5.
27. Wilson, M.; Pratten, J., Lethal photosensitisation of Staphylococcus aureus[J]. Microbios 1994, 78(316),163-168.
28. Ochsner, M., Photophysical and photobiological processes in the photodynamic therapy of tumours[J]. Journal of Photochemistry and Photobiology B:Biology 1997,39 (1),1-18.
1. Chen J, Jin M, Qiu ZG et al. A survey of drug resistance bla genes originating from synthetic plasmid vectors in six Chinese rivers[J]. Environmental science & technology 2012; 46:13448-54.
2. Jori G Photodynamic Therapy of Microbial Infections:State of the Art and Perspectives[J].2006; 25:505-20.
3. Wainwright M, Phoenix DA, Gaskell M et al. Photobactericidal activity of methylene blue derivatives against vancomycin-resistant Enterococcus spp[J]. Journal of Antimicrobial Chemotherapy 1999; 44:823-5.
4. Wainwright M, Phoenix DA, Marland J et al. A study of photobactericidal activity in the phenothiazinium series[J]. FEMS immunology and medical microbiology 1997; 19:75-80.
5. Tavares A, Carvalho C, Faustino MA et al. Antimicrobial photodynamic therapy:study of bacterial recovery viability and potential development of resistance after treatment[J]. Marine drugs 2010; 8:91-105.
6. Alvarez-Mico X, Calvete MJF, Hanack M et al. A new glycosidation method through nitrite displacement on substituted nitrobenzenes[J]. Carbohydrate Research 2007; 342:440-7.
7. Lau JTF, Lo P-C, Fong W-P et al. Preparation and Photodynamic Activities of Silicon(IV) Phthalocyanines Substituted with Permethylated β-Cyclodextrins[J]. Chemistry-A European Journal 2011; 17:7569-77.
8. Fu X, Sheng Z, Cherry GW et al. Epidemiological study of chronic dermal ulcers in China[J]. Wound Repair and Regeneration 1998; 6:21-7.
9. Ornitz DM, Itoh N. Fibroblast growth factors[J]. Genome Biol 2001; 2:3005.1-12.
10. Buntrock P, Jentzsch KD, Heder G Stimulation of wound healing, using brain extract with fibroblast growth factor (FGF) activity:I. quantitative and biochemical studies into formation of granulation tissue[J]. Experimental pathology 1982; 21:46-53.
11. Brown GL, Nanney LB, Griffen J et al. Enhancement of wound healing by topical treatment with epidermal growth factor[J]. New England Journal of Medicine 1989; 321:76-9.
12. Laato M, Niinikoski J, Lundberg C et al. Effect of epidermal growth factor (EGF) on experimental granulation tissue [J].Journal of Surgical Research 1986; 41:252-5.
13. Chan KY, Jones RR, Bark DH et al. Release of neuronotrophic factor from rabbit corneal epithelium during wound healing and nerve regeneration[J]. Experimental Eye Research 1987; 45: 633-46.
14. Klein M, Picard E, Vignaud J et al. Vascular endothelial growth factor gene and protein:strong expression in thyroiditis and thyroid carcinoma[J]. Journal of Endocrinology 1999; 161:41-9.
15. Meyer M, Clauss M, Lepple-Wienhues A et al. A novel vascular endothelial growth factor encoded by Orf virus, VEGF-E, mediates angiogenesis via signalling through VEGFR-2 (KDR) but not VEGFR-1 (Flt-1) receptor tyrosine kinases[J]. The EMBO journal 1999; 18:363-74.
16. Li QF, Reis ED, Zhang WX et al. Accelerated flap prefabrication with vascular endothelial growth factor[J]. Journal of reconstructive microsurgery 2000; 16:0045-50.
17. Derynck R, Goeddel DV, Ullrich A et al. Synthesis of messenger RNAs for transforming growth factors α and β and the epidermal growth factor receptor by human tumors[J]. Cancer Research 1987; 47:707-12.
18. Chen S-J, Yuan W, Mori Y et al. Stimulation of type I collagen transcription in human skin flbroblasts by TGF-β:involvement of Smad 3[J]. Journal of investigative dermatology 1999; 112: 49-57.
19. Jori G Tumour photosensitizers:approaches to enhance the selectivity and efficiency of photodynamic therapy[J]. Journal of Photochemistry and photobiology B:Biology 1996; 36:87-93.
20. Bierbaum G, Fuchs K, Lenz W et al. Presence of Staphylococcus aureus with reduced susceptibility to vancomycin in Germany[J]. European Journal of Clinical Microbiology and Infectious Diseases 1999; 18:691-6.
21. Hassan IA, Chadwick PR, Johnson AP. Clinical isolates of methicillin-resistant Staphylococcus aureus (MRSA) with reduced susceptibility to teicoplanin in Northwest England[J]. Journal of Antimicrobial Chemotherapy 2001; 48:454-5.
22. Hiramatsu K. The emergence of< i> Staphylococcus aureus with reduced susceptibility to vancomycin in Japan[J]. The American journal of medicine 1998; 104:7S-10S.
23. Zeina B, Greenman J, Purcell W et al. Killing of cutaneous microbial species by photodynamic therapy[J]. British Journal of Dermatology 2001; 144:274-8.
24. Hamblin MR, Zahra T, Contag CH et al. Optical monitoring and treatment of potentially lethal wound infections in vivo[J]. Journal of Infectious Diseases 2003; 187:1717-26.
25. Ishikawa Y, YAMASHITA A, Uno T. Efficient Photocleavage of DNA by Cationic Porphyrin-Acridine Hybrids with the Effective Length of Diamino Alkyl Linkage[J]. Chemical and pharmaceutical bulletin 2001; 49:287-93.
26. Zhao Z, Li Y, Meng S et al. Susceptibility of methicillin-resistant Staphylococcus aureus to photodynamic antimicrobial chemotherapy with a-d-galactopyranosyl zinc phthalocyanines:in vitro study [J]. Lasers in medical science 2013:1-8.
27. Vecchio D, Dai T, Huang L et al. Antimicrobial photodynamic therapy with RLP068 kills methicillin-resistant Staphylococcus aureus and improves wound healing in a mouse model of infected skin abrasion PDT with RLP068/C1 in infected mouse skin abrasion[J]. Journal of Biophotonics 2013; 6:733-42.
28. Simonetti O, Cirioni O, Orlando F et al. Effectiveness of antimicrobial photodynamic therapy with a single treatment of RLP068/C1 in an experimental model of Staphylococcus aureus wound infection[J]. British Journal ofDermatology 2011; 164:987-95.
29. Banfi S, Caruso E, Buccafurni L et al. Antibacterial activity of tetraaryl-porphyrin photosensitizers:an in vitro study on Gram negative and Gram positive bacteria[J]. Journal of photochemistry and photobiology B:Biology 2006; 85:28-38.
30. Salmon-Divon M, Nitzan Y, Malik Z. Mechanistic aspects of Escherichia coli photodynamic inactivation by cationic tetra-meso (N-methylpyridyl) porphine[J]. Photochemical & Photobiological Sciences 2004; 3:423-9.
1. Bagchi B, Basu S. ROLE OF DYE MOLECULES REMAINING OUTSIDE THE CELL DURING PHOTODYNAMIC INACTIVATION OF ESCHERICHIA COLI IN THE PRESENCE OF ACRIFLAVINE[J]. Photochemistry and Photobiology 1979; 29:403-5.
2. Bhatti M, MacRobert A, Meghji S et al. A Study of the Uptake of Toluidine Blue O by Porphyromonas gingivalis and the Mechanism of Lethal Photosensitization[J]. Photochemistry and Photobiology 1998; 68:370-6.
3. Tavares A, Carvalho CM, Faustino MA et al. Antimicrobial photodynamic therapy:study of bacterial recovery viability and potential development of resistance after treatment[J]. Mar Drugs 2010; 8:91-105.
4. Calzavara-Pinton PG, Venturini M, Sala R. A comprehensive overview of photodynamic therapy in the treatment of superficial fungal infections of the skin[J]. Journal of photochemistry and photobiology B, Biology 2005; 78:1-6.
5. Lambrechts SA, Aalders MC, Verbraak FD et al. Effect of albumin on the photodynamic inactivation of microorganisms by a cationic porphyrin[J]. Journal of photochemistry and photobiology B, Biology 2005; 79:51-7.
6. Sol V, Branland P, Chaleix V et al. Amino porphyrins as photoinhibitors of Gram-positive and-negative bacteria[J]. Bioorg Med Chem Lett 2004; 14:4207-11.
7. Jori G. Tumour photosensitizers:approaches to enhance the selectivity and efficiency of photodynamic therapy[J]. Journal of Photochemistry and Photobiology B:Biology 1996; 36:87-93.
8. Rodrigues GB, Dias-Baruffi M, Holman N et al. In vitro photodynamic inactivation of Candida species and mouse fibroblasts with phenothiazinium photosensitisers and red light[J]. Photodiagnosis Photodyn Ther 2013; 10:141-9.
9. Chakraborry SP, Sahu SK, Pramanik P et al. In vitro antimicrobial activity of nanoconjugated vancomycin against drug resistant Staphylococcus aureus[J]. International journal of pharmaceutics 2012; 436:659-76.
10. Lv F, Li Y, Cao B et al. Galactose substituted zinc phthalocyanines as near infrared fluorescence probes for liver cancer imaging[J]. Journal of materials science Materials in medicine 2013; 24: 811-9.
11. Alvarez-Mico X, Calvete MJF, Hanack M et al. A new glycosidation method through nitrite displacement on substituted nitrobenzenes[J]. Carbohydrate Research 2007; 342:440-7.
12. Lau JTF, Lo P-C, Fong W-P et al. Preparation and Photodynamic Activities of Silicon(IV) Phthalocyanines Substituted with Permethylated β-Cyclodextrins[J]. Chemistry-A European Journal 2011; 17:7569-77.
13. Lilburn TG, Gu J, Cai H et al. Comparative genomics of the family Vibrionaceae reveals the wide distribution of genes encoding virulence-associated proteins[J]. BMC genomics 2010; 11:369.
14. Wainwright M. Photodynamic antimicrobial chemotherapy (PACT) [J]. Journal of Antimicrobial Chemotherapy 1998; 42:13-28.
15. Zeina B, Greenman J, Purcell W et al. Killing of cutaneous microbial species by photodynamic therapy[J]. British Journal of Dermatology 2001; 144:274-8.
16. Wilson M, Pratten J. Lethal photosensitisation of Staphylococcus aureus. Microbios 1994; 78: 163-8.
17. Wilson M, Yianni C. Killing of methicillin-resistant Staphylococcus aureus by low-power laser light[J]. Journal of Medical Microbiology 1995; 42:62-6.
18. Yang Y-T, Chien H-F, Chang P-H et al. Photodynamic inactivation of chlorin e6-loaded CTAB-liposomes againstCandida albicans[J]. Lasers in surgery and medicine 2013; 45:175-85.
19. Zhao Z, Li Y, Meng S et al. Susceptibility of methicillin-resistant Staphylococcus aureus to photodynamic antimicrobial chemotherapy with α-d-galactopyranosyl zinc phthalocyanines:in vitro study[J]. Lasers in medical science 2013:1-8.
20. Hamblin MR, Hasan T. Photodynamic therapy:a new antimicrobial approach to infectious disease? [J] Photochemical & Photobiological Sciences 2004; 3:436-50.
21.于克贵.新型卟啉化合物的设计合成及生物活性研究[D].西南大学,2008.
22. Soncin M, Fabris C, Busetti A et al. Approaches to selectivity in the Zn(ii)-phthalocyanine-photosensitized inactivation of wild-type and antibiotic-resistant Staphylococcus aureus[J]. Photochemical & Photobiological Sciences 2002; 1:815-9.
23. Jori G, Brown SB. Photosensitized inactivation of microorganisms [J]. Photochemical & Photobiological Sciences 2004; 3:403-5.
24. Salmon-Divon M, Nitzan Y, Malik Z. Mechanistic aspects of Escherichia coli photodynamic inactivation by cationic tetra-meso(N-methylpyridyl)porphine[J]. Photochemical & Photobiological Sciences 2004; 3:423-9.
1.葛绳德.烧伤和创伤后革兰阳性细菌感染[J1.国外医学：创伤与外科基本问题分册,1993,14(1)：29-33.
2. Duckworth GJ. Diagnosis and management of methicillin resistant Staphylococcus aureus infection[J]. BMJ:British Medical Journal 1993; 307:1049.
3. MORADI N, JAVADPOUR S, KARMOSTAJI A. REDUCED SENSITIVITY OF STAPHYLOCOCCUS AUREUS TO VANCOMYCIN[J]. MEDICAL JOURNAL OF HORMOZGAN UNIVERSITY 2011.
4. Tavares A, Carvalho CM, Faustino MA et al. Antimicrobial photodynamic therapy:study of bacterial recovery viability and potential development of resistance after treatment[J]. Mar Drugs 2010; 8:91-105.
5. Polo L, Segalla A, Bertoloni G et al. Polylysine-porphycene conjugates as efficient photosensitizers for the inactivation of microbial pathogens[J]. Journal of Photochemistry and Photobiology B:Biology 2000; 59:152-8.
6. Soukos NS, Wilson M, Burns T et al. Photodynamic effects of toluidine blue on human oral keratinocytes and fibroblasts and Streptococcus sanguis evaluated in vitro[J]. Lasers in surgery and medicine 1996; 18:253-9.
7. Dai T, Huang Y-Y, Hamblin MR. Photodynamic therapy for localized infections-state of the art[J]. Photodiagnosis and photodynamic therapy 2009; 6:170-88.
8. 赵京禹,付小兵,雷永红,等.大鼠小面积全层皮肤缺损创面模型的制备[J].感染.炎症.修复,2008,9(1)：64-64.
9. 龙琦,尹晓娟,封志纯.神经生长因子和碱性成纤维细胞生长因子对缺氧缺血脑损伤新生大鼠内源性神经干细胞的影响[J].实用医学杂志,2009,25(1)：36-39.
10. Masuoka K, Ishihara M, Asazuma T et al. The interaction of chitosan with fibroblast growth factor-2 and its protection from inactivation[J]. Biomaterials 2005; 26:3277-84.
11. Huang L, Dai T, Hamblin M. Antimicrobial Photodynamic Inactivation and Photodynamic Therapy for Infections. In:Gomer CJ, ed[J]. Photodynamic Therapy:Humana Press,2010; 155-73.
12. Dai T, Tegos GP, Zhiyentayev T et al. Photodynamic therapy for methicillin-resistant Staphylococcus aureus infection in a mouse skin abrasion model[J]. Lasers in surgery and medicine 2010; 42:38-44.
13. Hamblin MR, Hasan T. Photodynamic therapy:a new antimicrobial approach to infectious disease? [J].Photochemical & Photobiological Sciences 2004; 3:436-50.
14. Park J-H, Ann M-Y, Kim Y-C et al. In vitro and in vivo antimicrobial effect of photodynamic therapy using a highly pure chlorin e6 against Staphylococcus aureus Xen29[J]. Biological & pharmaceutical bulletin 2011; 35:509-14.
15. O'Riordan K, Sharlin DS, Gross J et al. Photoinactivation of Mycobacteria in vitro and in a new murine model of localized Mycobacterium bovis BCG-induced granulomatous infection[J]. Antimicrobial agents and chemotherapy 2006; 50:1828-34.
16.杨帆,白祥军,易成腊,等.急诊负压封闭引流术治疗挤压综合征[J].中华创伤杂志,2009,25(2)：103-106.
17. Galeano M, Deodato B, Altavilla D et al. Effect of recombinant adeno-associated virus vector-mediated vascular endothelial growth factor gene transfer on wound healing after burn injury*[J]. Critical care medicine 2003; 31:1017-25.
18. Pierce GF, Tarpley JE, Allman RM et al. Tissue repair processes in healing chronic pressure ulcers treated with recombinant platelet-derived growth factor BB[J], The American journal of pathology 1994; 145:1399.
19. McGee GS, Davidson JM, Buckley A et al. Recombinant basic fibroblast growth factor accelerates wound healing[J]. Journal of Surgical Research 1988; 45:145-53.
20. Kobayashi E, Yamauchi H. Interleukin-6 and a delay of neutrophil apoptosis after major surgery[J]. Archives of Surgery 1997; 132:209.
21. Biffl WL, Moore EE, Moore FA et al. Interleukin-6 delays neutrophil apoptosis via a mechanism involving platelet-activating factor[J]. Journal of Trauma-Injury, Infection, and Critical Care 1996; 40:575-9.
1. Duckworth GJ. Diagnosis and management of methicillin resistant Staphylococcus aureus infection[J]. BMJ:British Medical Journal 1993; 307:1049.
2. MORADI N, JAVADPOUR S, KARMOSTAJI A. REDUCED SENSITIVITY OF STAPHYLOCOCCUS AUREUS TO VANCOMYCIN[J]. MEDICAL JOURNAL OF HORMOZGAN UNIVERSITY 2011.
3. Van Delden C, Iglewski BH. Cell-to-cell signaling and Pseudomonas aeruginosa infections[J]. Emerging infectious diseases 1998; 4:551-60.
4. Gordon SM, Serkey JM, Keys TF et al. Secular trends in nosocomial bloodstream infections in a 55-bed cardiothoracic intensive care unit [J]. The Annals of thoracic surgery 1998; 65:95-100.
5. 赵京禹,付小兵,雷永红,等.大鼠小面积全层皮肤缺损创面模型的制备[J].感染.炎症.修复,2008,9(1)：64-64..
6. Barrett JF. MRSA:status and prospects for therapy? An evaluation of key papers on the topic of MRSA and antibiotic resistance[J]. Expert opinion on therapeutic targets 2004; 8:515-9.
7. Berger-Bachi B, Strassle A, Gustafson JE et al. Mapping and characterization of multiple chromosomal factors involved in methicillin resistance in Staphylococcus aureus[J]. Antimicrobial agents and chemotherapy 1992; 36:1367-73.
8. 谭黎明.唐小异,赵敏,等.黄连,黄芩提取物对烫伤后感染铜绿假单胞菌的药效初步观察[J].湖南师范大学学报(医学版)ISTIC,2011,8(1)..
9. Haddadin A, Fappiano S, Lipsett P. Methicillin resistant Staphylococcus aureus (MRSA) in the intensive care unit[J]. Postgraduate medical journal 2002; 78:385-92.
10. Lambrechts SA, Demidova TN, Aalders MC et al. Photodynamic therapy for Staphylococcus aureus infected burn wounds in mice[J]. Photochemical & Photobiological Sciences 2005; 4:503-9.
11. Zolfaghari PS, Packer S, Singer M et al. In vivo killing of Staphylococcus aureus using a light-activated antimicrobial agent[J]. BMC microbiology 2009; 9:27.
12. Hamblin MR, Zahra T, Contag CH et al. Optical monitoring and treatment of potentially lethal wound infections in vivo[J]. The Journal of infectious diseases 2003; 187:1717-25.
13. Park J-H, Ahn M-Y, Kim Y-C et al. In vitro and in vivo antimicrobial effect of photodynamic therapy using a highly pure chlorin e6 against Staphylococcus aureus Xen29[J]. Biological & pharmaceutical bulletin 2011; 35:509-14.
14. Ragas X, Sanchez-Garcfa D, Ruiz-Gonzalez R et al. Cationic porphycenes as potential photosensitizers for antimicrobial photodynamic therapy [J]. Journal of medicinal chemistry 2010; 53: 7796-803.
15.葛绳德.烧伤和创伤后革兰阳性细菌感染[J].国外医学：创伤与外科基本问题分册,1993,14(1)：29-33.
16. Galeano M, Deodato B, Altavilla D et al. Effect of recombinant adeno-associated virus vector-mediated vascular endothelial growth factor gene transfer on wound healing after burn injury* [J]. Critical care medicine 2003; 31:1017-25.
17. Pierce GF, Tarpley JE, Allman RM et al. Tissue repair processes in healing chronic pressure ulcers treated with recombinant platelet-derived growth factor BB[J]. The American journal of pathology 1994; 145:1399.
18. McGee GS, Davidson JM, Buckley A et al. Recombinant basic fibroblast growth factor accelerates wound healing [J]. Journal of Surgical Research 1988; 45:145-53.
19. Kobayashi E, Yamauchi H. Interleukin-6 and a delay of neutrophil apoptosis after major surgery[J]. Archives of Surgery 1997; 132:209.
20. Biffl WL, Moore EE, Moore FA et al. Interleukin-6 delays neutrophil apoptosis via a mechanism involving platelet-activating factor [J]. Journal of Trauma-Injury, Infection, and Critical Care 1996; 40:575-9.
1. Bagchi B, Basu S. ROLE OF DYE MOLECULES REMAINING OUTSIDE THE CELL DURING PHOTODYNAMIC INACTIVATION OF ESCHERICHIA COLI IN THE PRESENCE OF ACRIFLAVINE[J]. Photochemistry and Photobiology 1979; 29:403-5.
2. Bhatti M, MacRobert A, Meghji S et al. A Study of the Uptake of Toluidine Blue O by Porphyromonas gingivalis and the Mechanism of Lethal Photosensitization[J]. Photochemistry and Photobiology 1998; 68:370-6.
3. Tavares A, Carvalho CM, Faustino MA et al. Antimicrobial photodynamic therapy:study of bacterial recovery viability and potential development of resistance after treatment[J]. Mar Drugs 2010; 8:91-105.
4. Hamblin MR, Zahra T, Contag CH et al. Optical monitoring and treatment of potentially lethal wound infections in vivo[J], The Journal of infectious diseases 2003; 187:1717-25.
5. Park J-H, Ahn M-Y, Kim Y-C et al. In vitro and in vivo antimicrobial effect of photodynamic therapy using a highly pure chlorin e6 against Staphylococcus aureus Xen29[J]. Biological & pharmaceutical bulletin 2011; 35:509-14.
6. Luan X, Qin Y, Bi L et al. Histological evaluation of the safety of toluidine blue-mediated photosensitization to periodontal tissues in mice[J]. Lasers in medical science 2009; 24:162-6.
7. Dai T, Tegos GP, Zhiyentayev T et al. Photodynamic therapy for methicillin-resistant Staphylococcus aureus infection in a mouse skin abrasion model[J]. Lasers in surgery and medicine 2010; 42:38-44.
8. Lambrechts SA, Demidova TN, Aalders MC et al. Photodynamic therapy for Staphylococcus aureus infected burn wounds in mice[J]. Photochemical & Photobiological Sciences 2005; 4:503-9.
9. Hamblin MR, O'Donnell DA, Murthy N et al. Rapid Control of Wound Infections by Targeted Photodynamic Therapy Monitored by In Vivo Bioluminescence Imaging[J]. Photochemistry and photobiology 2002; 75:51-7.
10. Soslow RA, Dannenberg AJ, Rush D et al. COX-2 is expressed in human pulmonary, colonic, and mammary tumors[J]. Cancer 2000; 89:2637-45.
11.葛绳德.烧伤和创伤后革兰阳性细菌感染[J]. 国外医不：创伤与外科基本问题分册1933;14：29-33.
12. Oda Y, Kagami H, Ueda M. Accelerating effects of basic fibroblast growth factor on wound healing of rat palatal mucosa[J]. Journal of oral and maxillofacial surgery 2004; 62:73-80.
13. Desire L, Courtois Y, Jeanny JC. Endogenous and Exogenous Fibroblast Growth Factor 2 Support Survival of Chick Retinal Neurons by Control of Neuronal Neuronal bcl-xL and bcl-2 Expression Through a Fibroblast Berowth Factor Receptor 1-and Erk-Dependent Pathway[J]. Journal of neurochemistry 2000; 75:151-63.
14. Takamiya M, Saigusa K, Nakayashiki N et al. Studies on mRNA expression of basic fibroblast growth factor in wound healing for wound age determination[J]. International journal of legal medicine 2003; 117:46-50.
15.洪振丰, 朱洪民, 郑海音et a1.康美肤烧伤膏对大鼠烫伤创面碱性成纤维细胞生长因子及其受体表达的影响[J].中华中医药学刊2007；25：2071-2.
16. Seegers HC, Hood VC, Kidd BL et al. Enhancement of angiogenesis by endogenous substance P release and neurokinin-1 receptors during neurogenic inflammation[J]. Journal of Pharmacology and Experimental Therapeutics 2003; 306:8-12.
17.朱立新,耿小平,范上达.多种血管新生指标在肝细胞肝癌中的表达及敏感性比较[J].消化外科2003;2：153-7.
18. Salo P, Bray R, Seerattan R et al. Neuropeptides regulate expression of matrix molecule, growth factor and inflammatory mediator mRNA in explants of normal and healing medial collateral ligament[J]. Regulatory peptides 2007; 142:1-6.
2. Plowman R, Graves N, Griffin M A S, et al. The rate and cost of hospital-acquired infections occurring in patients admitted to selected specialties of a district general hospital in England and the national burden imposed[J]. Journal of Hospital Infection,2001,47(3):198-209.
3. Chen J, Jin M, Qiu Z G, et al. A survey of drug resistance bla genes originating from synthetic plasmid vectors in six Chinese rivers[J]. Environmental science & technology,2012,46(24): 13448-13454.
4. Wainwright M, Phoenix D A, Gaskell M, et al. Photobactericidal activity of methylene blue derivatives against vancomycin-resistant Enterococcus spp[J]. Journal of Antimicrobial Chemotherapy,1999,44(6):823-825.
5. Tavares A, Carvalho C, Faustino M A, et al. Antimicrobial photodynamic therapy:study of bacterial recovery viability and potential development of resistance after treatment[J]. Marine drugs, 2010,8(1):91-105.
6. Dai T, Huang Y Y, Hamblin M R. Photodynamic therapy for localized infections-state of the art[J]. Photodiagnosis and photodynamic therapy,2009,6(3):170-188.
7. MOAN J, Peng Q. An outline of the hundred-year history of PDT[J]. Anticancer research,2003, 23(5A):3591-3600.
8. Ochsner M. Photophysical and photobiological processes in the photodynamic therapy of tumours[J]. Journal of Photochemistry and Photobiology B:Biology,1997,39(1):1-18.
9. Lavi A, Weitman H, Holmes R T, et al. The depth of porphyrin in a membrane and the membrane's physical properties affect the photosensitizing efficiency[J]. Biophysical journal,2002,82(4): 2101-2110.
10. Soukos N S, Wilson M, Burns T, et al. Photodynamic effects of toluidine blue on human oral keratinocytes and fibroblasts and Streptococcus sanguis evaluated in vitro[J]. Lasers in surgery and medicine,1996,18(3):253-259.
11. Salmon-Divon M, Nitzan Y, Malik Z. Mechanistic aspects of Escherichia coli photodynamic inactivation by cationic tetra-meso (N-methylpyridyl) porphine[J]. Photochemical & Photobiological Sciences,2004,3(5):423-429.
12. Shih M H, Huang F C. Repetitive methylene blue-mediated photoantimicrobial chemotherapy changes the susceptibility and expression of the outer membrane proteins of< i> Pseudomonas aeruginosa[J]. Photodiagnosis and photodynamic therapy,2013,10(4):664-671.
13. Rosseti I B, Chagas L R, Costa M S. Photodynamic antimicrobial chemotherapy (PACT) inhibits biofilm formation by Candida albicans, increasing both ROS production and membrane permeability[J]. Lasers in medical science,2013:1-6.
14. Hancock R E W. The bacterial outer membrane as a drug barrier[J]. Trends in microbiology,1997, 5(1):37-42.
15. Soukos N S, Ximenez-Fyvie L A, Hamblin M R, et al. Targeted antimicrobial photochemotherapy[J]. Antimicrobial agents and chemotherapy,1998,42(10):2595-2601.
16. Hamblin M R, O'Donnell D A, Murthy N, et al. Polycationic photosensitizer conjugates:effects of chain length and Gram classification on the photodynamic inactivation of bacteria[J]. Journal of Antimicrobial Chemotherapy,2002,49(6):941-951.
17. Nitzan Y, Ashkenazi H. Photoinactivation of Acinetobacter baumannii and Escherichia coli B by a cationic hydrophilic porphyrin at various light wavelengths[J]. Current microbiology,2001,42(6): 408-414.
18. Valduga G, Breda B, Giacometti G M, et al. Photosensitization of Wild and Mutant Strains of< i> Escherichia coli by< i> meso-Tetra (< i> N-methyl-4-pyridyl) porphine[J]. Biochemical and biophysical research communications,1999,256(1):84-88.
19. Je J Y, Kim S K. Antimicrobial action of novel chitin derivative[J]. Biochimica et Biophysica Acta(BBA)-General Subjects,2006,1760(1):104-109.
20. Jori G, Brown S B. Photosensitized inactivation of microorganisms[J]. Photochemical & Photobiological Sciences,2004,3(5):403-405.
21. Soncin M, Fabris C, Busetti A, et al. Approaches to selectivity in the Zn (Ⅱ)-phthalocyanine-photosensitized inactivation of wild-type and antibiotic-resistant Staphylococcus aureus[J]. Photochemical & Photobiological Sciences,2002,1(10):815-819.
22. Bertoloni G, Lauro F M, Cortella G, et al. Photosensitizing activity of hematoporphyrin on< i> Staphylococcus aureus cells[J]. Biochimica et Biophysica Acta (BBA)-General Subjects,2000, 1475(2):169-174.
23. Bertolini G, Rossi F, Valduga G, et al. Photosensitizing activity of water-and lipid-soluble phthalocyanines on< i> Escherichia coli[J]. FEMS microbiology letters,1990,71(1):149-155.
24. Asadi M, Safaei E, Ranjbar B, et al. Thermodynamic and spectroscopic study on the binding of cationic Zn (Ⅱ) and Co (Ⅱ) tetrapyridinoporphyrazines to calf thymus DNA:the role of the central metal in binding parameters[J]. New journal of chemistry,2004,28(10):1227-1234.
25. Ravanat J L, Berger M, Benard F, et al. Phthalocyanine and naphthalocyanine photosensitized oxidation of 2'-deoxyguanosine:distinct type Ⅰ and type Ⅱ products[J]. Photochemistry and photobiology,1984,39(6):809-814.
26. Sheu C, Foote C S. Endoperoxide formation in a guanosine derivative[J]. Journal of the American Chemical Society,1993,115(22):10446-10447.
27. Cadet J, Douki T, Gasparutto D, et al. Oxidative damage to DNA:formation, measurement and biochemical features[J]. Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis, 2003,531(1):5-23.
28. Cadet J, Ravanat J L, Martinez G R, et al. Singlet oxygen oxidation of isolated and cellular DNA: product formation and mechanistic insights[J]. Photochemistry and photobiology,2006,82(5): 1219-1225.
29. Spesia M B, Caminos D A, Pons P, et al. Mechanistic insight of the photodynamic inactivation of< i> Escherichia coli by a tetracationic zinc (Ⅱ) phthalocyanine derivative[J]. Photodiagnosis and photodynamic therapy,2009,6(1):52-61.
30. Hamblin M R, Hasan T. Photodynamic therapy:a new antimicrobial approach to infectious disease?[J]. Photochemical & Photobiological Sciences,2004,3(5):436-450.
31. Imray F P, MacPhee D G. The role of DNA polymerase I and the rec system in survival of bacteria and bacteriophages damaged by the photodynamic action of acridine orange[J]. Molecular and General Genetics MGG,1973,123(4):289-298.
32. John D C A, Rosamund J, Douglas K T. Tight binding of a copper (Ⅱ) phthalocyanine (Cuprolinic Blue) to DNA[J]. Biochemical and biophysical research communications,1989,159(3):1256-1262.
33. Maclean M, Macgregor S J, Anderson J G, et al. The role of oxygen in the visible-light inactivation of< i> Staphylococcus aureus[J]. Journal of Photochemistry and Photobiology B: Biology,2008,92(3):180-184.
34. Nitzan Y, Gutterman M, Malik Z, et al. INACTIVATION OF GRAM-NEGATIVE BACTERIA BY PHOTOSENSITIZED PORPHYRINS[J]. Photochemistry and photobiology,1992,55(1):89-96.
35. Wainwright M. 'Safe' photoantimicrobials for skin and soft-tissue infections[J]. International journal of antimicrobial agents,2010,36(1):14-18.
36. Wilson M, Yianni C. Killing of methicillin-resistant Staphylococcus aureus by low-power laser light[J]. Journal of medical microbiology,1995,42(1):62-66.
37. Usacheva M N, Teichert M C, Biel M A. Comparison of the methylene blue and toluidine blue photobactericidal efficacy against gram-positive and gram-negative microorganisms[J]. Lasers in surgery and medicine,2001,29(2):165-173.
38. Wainwright M, Phoenix D A, Laycock S L, et al. Photobactericidal activity of phenothiazinium dyes against methicillin-resistant strains of Staphylococcus aureus[J]. FEMS microbiology letters, 1998,160(2):177-181.
39. Phoenix D A, Sayed Z, Hussain S, et al. The phototoxicity of phenothiazinium derivatives against Escherichia coli and Staphylococcus aureus[J]. FEMS Immunology & Medical Microbiology,2003, 39(1):17-22.
40. Kubin A, Wierrani F, Jindra R H, et al. Antagonistic effects of combination photosensitization by hypericin, meso-tetrahydroxyphenylchlorin (mTHPC) and photofrin Ⅱ on Staphylococcus aureus[J]. Drugs under experimental and clinical research,1998,25(1):13-21.
41. Wierrani F. [Experimental investigations and clinical use of photodynamic therapy (PDT) in the Rudolf Foundation Hospital][J]. Gynakologisch-geburtshilfliche Rundschau,1998,39(4):217-225.
42. Segalla A, Borsarelli C D, Braslavsky S E, et al. Photophysical, photochemical and antibacterial photosensitizing properties of a novel octacationic Zn (Ⅱ)-phthalocyanine[J]. Photochemical & Photobiological Sciences,2002,1(9):641-648.
43. Szpakowska M, Lasocki K, Grzybowski J, et al. Photodynamic activity of the haematoporphyrin derivative with rutin and arginine substituents (HpD-Rut< sub> 2-Arg< sub> 2) against staphylococcus aureus and pseudomonas aeruginosa[J]. Pharmacological Research,2001,44(3): 243-246.
44. Nitzan Y, Salmon-Divon M, Shporen E, et al. ALA induced photodynamic effects on gram positive and negative bacteria[J]. Photochemical & Photobiological Sciences,2004,3(5):430-435.
45. Gross S, Brandis A, Chen L, et al. Protein-A-mediated Targeting of Bacteriochlorophyll-IgG to Staphylococcus aureus:A Model for Enhanced Site-Specific Photocytotoxicity[J]. Photochemistry and photobiology,1997,66(6):872-878.
46. Embleton M L, Nair S P, Cookson B D, et al. Selective lethal photosensitization of methicillin-resistant Staphylococcus aureus using an IgG-tin (IV) chlorin e6 conjugate[J]. Journal of Antimicrobial Chemotherapy,2002,50(6):857-864.
47 Embleton M L, Nair S P, Cookson B D, et al. Antibody-directed photodynamic therapy of methicillinresistant Staphylococcus aureus [J]. Microbial Drug Resistance,2004,10(2):92-97.
48. Gad F, Zahra T, Hasan T, et al. Effects of growth phase and extracellular slime on photodynamic inactivation of gram-positive pathogenic bacteria[J]. Antimicrobial agents and chemotherapy,2004, 48(6):2173-2178.
49. Van der Meulen F W, Ibrahim K, Sterenborg H, et al. Photodynamic destruction of< i> Haemophilus parainfluenzae by endogenously produced porphyrins[J]. Journal of Photochemistry and Photobiology B:Biology,1997,40(3):204-208.
50. Wilson M. Lethal photosensitisation of oral bacteria and its potential application in the photodynamic therapy of oral infections[J]. Photochemical & Photobiological Sciences,2004,3(5): 412-418.
51. Henry C A, Dyer B, Wagner M, et al. Phototoxicity of argon laser irradiation on biofilms of< i> Porphyromonas and< i> Prevotella species[J]. Journal of Photochemistry and Photobiology B: Biology,1996,34(2):123-128.
52. Henry C A, Judy M, Dyer B, et al. Sensitivity of Porphyromonas and Prevotella species in liquid media to argon laser[J]. Photochemistry and photobiology,1995,61(4):410-413.
53. Matevski D, Weersink R, Tenenbaum H C, et al. Lethal photosensitization of periodontal pathogens by a red-filtered Xenon lamp in vitro[J]. Journal of periodontal research,2003,38(4): 428-435.
54. Ashkenazi H, Nitzan Y, Gal D. Photodynamic Effects of Antioxidant Substituted Porphyrin Photosensitizers on Gram-positive and-negative Bacteria[J]. Photochemistry and photobiology, 2003,77(2):186-191.
55. Usacheva M N, Teichert M C, Biel M A. The interaction of lipopolysaccharides with phenothiazine dyes[J]. Lasers in surgery and medicine,2003,33(5):311-319.
56. Komerik N, Wilson M, Poole S. The Effect of Photodynamic Action on Two Virulence Factors of Gram-negative Bacteria[J]. Photochemistry and photobiology,2000,72(5):676-680.
57. Szpakowska M, Reiss J, Graczyk A, et al. Susceptibility of< i> Pseudomonas aeruginosa to a photodynamic effect of the arginine hematoporphyrin derivative[J]. International journal of antimicrobial agents,1997,8(1):23-27.
58. Sol V, Branland P, Chaleix V, et al. Amino porphyrins as photoinhibitors of Gram-positive and-negative bacteria[J]. Bioorganic & medicinal chemistry letters,2004,14(16):4207-4211.
59. Tegos G P, Demidova T N, Arcila-Lopez D, et al. Cationic fullerenes are effective and selective antimicrobial photosensitizers[J]. Chemistry & biology,2005,12(10):1127-1135.
60. Spesia M B, Milanesio M E, Durantini E N. Synthesis, properties and photodynamic inactivation of< i> Escherichia coli by novel cationic tullerene C< sub> 60 derivatives[J]. European journal of medicinal chemistry,2008,43(4):853-861.
61. Lee C F, Lee C J, Chen C T, et al.8-Aminolaevulinic acid mediated photodynamic antimicrobial chemotherapy on< i> Pseudomonas aeruginosa planktonic and biofilm cultures[J]. Journal of Photochemistry and Photobiology B:Biology,2004,75(1):21-25.
62. Hashimoto M C E, Prates R A, Kato I T, et al. Antimicrobial Photodynamic Therapy on Drug-resistant Pseudomonas aeruginosa-induced Infection. An In Vivo Study[J]. Photochemistry and photobiology,2012,88(3):590-595.
63. Donnelly R F, Cassidy C M, Loughlin R G, et al. Delivery of Methylene Blue and meso-tetra (N-methyl-4-pyridyl) porphine tetra tosylate from cross-linked poly (vinyl alcohol) hydrogels:a potential means of photodynamic therapy of infected wounds[J]. Journal of Photochemistry and Photobiology B:Biology,2009,96(3):223-231.
64. Demidova T N, Gad F, Zahra T, et al. Monitoring photodynamic therapy of localized infections by bioluminescence imaging of genetically engineered bacteria[J]. Journal of Photochemistry and Photobiology B:Biology,2005,81(1):15-25.
65. Hamblin M R, O'Donnell D A, Murthy N, et al. Rapid Control of Wound Infections by Targeted Photodynamic Therapy Monitored by In Vivo Bioluminescence Imaging[J]. Photochemistry and photobiology,2002,75(1):51-57.
66. Hamblin M R, Zahra T, Contag C H, et al. Optical monitoring and treatment of potentially lethal wound infections in vivo[J]. Journal of Infectious Diseases,2003,187(11):1717-1726.
67. Wong T W, Wang Y Y, Sheu H M, et al. Bactericidal effects of toluidine blue-mediated photodynamic action on Vibrio vulnificus[J]. Antimicrobial agents and chemotherapy,2005,49(3): 895-902.
68. Zolfaghari P S, Packer S, Singer M, et al. In vivo killing of Staphylococcus aureus using a light-activated antimicrobial agent[J]. BMC microbiology,2009,9(1):27.
69. Dai T, Tegos G P, Zhiyentayev T, et al. Photodynamic therapy for methicillin-resistant Staphylococcus aureus infection in a mouse skin abrasion model[J]. Lasers in surgery and medicine, 2010,42(1):38-44.
70. Simonetti O, Cirioni O, Orlando F, et al. Effectiveness of antimicrobial photodynamic therapy with a single treatment of RLP068/C1 in an experimental model of Staphylococcus aureus wound infection[J]. British Journal of Dermatology,2011,164(5):987-995.
71. Orenstein A, Klein D, Kopolovic J, et al. The use of porphyrins for eradication of Staphylococcus aureus in bum wound infections[J]. FEMS Immunology & Medical Microbiology,1997,19(4): 307-314.
72. Lambrechts S A G, Demidova T N, Aalders M C G, et al. Photodynamic therapy for Staphylococcus aureus infected burn wounds in mice[J]. Photochemical & Photobiological Sciences, 2005,4(7):503-509.
73. Dai T, Tegos G P, Lu Z, et al. Photodynamic therapy for Acinetobacter baumannii burn infections in mice[J]. Antimicrobial agents and chemotherapy,2009,53(9):3929-3934.
74. Bisland S K, Chien C, Wilson B C, et al. Pre-clinical in vitro and in vivo studies to examine the potential use of photodynamic therapy in the treatment of osteomyelitis[J]. Photochemical & Photobiological Sciences,2006,5(1):31-38.
75. Berthiaume F, Reiken S R, Toner M, et al. Antibody-targeted photolysis of bacteria in vivo[J]. Nature Biotechnology,1994,12(7):703-706.
76. Gad F, Zahra T, Francis K P, et al. Targeted photodynamic therapy of established soft-tissue infections in mice[J]. Photochemical & Photobiological Sciences,2004,3(5):451-458.
77. Tardivo J P, Baptista M S. Treatment of osteomyelitis in the feet of diabetic patients by photodynamic antimicrobial chemotherapy[J]. Photomedicine and laser surgery,2009,27(1): 145-150.
78. Teichert M C, Jones J W, Usacheva M N, et al. Treatment of oral candidiasis with methylene blue-mediated photodynamic therapy in an immunodeficient murine model[J]. Oral Surgery, Oral Medicine, Oral Pathology, Oral Radiology, and Endodontology,2002,93(2):155-160.
79. de Souza S C, Junqueira J C, Balducci I, et al. Photosensitization of different< i> Candida species by low power laser light[J]. Journal of Photochemistry and Photobiology B:Biology,2006, 83(1):34-38.
80. Donnelly R F, McCarron P A, Tunney M M, et al. Potential of photodynamic therapy in treatment of fungal infections of the mouth. Design and characterisation of a mucoadhesive patch containing toluidine blue O[J]. Journal of Photochemistry and Photobiology B:Biology,2007,86(1):59-69.
81. Rodrigues G B, Dias-Baruffi M, Holman N, et al.< i> In vitro photodynamic inactivation of< i> Candida species and mouse fibroblasts with phenothiazinium photosensitisers and red light[J]. Photodiagnosis and photodynamic therapy,2013,10(2):141-149.
82. Maisch T, Szeimies R M, Jori G, et al. Antibacterial photodynamic therapy in dermatology[J]. Photochemical & Photobiological Sciences,2004,3(10):907-917.
83. Bliss J M, Bigelow C E, Foster T H, et al. Susceptibility of Candida species to photodynamic effects of photofrin[J]. Antimicrobial agents and chemotherapy,2004,48(6):2000-2006.
84. Zofadek T, Nhi N B, Jagietto I, et al. Diamino acid derivatives of porphyrins penetrate into yeast cells, induce photodamage, but have no mutagenic effect[J]. Photochemistry and photobiology,1997, 66(2):253-259.
85. Donnelly R F, McCarron P A, Tunney M M, et al. Potential of photodynamic therapy in treatment of fungal infections of the mouth. Design and characterisation of a mucoadhesive patch containing toluidine blue O[J]. Journal of Photochemistry and Photobiology B:Biology,2007,86(1):59-69.
86. Lambrechts SAG, Schwartz K R, Aalders M C G, et al. Photodynamic inactivation of fibroblasts by a cationic porphyrin[J]. Lasers in medical science,2005,20(2):62-67.
87. Chabrier-Rosello Y, Foster T H, Perez-Nazario N, et al. Sensitivity of Candida albicans germ tubes and biofilms to photofrin-mediated phototoxicity[J]. Antimicrobial agents and chemotherapy,2005, 49(10):4288-4295.
88. Moretti M B, Garcia S C, Batlle A. Porphyrin Biosynthesis Intermediates Are Not Regulating δ-Aminolevulinic Acid Transport in< i> Saccharomyces cerevisiae[J]. Biochemical and biophysical research communications,2000,272(3):946-950.
89. Donnelly R F, McCarron P A, Lightowler J M, et al. Bioadhesive patch-based delivery of 5-aminolevulinic acid to the nail for photodynamic therapy of onychomycosis[J]. Journal of controlled release,2005,103(2):381-392.
90. Piraccini B M, Rech G, Tosti A. Photodynamic therapy of onychomycosis caused by< i> Trichophyton rubrum[J]. Journal of the American Academy of Dermatology,2008,59(5): S75-S76.
91. Bertoloni G, Rossi F, Valduga G, et al. Photosensitizing activity of water-and lipid-soluble phthalocyanines on prokaryotic and eukaryotic microbial cells[J]. Microbios,1991,71(286):33-46.
92. Mantareva V, Kussovski V, Angelov I, et al. Photodynamic activity of water-soluble phthalocyanine zinc (Ⅱ) complexes against pathogenic microorganisms[J]. Bioorganic & medicinal chemistry,2007,15(14):4829-4835.
93. Segalla A, Borsarelli C D, Braslavsky S E, et al. Photophysical, photochemical and antibacterial photosensitizing properties of a novel octacationic Zn (Ⅱ)-phthalocyanine[J]. Photochemical & Photobiological Sciences,2002,1(9):641-648.
94. Lyon J P, Moreira L M, de Moraes P C G, et al. Photodynamic therapy for pathogenic fungi[J]. Mycoses,2011,54(5):e265-e271.
95. Mohr H, Bachmann B, Klein-Struckmeier A, et al. Virus inactivation of blood products by phenothiazine dyes and light[J]. Photochemistry and photobiology,1997,65(3):441-445.
96. Mohr H, Knilver-Hopf J, Gravemann U, et al. West Nile virus in plasma is highly sensitive to methylene blue-light treatment[J]. Transfusion,2004,44(6):886-890.
97. Ben-Hur E, Geacintov N E, Studamire B, et al. The effect of irradiance on virus sterilization and photodynamic damage in red blood cells sensitized by phthalocyanines[J]. Photochemistry and photobiology,1995,61(2):190-195.
98. Ben-Hur E, Barshtein G, Chen S, et al. Photodynamic treatment of red blood cell concentrates for virus inactivation enhances red blood cell aggregation:protection with antioxidants[J]. Photochemistry and photobiology,1997,66(4):509-512.
99. Lambrechts S A G, Aalders M C G, Verbraak F D, et al. Effect of albumin on the photodynamic inactivation of microorganisms by a cationic porphyrin[J. Journal of Photochemistry and Photobiology B:Biology,2005,79(1):51-57.
100. Zanin I C J, Lobo M M, Rodrigues L K A, et al. Photosensitization of in vitro biofilms by toluidine blue O combined with a light-emitting diode[J]. European journal of oral sciences,2006, 114(1):64-69.
101. Bonsor S J, Nichol R, Reid T M S, et al. Microbiological evaluation of photo-activated disinfection in endodontics (an in vivo study)[J]. British dental journal,2006,200(6):337-341.
102. Silva Garcez A, Nunez S C, Lage-Marques J L, et al. Efficiency of NaOCl and laser-assisted photosensitization on the reduction of< i> Enterococcus faecalis in vitro[J]. Oral Surgery, Oral Medicine, Oral Pathology, Oral Radiology, and Endodontology,2006,102(4):e93-e98.
103. Konopka K, Goslinski T. Photodynamic therapy in dentistry [J]. Journal of Dental Research,2007, 86(8):694-707.
104. Millson C E, Wilson M, MacRobert A J, et al. Ex-vivo treatment of gastric< i> Helicobacter infection by photodynamic therapy[J]. Journal of Photochemistry and Photobiology B:Biology,1996, 32(1):59-65.
105. Lembo A J, Ganz R A, Sheth S, et al. Treatment of Helicobacter pylori infection with intra-gastric violet light phototherapy:A pilot clinical trial[J]. Lasers in surgery and medicine,2009,41(5): 337-344.
106. O' Riordan K, Akilov O E, Chang S K, et al. Real-time fluorescence monitoring of phenothiazinium photosensitizers and their anti-mycobacterial photodynamic activity against Mycobacterium bovis BCG in in vitro and in vivo models of localized infection[J]. Photochemical & Photobiological Sciences,2007,6(10):1117-1123.
107. O'Riordan K, Sharlin D S, Gross J, et al. Photoinactivation of Mycobacteria in vitro and in a new murine model of localized Mycobacterium bovis BCG-induced granulomatous infection[J]. Antimicrobial agents and chemotherapy,2006,50(5):1828-1834.
108. Imlay J A. The molecular mechanisms and physiological consequences of oxidative stress: lessons from a model bacterium[J]. Nature Reviews Microbiology,2013,11(7):443-454.
1. Hamblin, M. R.; Hasan, T., Photodynamic therapy:a new antimicrobial approach to infectious disease? [J]. Photochemical& Photobiological Sciences 2004,3(5),436-450.
2. Gould, I. M., Community-acquired MRSA:can we control it? [J]. Lancet 2006,368 (9538), 824-6.
3. Wainwright, M, Photodynamic antimicrobial chemotherapy (PACT) [J]. Journal of Antimicrobial Chemotherapy 1998,42 (1),13-28.
4. Donnelly, R. F.; McCarron, P. A.; Tunney, M. M., Antifungal photodynamic therapy[J]. Microbiological Research 2008,163 (1),1-12.
5. Bagchi, B.; Basu, S., ROLE OF DYE MOLECULES REMAINING OUTSIDE THE CELL DURING PHOTODYNAMIC INACTIVATION OF ESCHERICHIA COLI IN THE PRESENCE OF ACRIFLAVINE[J]. Photochemistry and Photobiology 1979,29 (2),403-405.
6. Bhatti, M.; MacRobert, A.; Meghji, S.; Henderson, B.; Wilson, M., A Study of the Uptake of Toluidine Blue O by Porphyromonas gingivalis and the Mechanism of Lethal Photosensitization[JJ. Photochemistry and Photobiology 1998,68 (3),370-376.
7. Tavares, A.; Carvalho, C. M.; Faustino, M. A.; Neves, M. G.; Tome, J. P.; Tome, A. C.; Cavaleiro, J. A.; Cunha, A.; Gomes, N. C.; Alves, E.; Almeida, A., Antimicrobial photodynamic therapy:study of bacterial recovery viability and potential development of resistance after treatment[J]. Mar Drugs 2010,8(1),91-105.
8. Wainwright, M.,'Safe'photoantimicrobials for skin and soft-tissue infections[J]. International Journal of Antimicrobial Agents 2010,36 (1),14-18.
9. Tegos, G. P.; Demidova, T. N.; Arcila-Lopez, D.; Lee, H.; Wharton, T.; Gali, H.; Hamblin, M. R., Cationic Fullerenes Are Effective and Selective Antimicrobial Photosensitizers[J]. Chemistry & Biology 2005,12 (10),1127-1135.
10. Mohr, H.; Bachmann, B.; Klein-Struckmeier, A.; Lambrecht, B., Virus Inactivation of Blood Products by Phenothiazine Dyes and Light[J]. Photochemistry and Photobiology 1997,65 (3), 441-445.
11. Mohr, H.; Kniiver-Hopf, J.; Gravemann, U.; Redecker-Klein, A.; Muller, T. H., West Nile virus in plasma is highly sensitive to methylene blue-light treatment[J]. Transfusion 2004,44 (6),886-890.
12. Lambrechts, S. A. G.; Aalders, M. C. G.; Verbraak, F. D.; Lagerberg, J. W. M.; Dankert, J. B.; Schuitmaker, J. J., Effect of albumin on the photodynamic inactivation of microorganisms by a cationic porphyrin[J]. Journal of Photochemistry and Photobiology B:Biology 2005,79 (1),51-57.
13. Wainwright, M.; Phoenix, D. A.; Laycock, S. L.; Wareing, D. R. A.; Wright, P. A., Photobactericidal activity of phenothiazinium dyes against methicillin-resistant strains of Staphylococcus aureus[J]. FEMS Microbiology Letters 1998,160 (2),177-181.
14. Wilson, M.; Yianni, C., Killing of methicillin-resistant Staphylococcus aureus by low-power laser light[J]. Journal of Medical Microbiology 1995,42 (1),62-66.
15. Ashkenazi, H.; Nitzan, Y.; Gal, D., Photodynamic Effects of Antioxidant Substituted Porphyrin Photosensitizers on Gram-positive and -negative Bacteriai[J]. Photochemistry and Photobiology 2003, 77(2),186-191.
16. Spesia, M. B.; Caminos, D. A.; Pons, P.; Durantini, E. N., Mechanistic insight of the photodynamic inactivation of Escherichia coli by a tetracationic zinc(Ⅱ) phthalocyanine derivative [J]. Photodiagnosis and photodynamic therapy 2009, 6(1),52-61.
17. Foley, J. W.; Song, X.; Demidova, T. N.; Jilal, F.; Hamblin, M. R., Synthesis and Properties of Benzo[a]phenoxazinium Chalcogen Analogues as Novel Broad-Spectrum Antimicrobial Photosensitizers[J]. Journal of medicinal chemistry 2006,49 (17),5291-5299.
18. Grinholc, M.; Szramka, B.; Kurlenda, J.; Graczyk, A.; Bielawski, K. P., Bactericidal effect of photodynamic inactivation against methicillin-resistant and methicillin-susceptible Staphylococcus aureus is strain-dependent[J]. Journal of Photochemistry and Photobiology B:Biology 2008,90 (1), 57-63.
19. Lilburn, T. G; Gu, J.; Cai, H.; Wang, Y, Comparative genomics of the family Vibrionaceae reveals the wide distribution of genes encoding virulence-associated proteins[J]. BMC genomics 2010, 11,369.
20. Sun, A.; Zhang, G.; Xu, Y, Photobleaching of metal phthalocyanine sulfonates under UV and visible light irradiation over TiO2 semiconductor[J]. Materials Letters 2005,59 (29-30),4016-4019.
21. Karmakova, T.; Feofanov, A.; Nazarova, A.; Grichine, A.; Yakubovskaya, R.; Luk'yanets,E.; Maurizot, J.-C.; Vigny, P., Distribution of metal-free sulfonated phthalocyanine in subcutaneously transplanted murine tumors[J]. Journal of Photochemistry and Photobiology B:Biology 2004,75 (1-2),81-87.
22. Ceyhan, T.; Altndal, A.; Ozkaya, A. R.; Salih, B.; Bekaroglu, O., Novel ball-type four dithioerythritol bridged metallophthalocyanines and their water-soluble derivatives:Synthesis and characterization, and electrochemical, electrocatalytic, electrical and gas sensing properties[J]. Dalton Transactions 2010,39 (41),9801-9814.
23. Drechsler, U.; Pfaff, M.; Hanack, M., Synthesis of Novel Functionalised Zinc Phthalocyanines Applicable in Photodynamic Therapy[J]. European Journal of Organic Chemistry 1999,1999 (12), 3441-3453.
24. Eisenberg, C.; Seta, N.; Appel, M.; Feldmann, G.; Durand, G.; Feger, J., Asialoglycoprotein receptor in human isolated hepatocytes from normal liver and its apparent increase in liver with histological alterations[J]. Journal ofHepatology 1991,13 (3),305-309.
25.曹波.新型水溶性光敏剂的评价和机制研究[D].北京：北京协和医学院,2012：20-50.
26. Gois, M. M.; Kurachi, C.; Santana, E. J.; Mima, E. G.; Spolidorio, D. M.; Pelino, J. E.; Salvador Bagnato, V., Susceptibility of Staphylococcus aureus to porphyrin-mediated photodynamic antimicrobial chemotherapy:an in vitro study[J]. Lasers in medical science 2010,25 (3),391-5.
27. Wilson, M.; Pratten, J., Lethal photosensitisation of Staphylococcus aureus[J]. Microbios 1994, 78(316),163-168.
28. Ochsner, M., Photophysical and photobiological processes in the photodynamic therapy of tumours[J]. Journal of Photochemistry and Photobiology B:Biology 1997,39 (1),1-18.
1. Chen J, Jin M, Qiu ZG et al. A survey of drug resistance bla genes originating from synthetic plasmid vectors in six Chinese rivers[J]. Environmental science & technology 2012; 46:13448-54.
2. Jori G Photodynamic Therapy of Microbial Infections:State of the Art and Perspectives[J].2006; 25:505-20.
3. Wainwright M, Phoenix DA, Gaskell M et al. Photobactericidal activity of methylene blue derivatives against vancomycin-resistant Enterococcus spp[J]. Journal of Antimicrobial Chemotherapy 1999; 44:823-5.
4. Wainwright M, Phoenix DA, Marland J et al. A study of photobactericidal activity in the phenothiazinium series[J]. FEMS immunology and medical microbiology 1997; 19:75-80.
5. Tavares A, Carvalho C, Faustino MA et al. Antimicrobial photodynamic therapy:study of bacterial recovery viability and potential development of resistance after treatment[J]. Marine drugs 2010; 8:91-105.
6. Alvarez-Mico X, Calvete MJF, Hanack M et al. A new glycosidation method through nitrite displacement on substituted nitrobenzenes[J]. Carbohydrate Research 2007; 342:440-7.
7. Lau JTF, Lo P-C, Fong W-P et al. Preparation and Photodynamic Activities of Silicon(IV) Phthalocyanines Substituted with Permethylated β-Cyclodextrins[J]. Chemistry-A European Journal 2011; 17:7569-77.
8. Fu X, Sheng Z, Cherry GW et al. Epidemiological study of chronic dermal ulcers in China[J]. Wound Repair and Regeneration 1998; 6:21-7.
9. Ornitz DM, Itoh N. Fibroblast growth factors[J]. Genome Biol 2001; 2:3005.1-12.
10. Buntrock P, Jentzsch KD, Heder G Stimulation of wound healing, using brain extract with fibroblast growth factor (FGF) activity:I. quantitative and biochemical studies into formation of granulation tissue[J]. Experimental pathology 1982; 21:46-53.
11. Brown GL, Nanney LB, Griffen J et al. Enhancement of wound healing by topical treatment with epidermal growth factor[J]. New England Journal of Medicine 1989; 321:76-9.
12. Laato M, Niinikoski J, Lundberg C et al. Effect of epidermal growth factor (EGF) on experimental granulation tissue [J].Journal of Surgical Research 1986; 41:252-5.
13. Chan KY, Jones RR, Bark DH et al. Release of neuronotrophic factor from rabbit corneal epithelium during wound healing and nerve regeneration[J]. Experimental Eye Research 1987; 45: 633-46.
14. Klein M, Picard E, Vignaud J et al. Vascular endothelial growth factor gene and protein:strong expression in thyroiditis and thyroid carcinoma[J]. Journal of Endocrinology 1999; 161:41-9.
15. Meyer M, Clauss M, Lepple-Wienhues A et al. A novel vascular endothelial growth factor encoded by Orf virus, VEGF-E, mediates angiogenesis via signalling through VEGFR-2 (KDR) but not VEGFR-1 (Flt-1) receptor tyrosine kinases[J]. The EMBO journal 1999; 18:363-74.
16. Li QF, Reis ED, Zhang WX et al. Accelerated flap prefabrication with vascular endothelial growth factor[J]. Journal of reconstructive microsurgery 2000; 16:0045-50.
17. Derynck R, Goeddel DV, Ullrich A et al. Synthesis of messenger RNAs for transforming growth factors α and β and the epidermal growth factor receptor by human tumors[J]. Cancer Research 1987; 47:707-12.
18. Chen S-J, Yuan W, Mori Y et al. Stimulation of type I collagen transcription in human skin flbroblasts by TGF-β:involvement of Smad 3[J]. Journal of investigative dermatology 1999; 112: 49-57.
19. Jori G Tumour photosensitizers:approaches to enhance the selectivity and efficiency of photodynamic therapy[J]. Journal of Photochemistry and photobiology B:Biology 1996; 36:87-93.
20. Bierbaum G, Fuchs K, Lenz W et al. Presence of Staphylococcus aureus with reduced susceptibility to vancomycin in Germany[J]. European Journal of Clinical Microbiology and Infectious Diseases 1999; 18:691-6.
21. Hassan IA, Chadwick PR, Johnson AP. Clinical isolates of methicillin-resistant Staphylococcus aureus (MRSA) with reduced susceptibility to teicoplanin in Northwest England[J]. Journal of Antimicrobial Chemotherapy 2001; 48:454-5.
22. Hiramatsu K. The emergence of< i> Staphylococcus aureus with reduced susceptibility to vancomycin in Japan[J]. The American journal of medicine 1998; 104:7S-10S.
23. Zeina B, Greenman J, Purcell W et al. Killing of cutaneous microbial species by photodynamic therapy[J]. British Journal of Dermatology 2001; 144:274-8.
24. Hamblin MR, Zahra T, Contag CH et al. Optical monitoring and treatment of potentially lethal wound infections in vivo[J]. Journal of Infectious Diseases 2003; 187:1717-26.
25. Ishikawa Y, YAMASHITA A, Uno T. Efficient Photocleavage of DNA by Cationic Porphyrin-Acridine Hybrids with the Effective Length of Diamino Alkyl Linkage[J]. Chemical and pharmaceutical bulletin 2001; 49:287-93.
26. Zhao Z, Li Y, Meng S et al. Susceptibility of methicillin-resistant Staphylococcus aureus to photodynamic antimicrobial chemotherapy with a-d-galactopyranosyl zinc phthalocyanines:in vitro study [J]. Lasers in medical science 2013:1-8.
27. Vecchio D, Dai T, Huang L et al. Antimicrobial photodynamic therapy with RLP068 kills methicillin-resistant Staphylococcus aureus and improves wound healing in a mouse model of infected skin abrasion PDT with RLP068/C1 in infected mouse skin abrasion[J]. Journal of Biophotonics 2013; 6:733-42.
28. Simonetti O, Cirioni O, Orlando F et al. Effectiveness of antimicrobial photodynamic therapy with a single treatment of RLP068/C1 in an experimental model of Staphylococcus aureus wound infection[J]. British Journal ofDermatology 2011; 164:987-95.
29. Banfi S, Caruso E, Buccafurni L et al. Antibacterial activity of tetraaryl-porphyrin photosensitizers:an in vitro study on Gram negative and Gram positive bacteria[J]. Journal of photochemistry and photobiology B:Biology 2006; 85:28-38.
30. Salmon-Divon M, Nitzan Y, Malik Z. Mechanistic aspects of Escherichia coli photodynamic inactivation by cationic tetra-meso (N-methylpyridyl) porphine[J]. Photochemical & Photobiological Sciences 2004; 3:423-9.
1. Bagchi B, Basu S. ROLE OF DYE MOLECULES REMAINING OUTSIDE THE CELL DURING PHOTODYNAMIC INACTIVATION OF ESCHERICHIA COLI IN THE PRESENCE OF ACRIFLAVINE[J]. Photochemistry and Photobiology 1979; 29:403-5.
2. Bhatti M, MacRobert A, Meghji S et al. A Study of the Uptake of Toluidine Blue O by Porphyromonas gingivalis and the Mechanism of Lethal Photosensitization[J]. Photochemistry and Photobiology 1998; 68:370-6.
3. Tavares A, Carvalho CM, Faustino MA et al. Antimicrobial photodynamic therapy:study of bacterial recovery viability and potential development of resistance after treatment[J]. Mar Drugs 2010; 8:91-105.
4. Calzavara-Pinton PG, Venturini M, Sala R. A comprehensive overview of photodynamic therapy in the treatment of superficial fungal infections of the skin[J]. Journal of photochemistry and photobiology B, Biology 2005; 78:1-6.
5. Lambrechts SA, Aalders MC, Verbraak FD et al. Effect of albumin on the photodynamic inactivation of microorganisms by a cationic porphyrin[J]. Journal of photochemistry and photobiology B, Biology 2005; 79:51-7.
6. Sol V, Branland P, Chaleix V et al. Amino porphyrins as photoinhibitors of Gram-positive and-negative bacteria[J]. Bioorg Med Chem Lett 2004; 14:4207-11.
7. Jori G. Tumour photosensitizers:approaches to enhance the selectivity and efficiency of photodynamic therapy[J]. Journal of Photochemistry and Photobiology B:Biology 1996; 36:87-93.
8. Rodrigues GB, Dias-Baruffi M, Holman N et al. In vitro photodynamic inactivation of Candida species and mouse fibroblasts with phenothiazinium photosensitisers and red light[J]. Photodiagnosis Photodyn Ther 2013; 10:141-9.
9. Chakraborry SP, Sahu SK, Pramanik P et al. In vitro antimicrobial activity of nanoconjugated vancomycin against drug resistant Staphylococcus aureus[J]. International journal of pharmaceutics 2012; 436:659-76.
10. Lv F, Li Y, Cao B et al. Galactose substituted zinc phthalocyanines as near infrared fluorescence probes for liver cancer imaging[J]. Journal of materials science Materials in medicine 2013; 24: 811-9.
11. Alvarez-Mico X, Calvete MJF, Hanack M et al. A new glycosidation method through nitrite displacement on substituted nitrobenzenes[J]. Carbohydrate Research 2007; 342:440-7.
12. Lau JTF, Lo P-C, Fong W-P et al. Preparation and Photodynamic Activities of Silicon(IV) Phthalocyanines Substituted with Permethylated β-Cyclodextrins[J]. Chemistry-A European Journal 2011; 17:7569-77.
13. Lilburn TG, Gu J, Cai H et al. Comparative genomics of the family Vibrionaceae reveals the wide distribution of genes encoding virulence-associated proteins[J]. BMC genomics 2010; 11:369.
14. Wainwright M. Photodynamic antimicrobial chemotherapy (PACT) [J]. Journal of Antimicrobial Chemotherapy 1998; 42:13-28.
15. Zeina B, Greenman J, Purcell W et al. Killing of cutaneous microbial species by photodynamic therapy[J]. British Journal of Dermatology 2001; 144:274-8.
16. Wilson M, Pratten J. Lethal photosensitisation of Staphylococcus aureus. Microbios 1994; 78: 163-8.
17. Wilson M, Yianni C. Killing of methicillin-resistant Staphylococcus aureus by low-power laser light[J]. Journal of Medical Microbiology 1995; 42:62-6.
18. Yang Y-T, Chien H-F, Chang P-H et al. Photodynamic inactivation of chlorin e6-loaded CTAB-liposomes againstCandida albicans[J]. Lasers in surgery and medicine 2013; 45:175-85.
19. Zhao Z, Li Y, Meng S et al. Susceptibility of methicillin-resistant Staphylococcus aureus to photodynamic antimicrobial chemotherapy with α-d-galactopyranosyl zinc phthalocyanines:in vitro study[J]. Lasers in medical science 2013:1-8.
20. Hamblin MR, Hasan T. Photodynamic therapy:a new antimicrobial approach to infectious disease? [J] Photochemical & Photobiological Sciences 2004; 3:436-50.
21.于克贵.新型卟啉化合物的设计合成及生物活性研究[D].西南大学,2008.
22. Soncin M, Fabris C, Busetti A et al. Approaches to selectivity in the Zn(ii)-phthalocyanine-photosensitized inactivation of wild-type and antibiotic-resistant Staphylococcus aureus[J]. Photochemical & Photobiological Sciences 2002; 1:815-9.
23. Jori G, Brown SB. Photosensitized inactivation of microorganisms [J]. Photochemical & Photobiological Sciences 2004; 3:403-5.
24. Salmon-Divon M, Nitzan Y, Malik Z. Mechanistic aspects of Escherichia coli photodynamic inactivation by cationic tetra-meso(N-methylpyridyl)porphine[J]. Photochemical & Photobiological Sciences 2004; 3:423-9.
1.葛绳德.烧伤和创伤后革兰阳性细菌感染[J1.国外医学：创伤与外科基本问题分册,1993,14(1)：29-33.
2. Duckworth GJ. Diagnosis and management of methicillin resistant Staphylococcus aureus infection[J]. BMJ:British Medical Journal 1993; 307:1049.
3. MORADI N, JAVADPOUR S, KARMOSTAJI A. REDUCED SENSITIVITY OF STAPHYLOCOCCUS AUREUS TO VANCOMYCIN[J]. MEDICAL JOURNAL OF HORMOZGAN UNIVERSITY 2011.
4. Tavares A, Carvalho CM, Faustino MA et al. Antimicrobial photodynamic therapy:study of bacterial recovery viability and potential development of resistance after treatment[J]. Mar Drugs 2010; 8:91-105.
5. Polo L, Segalla A, Bertoloni G et al. Polylysine-porphycene conjugates as efficient photosensitizers for the inactivation of microbial pathogens[J]. Journal of Photochemistry and Photobiology B:Biology 2000; 59:152-8.
6. Soukos NS, Wilson M, Burns T et al. Photodynamic effects of toluidine blue on human oral keratinocytes and fibroblasts and Streptococcus sanguis evaluated in vitro[J]. Lasers in surgery and medicine 1996; 18:253-9.
7. Dai T, Huang Y-Y, Hamblin MR. Photodynamic therapy for localized infections-state of the art[J]. Photodiagnosis and photodynamic therapy 2009; 6:170-88.
8. 赵京禹,付小兵,雷永红,等.大鼠小面积全层皮肤缺损创面模型的制备[J].感染.炎症.修复,2008,9(1)：64-64.
9. 龙琦,尹晓娟,封志纯.神经生长因子和碱性成纤维细胞生长因子对缺氧缺血脑损伤新生大鼠内源性神经干细胞的影响[J].实用医学杂志,2009,25(1)：36-39.
10. Masuoka K, Ishihara M, Asazuma T et al. The interaction of chitosan with fibroblast growth factor-2 and its protection from inactivation[J]. Biomaterials 2005; 26:3277-84.
11. Huang L, Dai T, Hamblin M. Antimicrobial Photodynamic Inactivation and Photodynamic Therapy for Infections. In:Gomer CJ, ed[J]. Photodynamic Therapy:Humana Press,2010; 155-73.
12. Dai T, Tegos GP, Zhiyentayev T et al. Photodynamic therapy for methicillin-resistant Staphylococcus aureus infection in a mouse skin abrasion model[J]. Lasers in surgery and medicine 2010; 42:38-44.
13. Hamblin MR, Hasan T. Photodynamic therapy:a new antimicrobial approach to infectious disease? [J].Photochemical & Photobiological Sciences 2004; 3:436-50.
14. Park J-H, Ann M-Y, Kim Y-C et al. In vitro and in vivo antimicrobial effect of photodynamic therapy using a highly pure chlorin e6 against Staphylococcus aureus Xen29[J]. Biological & pharmaceutical bulletin 2011; 35:509-14.
15. O'Riordan K, Sharlin DS, Gross J et al. Photoinactivation of Mycobacteria in vitro and in a new murine model of localized Mycobacterium bovis BCG-induced granulomatous infection[J]. Antimicrobial agents and chemotherapy 2006; 50:1828-34.
16.杨帆,白祥军,易成腊,等.急诊负压封闭引流术治疗挤压综合征[J].中华创伤杂志,2009,25(2)：103-106.
17. Galeano M, Deodato B, Altavilla D et al. Effect of recombinant adeno-associated virus vector-mediated vascular endothelial growth factor gene transfer on wound healing after burn injury*[J]. Critical care medicine 2003; 31:1017-25.
18. Pierce GF, Tarpley JE, Allman RM et al. Tissue repair processes in healing chronic pressure ulcers treated with recombinant platelet-derived growth factor BB[J], The American journal of pathology 1994; 145:1399.
19. McGee GS, Davidson JM, Buckley A et al. Recombinant basic fibroblast growth factor accelerates wound healing[J]. Journal of Surgical Research 1988; 45:145-53.
20. Kobayashi E, Yamauchi H. Interleukin-6 and a delay of neutrophil apoptosis after major surgery[J]. Archives of Surgery 1997; 132:209.
21. Biffl WL, Moore EE, Moore FA et al. Interleukin-6 delays neutrophil apoptosis via a mechanism involving platelet-activating factor[J]. Journal of Trauma-Injury, Infection, and Critical Care 1996; 40:575-9.
1. Duckworth GJ. Diagnosis and management of methicillin resistant Staphylococcus aureus infection[J]. BMJ:British Medical Journal 1993; 307:1049.
2. MORADI N, JAVADPOUR S, KARMOSTAJI A. REDUCED SENSITIVITY OF STAPHYLOCOCCUS AUREUS TO VANCOMYCIN[J]. MEDICAL JOURNAL OF HORMOZGAN UNIVERSITY 2011.
3. Van Delden C, Iglewski BH. Cell-to-cell signaling and Pseudomonas aeruginosa infections[J]. Emerging infectious diseases 1998; 4:551-60.
4. Gordon SM, Serkey JM, Keys TF et al. Secular trends in nosocomial bloodstream infections in a 55-bed cardiothoracic intensive care unit [J]. The Annals of thoracic surgery 1998; 65:95-100.
5. 赵京禹,付小兵,雷永红,等.大鼠小面积全层皮肤缺损创面模型的制备[J].感染.炎症.修复,2008,9(1)：64-64..
6. Barrett JF. MRSA:status and prospects for therapy? An evaluation of key papers on the topic of MRSA and antibiotic resistance[J]. Expert opinion on therapeutic targets 2004; 8:515-9.
7. Berger-Bachi B, Strassle A, Gustafson JE et al. Mapping and characterization of multiple chromosomal factors involved in methicillin resistance in Staphylococcus aureus[J]. Antimicrobial agents and chemotherapy 1992; 36:1367-73.
8. 谭黎明.唐小异,赵敏,等.黄连,黄芩提取物对烫伤后感染铜绿假单胞菌的药效初步观察[J].湖南师范大学学报(医学版)ISTIC,2011,8(1)..
9. Haddadin A, Fappiano S, Lipsett P. Methicillin resistant Staphylococcus aureus (MRSA) in the intensive care unit[J]. Postgraduate medical journal 2002; 78:385-92.
10. Lambrechts SA, Demidova TN, Aalders MC et al. Photodynamic therapy for Staphylococcus aureus infected burn wounds in mice[J]. Photochemical & Photobiological Sciences 2005; 4:503-9.
11. Zolfaghari PS, Packer S, Singer M et al. In vivo killing of Staphylococcus aureus using a light-activated antimicrobial agent[J]. BMC microbiology 2009; 9:27.
12. Hamblin MR, Zahra T, Contag CH et al. Optical monitoring and treatment of potentially lethal wound infections in vivo[J]. The Journal of infectious diseases 2003; 187:1717-25.
13. Park J-H, Ahn M-Y, Kim Y-C et al. In vitro and in vivo antimicrobial effect of photodynamic therapy using a highly pure chlorin e6 against Staphylococcus aureus Xen29[J]. Biological & pharmaceutical bulletin 2011; 35:509-14.
14. Ragas X, Sanchez-Garcfa D, Ruiz-Gonzalez R et al. Cationic porphycenes as potential photosensitizers for antimicrobial photodynamic therapy [J]. Journal of medicinal chemistry 2010; 53: 7796-803.
15.葛绳德.烧伤和创伤后革兰阳性细菌感染[J].国外医学：创伤与外科基本问题分册,1993,14(1)：29-33.
16. Galeano M, Deodato B, Altavilla D et al. Effect of recombinant adeno-associated virus vector-mediated vascular endothelial growth factor gene transfer on wound healing after burn injury* [J]. Critical care medicine 2003; 31:1017-25.
17. Pierce GF, Tarpley JE, Allman RM et al. Tissue repair processes in healing chronic pressure ulcers treated with recombinant platelet-derived growth factor BB[J]. The American journal of pathology 1994; 145:1399.
18. McGee GS, Davidson JM, Buckley A et al. Recombinant basic fibroblast growth factor accelerates wound healing [J]. Journal of Surgical Research 1988; 45:145-53.
19. Kobayashi E, Yamauchi H. Interleukin-6 and a delay of neutrophil apoptosis after major surgery[J]. Archives of Surgery 1997; 132:209.
20. Biffl WL, Moore EE, Moore FA et al. Interleukin-6 delays neutrophil apoptosis via a mechanism involving platelet-activating factor [J]. Journal of Trauma-Injury, Infection, and Critical Care 1996; 40:575-9.
1. Bagchi B, Basu S. ROLE OF DYE MOLECULES REMAINING OUTSIDE THE CELL DURING PHOTODYNAMIC INACTIVATION OF ESCHERICHIA COLI IN THE PRESENCE OF ACRIFLAVINE[J]. Photochemistry and Photobiology 1979; 29:403-5.
2. Bhatti M, MacRobert A, Meghji S et al. A Study of the Uptake of Toluidine Blue O by Porphyromonas gingivalis and the Mechanism of Lethal Photosensitization[J]. Photochemistry and Photobiology 1998; 68:370-6.
3. Tavares A, Carvalho CM, Faustino MA et al. Antimicrobial photodynamic therapy:study of bacterial recovery viability and potential development of resistance after treatment[J]. Mar Drugs 2010; 8:91-105.
4. Hamblin MR, Zahra T, Contag CH et al. Optical monitoring and treatment of potentially lethal wound infections in vivo[J], The Journal of infectious diseases 2003; 187:1717-25.
5. Park J-H, Ahn M-Y, Kim Y-C et al. In vitro and in vivo antimicrobial effect of photodynamic therapy using a highly pure chlorin e6 against Staphylococcus aureus Xen29[J]. Biological & pharmaceutical bulletin 2011; 35:509-14.
6. Luan X, Qin Y, Bi L et al. Histological evaluation of the safety of toluidine blue-mediated photosensitization to periodontal tissues in mice[J]. Lasers in medical science 2009; 24:162-6.
7. Dai T, Tegos GP, Zhiyentayev T et al. Photodynamic therapy for methicillin-resistant Staphylococcus aureus infection in a mouse skin abrasion model[J]. Lasers in surgery and medicine 2010; 42:38-44.
8. Lambrechts SA, Demidova TN, Aalders MC et al. Photodynamic therapy for Staphylococcus aureus infected burn wounds in mice[J]. Photochemical & Photobiological Sciences 2005; 4:503-9.
9. Hamblin MR, O'Donnell DA, Murthy N et al. Rapid Control of Wound Infections by Targeted Photodynamic Therapy Monitored by In Vivo Bioluminescence Imaging[J]. Photochemistry and photobiology 2002; 75:51-7.
10. Soslow RA, Dannenberg AJ, Rush D et al. COX-2 is expressed in human pulmonary, colonic, and mammary tumors[J]. Cancer 2000; 89:2637-45.
11.葛绳德.烧伤和创伤后革兰阳性细菌感染[J]. 国外医不：创伤与外科基本问题分册1933;14：29-33.
12. Oda Y, Kagami H, Ueda M. Accelerating effects of basic fibroblast growth factor on wound healing of rat palatal mucosa[J]. Journal of oral and maxillofacial surgery 2004; 62:73-80.
13. Desire L, Courtois Y, Jeanny JC. Endogenous and Exogenous Fibroblast Growth Factor 2 Support Survival of Chick Retinal Neurons by Control of Neuronal Neuronal bcl-xL and bcl-2 Expression Through a Fibroblast Berowth Factor Receptor 1-and Erk-Dependent Pathway[J]. Journal of neurochemistry 2000; 75:151-63.
14. Takamiya M, Saigusa K, Nakayashiki N et al. Studies on mRNA expression of basic fibroblast growth factor in wound healing for wound age determination[J]. International journal of legal medicine 2003; 117:46-50.
15.洪振丰, 朱洪民, 郑海音et a1.康美肤烧伤膏对大鼠烫伤创面碱性成纤维细胞生长因子及其受体表达的影响[J].中华中医药学刊2007；25：2071-2.
16. Seegers HC, Hood VC, Kidd BL et al. Enhancement of angiogenesis by endogenous substance P release and neurokinin-1 receptors during neurogenic inflammation[J]. Journal of Pharmacology and Experimental Therapeutics 2003; 306:8-12.
17.朱立新,耿小平,范上达.多种血管新生指标在肝细胞肝癌中的表达及敏感性比较[J].消化外科2003;2：153-7.
18. Salo P, Bray R, Seerattan R et al. Neuropeptides regulate expression of matrix molecule, growth factor and inflammatory mediator mRNA in explants of normal and healing medial collateral ligament[J]. Regulatory peptides 2007; 142:1-6.