聚合物纳米粒在肿瘤光动力治疗中的研究进展

光动力治疗创伤小,在恶性肿瘤治疗方面的应用已经得到了临床认可。治疗过程中需要给予光敏剂,在光照下产生分子氧对肿瘤细胞产生杀伤作用。但是,大多数光敏剂缺乏对肿瘤细胞的特异性,其在肿瘤中的富集主要与细胞高代谢有关,并且在水相媒介中溶解度比较差。纳米技术应用于光动力治疗提供了一种有效地体内运输光敏剂的方式。目前,聚合物纳米粒与光动力药物传递的研究越来越多,光敏剂通过纳米粒的运输为弥补光动力治疗的不足提供了可能,这是因为纳米载体可以将治疗浓度的光敏剂运送到肿瘤细胞而不造成非靶向组织的副损伤。本文将介绍对肿瘤光动力治疗中具有特异性的聚合物纳米粒的种类及在临床中的应用情况,为肿瘤靶向治疗提供新思路。     

ALA-PDT:新型光动力疗法

传统的肿瘤光动力疗法是利用集聚在肿瘤中的外源光敏剂吸收激发光后启动光动力反应 ,产生活性产物扑杀肿瘤组织。氨乙酸丙酸 (ＡＬＡ)是人体生理过程中血红素合成中的基本原料 ,是原卟啉的前体。在正常组织中ＡＬＡ转变成原卟啉后 ,在亚螯合物酶的作用下 ,再与Ｆｅ+ + 结合成血红素。而在肿瘤组织中亚螯合物酶活性低 ,如有原卟啉产生 ,则不能有效的将之转变为血红素 ,将导致原卟啉集聚。因此如外源输入原卟啉前体ＡＬＡ ,则可在肿瘤中内源生成原卟啉 ,作为内源光敏剂原卟啉应同样可启动光动力反应。本文以离体培养的肿瘤细胞为样品 ,探讨Ａ…     

钙信号在光动力疗法中的产生及作用

光动力疗法是基于光敏剂选择性地积聚在肿瘤组织中,肿瘤接受光照后凋亡或坏死的一种细胞毒性治疗方法.光敏剂的亚细胞定位决定了细胞光敏损伤的初始位置,线粒体、内质网、细胞膜、溶酶体,细胞骨架等均可成为光敏损伤的靶点.细胞内Ca2 作为一个广泛意义上的信号分子,参与了多种信号转导途径,在光动力疗法诱导肿瘤细胞凋亡过程中起了重要作用.从光动力疗法造成的亚细胞损伤出发,探讨了光动力疗法中钙信号的产生机制,并简要介绍了钙信号在光动力疗法诱导肿瘤细胞凋亡中的作用机制.     

光动力疗法中细胞凋亡的几种信号转导路径

光动力疗法是一种新型的治疗肿瘤的方法。光敏剂在肿瘤细胞中积累,受光激发后,产生毒性的活性氧,杀死肿瘤细胞。在光动力疗法中,细胞凋亡是细胞死亡的一种重要的形式。本文主要总结了死亡受体、线粒体和介导的凋亡信号转导路径。     

光动力疗法在治疗消化道肿瘤中的应用与研究进展

光动力疗法是目前临床上出现的一种新型治疗肿瘤的方法,利用光敏剂吸收可见-近红外光并在组织氧的参与下发生光化学反应,产生活性氧物质进而诱导肿瘤细胞凋亡或坏死。光动力疗法对肿瘤侵袭性低,具有较高的选择性和良好的患者依从性,因此被广泛用于各种消化道恶性肿瘤的姑息性治疗和挽救性治疗。本文对近年来国内外应用光动力疗法治疗消化道肿瘤的文献进行综述,对所报道的疾病类型、治疗病例数、光敏剂和光源、疗效和安全性等信息进行分类整理,并对所面临的挑战和近期的研究进展进行了汇总,以期全面和客观地了解光动力疗法在治疗消化道肿瘤中的应用和研究进展,探讨目前的新应用及存在的问题和可能的发展方向。     

具有自噬抑制作用的卟啉金属有机框架的制备及其光动力癌症治疗的研究*

光动力疗法(PDT)具有微创、可控、低毒、可重复治疗等优点,已成为临床医学中不可缺少的治疗手段。但由于肿瘤细胞的自我保护机制,大大降低了PDT疗效。使用PDT治疗方法的同时实施药理自噬抑制策略,切断因光动力治疗下严重氧化损伤下的保护性自噬。通过油浴加热法合成卟啉金属有机框架PCN-224,并在PCN-224上负载自噬抑制剂硫酸羟氯喹(HCQ),通过扫描电子显微镜(SEM)、粒径测试(DLS)、紫外可见光谱测试等方法检测,结果表明成功地合成了该材料,增强了卟啉光敏剂的水溶性,并且光照后对4T1小鼠乳腺癌细胞毒性明显增强,且装载了HCQ后进一步提高了肿瘤杀伤能力。     

喜树碱聚前药纳米粒子包埋吲哚箐绿用于化疗与光动力联合抗肿瘤治疗

肿瘤单一药物化疗的效果往往达不到理想的肿瘤治疗效果,且容易导致耐药。因此,肿瘤的药物化疗与其他的抗肿瘤治疗方法,如光热治疗和光动力治疗等,联合治疗具有明显优势,并受到越来越多的关注。本工作构建了一种还原性响应的新型智能纳米体系,采用喜树碱聚前药两亲分子(PEG-b-PCPTM)物理包埋光敏剂吲哚箐绿(ICG)。在肿瘤细胞的还原性微环境中,控制释放化疗药物喜树碱,激活化疗;同时,光敏剂ICG用于光动力治疗,从而实现化疗与光动力的联合治疗,表现出良好的抗肿瘤活性。     

细胞器靶向光敏剂的研究进展

光动力治疗是一种利用特定波长的激光激发光敏剂产生活性氧物种(ROS),进而对肿瘤细胞进行杀伤的治疗模式。然而,ROS的半衰期很短,且只能作用在产生部位附近,这明显限制了光动力治疗的疗效。细胞器是细胞能正常工作和运转不可缺失的部分。因此,将光敏剂有效地靶向递送至细胞器是一种提高光动力治疗效果的有效策略。本文将介绍有机靶向光敏剂的设计原理、靶向策略、目前面临的挑战和未来的发展方向。     

肿瘤光动力疗法诱导细胞凋亡机制研究进展

肿瘤光动力疗法（Photodynamic Therapy,PDT）是利用光敏剂分子接受光照后产生多种活性氧物质（reactive oxyger,ROS),使细胞结构和功能受到损伤,而导致细胞凋亡的一种独特的肿瘤治疗方法,已受到越来越多的重视。本文对近几年有关PDT诱导肿瘤细胞凋亡方面的研究进展作了综述性介绍。     

纳米金提高光敏剂单态氧产率的研究

光动力疗法是效果很好的癌症微创治疗方法,主要依靠光敏性药物(也称为光敏剂)进行癌细胞杀伤。在光动力治疗中,光敏剂单态氧产率是影响光动力效果的关键因素。利用纳米金的光学特性来提高光敏剂的单态氧产率为研制新型光敏剂来改进光动力治疗方法提供了一种新的途径。利用绿光LED灯、红光LED灯、氙灯和635 nm连续激光四种光源对混合有光敏剂原卟啉Ⅸ和纳米金的溶液进行光照。用单态氧检测试剂测定了光照后的单态氧产率。     

Design, synthesis, and biological evaluation of folic acid targeted tetraphenylporphyrin as novel photosensitizers for selective photodynamic therapy

Photodynamic therapy (PDT) is a cancer treatment involving systemic administration of a tumor-localizing photosensitizer; this, when activated by the appropriate light wavelength, interacts with molecular oxygen to form a toxic, short-lived species known as singlet oxygen, which is thought to mediate cellular death. Targeted PDT offers the opportunity of enhancing photodynamic efficiency by directly targeting diseased cells and tissues. Two new conjugates of three components, folic acid/hexane-1,6-diamine/4-carboxyphenylporphyrine 1 and folic acid/2,2'-(ethylenedioxy)-bis-ethylamine/4-carboxyphenylporphyrine 2 were synthesized. The conjugates were characterized by 1H NMR, MALDI, UV-visible spectroscopy, and fluorescence quantum yield. The targeted delivery of these photoactive compounds to KB nasopharyngeal cell line, which is one of the numerous tumor cell types that overexpress folate receptors was studied. It was found that after 24 h incubation, conjugates 1 and 2 cellular uptake was on average 7-fold higher than tetraphenylporphyrin (TPP) used as reference and that 1 and 2 cellular uptake kinetics increased steadily over the 24 h period, suggesting an active transport via receptor-mediated endocytosis. In corresponding results, conjugates 1 and 2 accumulation displayed a reduction of 70% in the presence of a competitive concentration of folic acid. Survival measurements demonstrated that KB cells were significantly more sensitive to conjugated porphyrins-mediated PDT. Under the same experimental conditions and the same photosensitizer concentration, TPP displayed no photocytotoxicity while conjugates 1 and 2 showed photodynamic activity with light dose values yielding 50% growth inhibition of 22.6 and 6.7 J/cm2, respectively.     

Direct and indirect photodynamic therapy effects on the cellular and molecular components of the tumor microenvironment

Photodynamic therapy (PDT) is a novel cancer treatment. It involves the activation of a photosensitizer (PS) with light of specific wavelength, which interacts with molecular oxygen to generate singlet oxygen and other reactive oxygen species (ROS) that lead to tumor cell death. When a tumor is treated with PDT, in addition to affect cancer cells, the extracellular matrix and the other cellular components of the microenvironment are altered and finally this had effects on the tumor cells survival. Furthermore, the heterogeneity in the availability of nutrients and oxygen in the different regions of a tridimensional tumor has a strong impact on the sensitivity of cells to PDT. In this review, we summarize how PDT affects indirectly to the tumor cells, by the alterations on the extracellular matrix, the cell adhesion and the effects over the immune response. Also, we describe direct PDT effects on cancer cells, considering the intratumoral role that autophagy mediated by hypoxia-inducible factor 1 (HIF-1) has on the efficiency of the treatment.     

Peptide-induced inflammatory increase in vascular permeability improves photosensitizer delivery and intersubject photodynamic treatment efficacy

Photodynamic therapy (PDT) treatment can exhibit high intersubject variability due to the inherent differences in drug delivery within the tissue to be treated. In this study, the increased perfusion of the lipid-associated photosensitizer verteporfin was studied using substance P, a peptide known to increase vascular permeability. The transvascular permeability coefficient was quantified before and after administration of substance P, and the mean value increased from 0.026 to 0.043 microm/s with the induced inflammation. Correspondingly, there was a 40-50% increase in uptake of verteporfin in the tumor parenchyma in tumors injected with substance P compared to those without. This increased drug uptake resulted in a modest increase in tumor doubling time from 4 days with regular PDT to 6.2 days with substance P and PDT. There was also a significant reduction in the interindividual variability in with substance P plus PDT from 64% to 13%. The resulting treatment was therefore more effective and there was less variability in dose between subjects.     

Direct tumor damage mechanisms of photodynamic therapy

Photodynamic therapy (PDT) is a clinically approved and rapidly developing cancer treatment regimen. It is a minimally invasive two-stage procedure that requires administration of a photosensitizing agent followed by illumination of the tumor with visible light usually generated by laser sources. A third component of PDT is molecular oxygen which is required for the most effective antitumor effects. In the presence of the latter, light of an appropriate wavelength excites the photosensitizer thereby producing cytotoxic intermediates that damage cellular structures. PDT has been approved in many countries for the treatment of lung, esophageal, bladder, skin and head and neck cancers. The antitumor effects of this treatment result from the combination of direct tumor cell photodamage, destruction of tumor vasculature and activation of an immune response. The mechanisms of the direct photodamage of tumor cells, the signaling pathways that lead to apoptosis or survival of sublethaly damaged cells, and potential novel strategies of improving the antitumor efficacy of PDT are discussed.     

Fluorescence characterisation of multiply-loaded anti-HER2 single chain Fv-photosensitizer conjugates suitable for photodynamic therapy.

We report the synthesis, spectroscopic properties and intracellular imaging of recombinant antibody single chain fragment (scFv) conjugates with photosensitizers used for photodynamic therapy of cancer (PDT). Two widely-studied photosensitizers have been selected: preclinical pyropheophorbide-a (PPa) and verteporfin (VP), which has been clinically approved for the treatment of acute macular degeneration (Visudyne). Pyropheophorbide-a and verteporfin have been conjugated to an anti-HER2 scFv containing on average ten photosensitizer molecules per scFv with a small contribution (相似文献   

Synthesis and photobiological study of a novel chlorin photosensitizer BCPD-18MA for photodynamic therapy

This paper reports synthesis and photobiological properties of a novel chlorin photosensitizer BCPD-18MA. Cytotoxicity, cellular uptake, subcellular location, biodistribution, photodynamic therapy (PDT) efficiency, cell apoptosis as well as histological analysis of the liposomal-delivered BCPD-18MA (L-BCPD-18MA) was studied using mammary adenocarcinoma MDA-MB-231 cells and Lewis lung carcinoma (LLC) implanted in C57BL/6 mice as experimental models. The results showed that L-BCPD-18 was incorporated rapidly into MDA-MB-231 cells and localized partially in mitochondria. L-BCPD-18 induced cell apoptosis by PDT. In addition, biodistribution of L-BCPD-18MA in LLC-bearing mice demonstrated a fast clearance rate of the drug and good skin-related tumor selectivity. Finally, entrapment of BCPD-18 into liposomes resulted in a dramatic impairment of dark toxicity and a notable improvement of PDT antitumor efficacy in vitro. Compared with liposomal-delivered BPDMA (L-BPDMA), L-BCPD-18MA exhibited low dark toxicity and high PDT efficiency on MDA-MB-231 cells. The photodynamic efficacy of L-BCPD-18MA on LLC-bearing mice is comparable to that of L-BPDMA, implying that L-BCPD-18MA is a potential antitumor candidate for PDT.     

In vitro studies on erythrosine-based photodynamic therapy of malignant and pre-malignant oral epithelial cells

Photodynamic Therapy (PDT) involves the administration of a tumor localizing photosensitizing agent, which upon activation with light of an appropriate wavelength leads to the destruction of the tumor cells. The aim of the present study was to determine the efficacy of erythrosine as a photosensitizer for the PDT of oral malignancies. The drug uptake kinetics of erythrosine in malignant (H357) and pre-malignant (DOK) oral epithelial cells and their susceptibility to erythrosine-based PDT was studied along with the determination of the subcellular localization of erythrosine. This was followed by initial investigations into the mechanism of cell killing induced following PDT involving both high and low concentrations of erythrosine. The results showed that at 37 °C the uptake of erythrosine by both DOK and H357 cells increased in an erythrosine dose dependent manner. However, the percentage of cell killing observed following PDT differed between the 2 cell lines; a maximum of ~80% of DOK cell killing was achieved as compared to ~60% killing for H357 cells. Both the DOK and H357 cell types exhibited predominantly mitochondrial accumulation of erythrosine, but the mitochondrial trans-membrane potential (ΔΨ(m)) studies showed that the H357 cells were far more resistant to the changes in ΔΨ(m) when compared to the DOK cells and this might be a factor in the apparent relative resistance of the H357 cells to PDT. Finally, cell death morphology and caspase activity analysis studies demonstrated the occurrence of extensive necrosis with high dose PDT in DOK cells, whereas apoptosis was observed at lower doses of PDT for both cell lines. For H357 cells, high dose PDT produced both apoptotic as well as necrotic responses. This is the first instance of erythrosine-based PDT's usage for cancer cell killing.     

新型光敏剂在肝癌中的应用

肝癌晚期,手术切除往往效果不佳,5年生存率低。因此,通过新的辅助治疗方式提高患者生存期是必要的。光动力疗法作为晚期肝癌的姑息性治疗方法,光敏剂是光动力疗法中至关重要的因素。几十年来,光敏剂经过不断发展,如今已出现了许多新型光敏剂,它们具有靶向性高、脂溶性强、生物利用度高等特点,随着肝脏肿瘤多学科合作模式的逐渐开展,新型光敏剂及光动力疗法也将在其中扮演重要的角色。     

Somatostatin Analogues for Receptor Targeted Photodynamic Therapy

Photodynamic therapy (PDT) is an established treatment modality, used mainly for anticancer therapy that relies on the interaction of photosensitizer, light and oxygen. For the treatment of pathologies in certain anatomical sites, improved targeting of the photosensitizer is necessary to prevent damage to healthy tissue. We report on a novel dual approach of targeted PDT (vascular and cellular targeting) utilizing the expression of neuropeptide somatostatin receptor (sst₂) on tumor and neovascular-endothelial cells. We synthesized two conjugates containing the somatostatin analogue [Tyr3]-octreotate and Chlorin e6 (Ce6): Ce6-K₃-[Tyr3]-octreotate (1) and Ce6-[Tyr3]-octreotate-K₃-[Tyr3]-octreotate (2). Investigation of the uptake and photodynamic activity of conjugates in-vitro in human erythroleukemic K562 cells showed that conjugation of [Tyr3]-octreotate with Ce6 in conjugate 1 enhances uptake (by a factor 2) in cells over-expressing sst₂ compared to wild-type cells. Co-treatment with excess free Octreotide abrogated the phototoxicity of conjugate 1 indicative of a specific sst₂-mediated effect. In contrast conjugate 2 showed no receptor-mediated effect due to its high hydrophobicity. When compared with un-conjugated Ce6, the PDT activity of conjugate 1 was lower. However, it showed higher photostability which may compensate for its lower phototoxicity. Intra-vital fluorescence pharmacokinetic studies of conjugate 1 in rat skin-fold observation chambers transplanted with sst₂ ⁺ AR42J acinar pancreas tumors showed significantly different uptake profiles compared to free Ce6. Co-treatment with free Octreotide significantly reduced conjugate uptake in tumor tissue (by a factor 4) as well as in the chamber neo-vasculature. These results show that conjugate 1 might have potential as an in-vivo sst₂ targeting photosensitizer conjugate.     

The effect of laser activation of 5,10,15,20-tetra-sulphophenyl-porphyrin loaded in K562 cells and human normal mononuclear cells

Photodynamic therapy (PDT) is a relatively new type of treatment in cancer, based on a photosensitizer, visible light and molecular oxygen. Reactive oxygen species are generated, causing tumor cells death by apoptosis or necrosis. Significant nowadays research efforts are focused on finding new photosensitizers with antineoplastic activity and an acceptable toxicological profile. Although consistent information exists regarding PDT in solid tumors, relatively few data are available for PDT of blood cancers. Therefore, we carried out a comparative study on lymphoblastic K562 cells and human normal peripheral blood mononuclear cells (PBMC) treated at a density of 2 x 10(5) cells/mL with 5,10,15,20-tetra-sulphophenyl-porphyrin (TSPP) and then irradiated with He-Ne laser light (lamda = 632.8 nm). The following cell functions were investigated: viability, multiplication, RNA synthesis, total RNA levels and apoptosis. After irradiation, the viability of TSPP-loaded tumor cells decrease, the multiplication rate and the total RNA level are drastically reduced and cells undergo apoptosis. TSPP alone loaded into cells but not activated by irradiation, does not affect these cell parameters. Human normal PBMC subjected to TSPP loading and laser-irradiation develop a different cellular response, their viability and proliferative capacity not being altered by experimental PDT. Accordingly, it appears that TSPP is a non-aggressive compound for cellular physiology and becomes cytotoxic only by irradiation; moreover laser-activated TSPP affects only cells that have a tumoral pattern.