二氢卟吩e_6的合成及其光敏化力和肿瘤光生物活性

由蚕沙叶绿素粗品 ,经酸碱降解反应制得二氢卟吩 e6 (1) ;并测定了 1在 D2 O中对 NADPH光氧化作用的敏化效应和对小鼠 S1 80 肉瘤的光动力损伤作用。初步试验结果表明 :1在非细胞体系内的光敏化力和对小鼠 S1 80 肉瘤的光动力疗效均优于参比药物血卟啉衍生物 (HPD)

二氢卟吩e_6锌的制备及对急性肝损伤的保护作用和实验性抗溃疡活性

蚕沙叶绿素粗品 ,经酸、碱降解及醋酸锌络合反应制得二氢卟吩 e6 锌 (1) ,并测定 1对吲哚美辛 (2 )诱发的大鼠胃溃疡的保护作用及对硫代乙酰胺 (3)、四氯化碳 (4 )所致小鼠急性肝损伤的防治作用。初步实验结果表明 ,ip110 0 mg/ kg,能显著降低 2诱发的大鼠胃溃疡指数 (P<0 .0 0 1)和溃疡个数 (P<0 .0 0 1) ;ip110 0 mg/ kg× 3,能显著降低小鼠 3(P<0 .0 0 5 )、4(P<0 .0 1)急性肝损伤后升高的 SGPT活性 ,提示

二氢卟吩e_6-C_(15)单甲酯:一种发展中的第二代光动力治癌新药候选化合物

目的 探讨二氢卟吩ｅ６Ｃ１５单甲酯（ＣＭＭＥ）作为第二代光动力治癌新药候选化合物的可行性。方法 以家蚕粪叶绿素粗提物为基始原料合成得ＣＭＭＥ。研究了ＣＭＭＥ在荷肉瘤１８０ 小鼠体内的分布、对还原辅酶Ⅱ钠盐（ＮＡＤＰＨ） 在重水中光氧化作用的敏化效应和对小鼠肉瘤１８０ 的光动力学疗效。结果 ＣＭＭＥ合成步骤相对简便，光敏化力强，不同时间的肿瘤／ 正常皮肤分布比达到２ ～１０，对动物移植瘤光动力疗效高于血卟啉衍生物，其抑制肿瘤生长５０％ 的剂量（ＩＤ５０） 为０－７６８ ｍｇ／ｋｇ。结论 ＣＭＭＥ是发展第二代光动力治癌新药的一种理想的候选化合物。

二氢卟吩e_6酰胺衍生物的光敏效应及肿瘤光生物活性

目的 寻找新型的光动力治疗肿瘤新药。方法 以蚕沙叶绿素粗提物为原料合成 4种二氢卟吩e6酰胺衍生物 (Ⅰ1～Ⅰ4 ) ,并测定其光敏效应和肿瘤光生物活性。结果 Ⅰ1～Ⅰ4 表现出较强的光敏效应 ,且强于参比药物血卟啉衍生物(hematoporphyrinderivative ,HPD) ;Ⅰ1～Ⅰ4 对小鼠S180 肉瘤有较好的光动力损伤作用 ,其中Ⅰ3 的光动力损伤作用要好于HPD。结论 提示二氢卟吩e6酰胺衍生物是一类具有发展前途的光动力抗肿瘤新药。

二氢卟吩e_6-6-酰胺化合物在重水中对NADPH氧化作用的光动力敏化效应

目的 测定二氢卟吩ｅ６６酰胺衍生物（ＣＥＡＤ） 的光动力敏化作用，为发展新的光动力药物提供依据。方法 用紫外分光光度法测定１２ 种二氢卟吩ｅ６６酰胺衍生物（ＣＥＡＤ） 在重水中对ＮＡＤＰＨ 氧化作用的光动力敏化效应，并测定了不同的有机介质（如甲醇、乙醇、四氢呋喃、二甲亚砜） 对光动力敏化效应的影响。结果 ＣＥＡＤ在重水中对ＮＡＤＰＨ氧化作用的光动力敏化效应明显高于血卟啉衍生物（Ｐ＜ ０－０５） ，且不同有机介质对光动力敏化效应的影响是不同的，其中二甲亚砜（ＤＭＳＯ） 对光动力敏化效应的影响最大（Ｐ＜０－０５）。结论 ＣＥＡＤ有可能是一类具有良好开发潜力的光动力治癌新药。

Ce6 nanoassemblies:Molecular mechanism and strategies for combinational anticancer therapy Special Collection:Aggregation-Induced Processes and Functions

Nowadays,cancer has become the leading cause of death worldwide,driving the need for effective therapeutics to improve patient prognosis.Photodynamic therapy(PDT)has been widely applied as an antitumor modality,owing to its minimal invasiveness,localized tumor damage,and high safety profile.However,its efficacy is limited by poor stability of photosensitizers,inadequate tumor accumulation,and a complex tumor microenvironment.To overcome these challenges,extensive endeavors have been made to explore the co-assembly of the widely used photosensitizer chlorin e6(Ce6)with various functional small molecules to enhance pharmacodynamic activity.This review provides a comprehensive overview of current studies on Ce6-based nanoparticles for effective PDT and precise delivery of functional molecules.The self-assembly mechanism will be discussed in detail,with a focus on potential strategies for combinational therapy with PDT.

Formation of plasmon quenching dips greatly enhances ^1O2 generation in a chlorin e6-gold nanorod coupled system

Photodynamic therapy （PDT）, as a noninvasive therapeutic method, has been actively explored recently for cancer treatment. However, owing to the weak absorption in the optically transparent windows of biological tissues, most com- mercial photosensitizers （PSs） exhibit low singlet oxygen （^1O2） quantum yields when excited by light within this window. Finding the best way to boost ^1O2 production for clinical applications using light sources within this window is, thus, a great challenge. Herein, we tackle this problem using plasmon resonance energy transfer （PRET） from plasmonic nanoparticles （NPs） to PSs and demonstrate that the formation of plasmon quenching dips is an effective way to enhance ^1O2 generation. The combination of the photosensitizer chlorin e6 （Ce6） and gold nanorods （AuNR） was employed as a model system. We observed a clear quenching dip in the longitudinal surface plasmon resonance （LSPR） band of the AuNRs when the LSPR band overlaps with the Q band of Ce6 and the spacing between Ce6 and the rods is within the acting distance of PRET. Upon irradiation with 660 nm continuous-wave laser light, we obtained a seven-fold enhancement in the ^1O2 signal intensity compared with that of a non-PRET sample, as determined using the ^1O2 electron spin resonance probe 2,2,6,6-tetramethyl-4-piperidine （TEMP）. Furthermore, we demonstrated that the PRET effect is more efficient in enhancing ^1O2 yield than the often-employed local field enhancement effect. The effectiveness of PRET is further extended to the in vitro level. Considering the flexibility in manipulating the localized SPR properties of plasmonic nanoparticles/nanostructures, our findings suggest that PRET-based strategies may be a general way to overcome the deficiency of most commercial organic PSs in biological optically transparent windows and promote their applications in clinical tumor treatments.

Preparation and characterization of pH-sensitive calcium carbonate-chlorin e6 nanoparticles for photodynamic therapy

In the present study,we combined CaCO_(3)NPs and Ce6 to construct CaCO_(3)-Ce6 nanoparticles (NPs).CaCO_(3)-Ce6 NPs were characterized in terms of particle size,zeta potential,UV-Vis absorption spectrum,fluorescence spectrum,FTIR spectrum,and pH-responsive behavior.The reactive oxygen species (ROS) generation in vitro was measured in 4T1 cells.The results showed that CaCO_(3)-Ce6 NPs were uniform-sized NPs with excellent fluorescence properties and pH-responsive behavior.The ability of ROS generation by CaCO_(3)-Ce6 NPs was stronger compared with Ce6 in 4T1 cells because Ca;could enhance the ROS generation,which could contribute to a stronger anti-tumor effect.

MnO_(2)-coated nanodiamond-driven photodynamic therapy for enhanced antitumor effect by addressing hypoxia and glutathione depletion

The generation of reactive oxygen species(ROS)at the tumor site to induce destruction is emerging as a novel strategy for cancer treatment,which involves photodynamic therapy(PDT).Nevertheless,tumors typically create a hypoxic environment and are equipped with an endogenous antioxidant defense system that could potentially impede the efficiency of the therapeutic approach.To overcome these drawbacks,herein,a tumor microenvironment-responsive the ND-PAA-CD-Ce6@MnO_(2)(NPCC@M)delivery system was fabricated by disulfide bond coupling chlorin e6(Ce6)to nanodiamond(ND)and further wrapped by MnO_(2)nanosheets to facilitate PDT.The use of disulfide bond not only stabilizes Ce6 in the blood circulation to prevent premature leakage,but also destroys the antioxidant barrier of overexpressed glutathione(GSH)in tumor cells.Moreover,the outer MnO_(2)was rapidly degraded by the endogenous hydrogen peroxide(H_(2)O_(2))in the acidic pH and GSH within the tumor cells,which leads to an abundance of O_(2)and while increases the level of 1O_(2)under laser irradiation.The results eventually broke the redox homeostasis and attenuate hypoxia,thereby inducing apoptosis and necrosis of tumor cells.Detailed in vitro and in vivo biological effect has revealed a good biosafety profile and a high tumor suppression effect.Such a novel ND-based system with tumor microenvironment-modulating capability to elevate oxygen content and promote GSH consumption in tumor cells opens new opportunities for enhanced ROS treatment paradigms.

An effective method to generate controllable levels of ROS for the enhancement of HUVEC proliferation using a chlorin e6-immobilized PET film as a photo-functional biomaterial

Reactive oxygen species(ROS)are byproducts of cellular metabolism;they play a significant role as secondary messengers in cell signaling.In cells,high concentrations of ROS induce apoptosis,senescence,and contact inhibition,while low concentrations of ROS result in angiogenesis,proliferation,and cytoskeleton remodeling.Thus,controlling ROS generation is an important factor in cell biology.We designed a chlorin e6(Ce6)-immobilized polyethylene terephthalate(PET)film(Ce6-PET)to produce extracellular ROS under red-light irradiation.The application of Ce6-PET films can regulate the generation of ROS by altering the intensity of light-emitting diode sources.We confirmed that the Ce6-PET film could effectively promote cell growth under irradiation at 500 μW/cm^(2) for 30 min in human umbilical vein endothelial cells.We also found that the Ce6-PET film is more efficient in generating ROS than a Ce6-incorporated polyurethane film under the same conditions.Ce6-PET fabrication shows promise for improving the localized delivery of extracellular ROS and regulating ROS formation through the optimization of irradiation intensity.

Brain endothelial cell-derived extracellular vesicles with a mitochondria-targeting photosensitizer effectively treat glioblastoma by hijacking the blood-brain barrier

Glioblastoma(GBM)is the most aggressive malignant brain tumor and has a high mortality rate.Photodynamic therapy(PDT)has emerged as a promising approach for the treatment of malignant brain tumors.However,the use of PDT for the treatment of GBM has been limited by its low blood-brain barrier(BBB)permeability and lack of cancer-targeting ability.Herein,brain endothelial cell-derived extracellular vesicles(bEVs)were used as a biocompatible nanoplatform to transport photosensitizers into brain tumors across the BBB.To enhance PDT efficacy,the photosensitizer chlorin e6(Ce6)was linked to mitochondria-targeting triphenylphosphonium(TPP)and entrapped into bEVs.TPPconjugated Ce6(TPP-Ce6)selectively accumulated in the mitochondria,which rendered brain tumor cells more susceptible to reactive oxygen species-induced apoptosis under light irradiation.Moreover,the encapsulation of TPP-Ce6 into b EVs markedly improved the aqueous stability and cellular internalization of TPP-Ce6,leading to significantly enhanced PDT efficacy in U87MG GBM cells.An in vivo biodistribution study using orthotopic GBM-xenografted mice showed that b EVs containing TPP-Ce6[b EV(TPP-Ce6)]substantially accumulated in brain tumors after BBB penetration via transferrin receptor-mediated transcytosis.As such,b EV(TPP-Ce6)-mediated PDT considerably inhibited the growth of GBM without causing adverse systemic toxicity,suggesting that mitochondria are an effective target for photodynamic GBM therapy.

Mesoporous silica nanorods intrinsically doped with photosensitizers as a multifunctional drug carrier for combination therapy of cancer

Mesoporous silica nanoparticles （MSNs） have attracted tremendous attention in recent years as drug delivery carriers due to their large surface areas, tunable sizes, facile modification and considerable biocompatibility. In this work, we fabricate an interesting type of MSNs which are intrinsically doped with photosensitizing molecules, chlorin e6 （Ce6）. By increasing the amount of Ce6 doped inside the silica matrix, it is found that the morphology of MSNs changes from spheres to rod-like shapes. The obtained Ce6-doped mesoporous silica nanorods （CMSNRs） are not only able to produce singlet oxygen for photodynamic therapy, but can also serve as a drug delivery platform with high drug loading capacity by utilizing their mesoporous structure. Compared to spherical nano- particles, it is found that CMSNRs with a larger aspect ratio show much faster uptake by cancer cells. With doxorubicin （DOX） employed as a model drug, the combined photodynamic and chemotherapy is carried out, achieving synergistic anti-tumor effects both in vitro and in vivo. Our study presents a new design of an MSN-based drug delivery platform, which intrinsically is fluorescent and able to serve as a photodynamic agent, promising for future imaging-guided combination therapy of cancer.

New approaches to diagnostics and treatment of cholangiocellular cancer based on photonics methods

Cholangiocellular cancer(CCC)is an oncological disease of the bile ducts characterized by a high mortality rate.To date,the use of standard methods for the diagnosis and treatment of CCC has not been able to reduce mortality from this disease.This work presents the results of fluorescence diagnostics(FD),which consists in using a modified optical fiber and photodynamic therapy(PDT)using a therapeutic laser instead of a low-intensity laser.This technique was tested on 43 patients in a clinical setting.The results obtained indicate a direct correlation between spectroscopic and video FD methods.Furthermore,a direct correlation was found between the photobleaching of a chlorin e6-based photosensitizer,with the commercial names of PhotoIon Radachlorin and Photoran and stricture regression.Our findings demonstrate the possibility of using a therapeutic laser with a wavelength of 660 nm for both diagnosis and treatment of bile ducts cancer,which results in a significant reduction of the operation time without decreasing its effectiveness.