复合纳米光疗剂在乳腺癌光疗法中的研究现状与展望

光疗法作为一种辅助替代疗法,因非侵入性的诊疗特点广泛用于乳腺癌的早期诊断与后期治疗。但现有光疗剂因疏水性及组织靶向性差、光稳定性低、体内毒副作用明显,限制了其应用范围。随着纳米技术的发展,新型复合纳米光疗剂应运而生。该文总结了近5年新型纳米光疗剂在乳腺癌光疗法中的最新进展,发现随着多功能纳米材料在乳腺癌成像诊疗一体化领域中的发展,经修饰改进后的光疗剂分别在改善光响应以提高光热转换或增加活性氧的生成、靶向肿瘤微环境/免疫细胞/癌细胞表面受体以实现药物的可控响应式释放、利用仿生材料及内源物质改善生物相容性等方面取得了进一步发展。虽然新型光疗剂在转移性乳腺癌模型的治疗中表现出高细胞杀伤率,并能有效抑制其复发转移,但在安全性和协同治疗兼容性等方面仍存在问题。未来研究不仅可以在光疗剂现有作用的基础上加以改进,还可以结合免疫疗法,开发给药途径更便捷的口服药物,以放大免疫反应,多途径协同抵御乳腺癌侵袭。

涉及光疗机制的生物光化学

本文对光生物和光化学的定义,反应机制的类型和光敏化作用等做了阐述。下面例举几个光疗的成果 1.光疗牛皮癣 经常使用的8-甲氧基补骨脂素在UVA的照射下,从基态被激发到三重态。它主要和DNA中的胸腺嘧啶,其次和色氨酸进行光环合加成,形成交联,阻止DNA和RNA的合成,抑制具过度增生 2.血卟啉衍生物(HPD)治癌 HPD有定位于癌组织的能力和光动力作用,可推断病人体内癌部位。 讨论了HPD的光疗机制,和酞菁相比,有各自的优缺点。 3.竹红菌素 主要治疗妇女外阴白色病变和疤痕疙瘩,抑制癌细胞生长。 讨论了竹红菌甲素和乙素及它们的氧化物的结构和活性。 在大于510nm的光照射下,也可抑制癌细胞的生长。列举了竹红菌素的优缺点。

Clinical Application of Photodynamic Therapy

Photodynamic therapy（PDT） is a new medical technology, the study on photodynamic therapy was in full swing in the past two decade. Scientists have made great progress in it. Photosensitizer,oxygen and light source play important role in photodynamic therapy. PDT is a light activated chemotherapy. A photon is adsorbed by a photosensitizer which moves the drug into an excited state. The excited drug can then pass its energy to oxygen to create a chemical radical called “singlet oxygen”. Singlet oxygen attacks cellular structures by oxidation. Such oxidative damage might be oxidation of cell membranes or proteins. When the accumulation of oxidative damage exceeds a threshold level,the cell begins to die. Photodynamic therapy allows selective treatment of localized cancer. PDT involves administration of a photosensitizer to the patients, followed by delivery of light to the cancerous region. The light activates the agent which kills the cancer cells. Without light,the agent is harmless. As a new therapy,photodynamic Therapy has great Advantage in treating cancers. 1. PDT avoids systemic treatment. The treatment occurs only where light is delivered, hence the patient does not undergo go needless systemic treatment when treating localized disease. Side-effects are avoided, from losing hair or suffering nausea to more serious complications. 2. PDT is selective. The photosensitizing agent will selectively accumulate in cancer cells and not in surrounding normal tissues. Hence ,there is selective targeting of the cancer and sparing of surrounding tissues. 3. when surgery is not possible. PDT kills cancer cells but does not damage collagenous tissue structures,and normal cells will repopulate these structures. Hence,if a patient has cancer in a structure that cannot be removed surgicaily（eg. ,the upper bronchi of the lung） ,PDT can still treat the site. 4. PDT is repeatable. Uniike radiation therapy,PDT can be used again and again. Hence,it offers a means of longterm management of cancer even if complete cure is not attainable.

Effect of Yiguanjian decoction on cell differentiation and proliferation in CCl_4-treated mice

AIM： To investigate the cellular mechanisms of action of Yiguanjian （YGJ） decoction in treatment of chronic hepatic injury. METHODS： One group of mice was irradiated, and received enhanced green fluorescent protein （EGFP）- positive bone marrow transplants followed by 13 wk of CCh injection and 6 wk of oral YGJ administration. A second group of Institute for Cancer Research mice was treated with 13 wk of CCI4 injection and 6 wk of oral YGJadministration. Liver function, histological changes in the liver, and Hyp content were analyzed. The expres- sion of m-smooth muscle actin （α-SMA）, F4/80, albumin （AIb）, EGFP, mitogen-activated protein kinase-2 （PKM2）, Ki-67, fetoprotein （AFP）, monocyte chemotaxis pro- tein-1 and CC chemokine receptor 2 were assayed. RESULTS： As hepatic damage progressed, EGFP-po- sitive marrow cells migrated into the liver and were mainly distributed along the fibrous septa. They showed a conspicuous coexpression of EGFP with ^-SMA and F4/80 but no coexpression with AIb. Moreover, the expression of PKM2, AFP and Ki-67 was enhanced dy- namically and steadily over the course of liver injury. YGJ abrogated the increases in the number of bone marrow-derived fibrogenic cells in the liver, inhibited expression of both progenitor and mature hepatocyte markers, and reduced fibrogenesis. CONCLUSION： YGJ decoction improves liver fibrosis by inhibiting the migration of bone marrow cells into the liver as well as inhibiting their differentiation and suppressing the proliferation of both progenitors and hepatocytes in the injured liver.

Evaluating the influence of 6 MV and 15 MV photon beams on prostate intensity-modulated radiation therapy plans

Objective We aimed to determine the ef ects of low- and high-energy intensity-modulated radiation therapy （IMRT） photon beams on the target volume planning and on the critical organs in the case of prostate can-cer. Methods Thirty plans were generated by using either 6 MV or 15 MV beams separately, and a combination of both 6 and 15 MV beams. Al plans were generated by using suitable planning objectives and dose con-straints, which were identical across the plans, except the beam energy. The plans were analyzed in terms of their target coverage, conformity, and homogeneity, regardless of the beam energy. Results The mean percentage values of V70 Gy for the rectal wal for the plans with 6 MV, 15 MV, and mixed-energy beams were 16.9%, 17.8%, and 16.4%, respectively, while the mean percentage values of V40 Gy were 53.6%, 52.3%, and 50.4%. The mean dose values to the femoral heads for the 6 MV, 15 MV, and mixed-en-ergy plans were 30.1 Gy, 25.5 Gy, and 25.4 Gy, respectively. The mean integral dose for the 6 MV plans was 10% larger than those for the 15 MV and mixed-energy plans.Conclusion These preliminary results suggest that mixed-energy IMRT plans may be advantageous with respect to the dosimetric characteristics of low- and high-energy beams. Although the reduction of dose to the organs at risk may not be clinical y relevant, in this study, IMRT plans using mixed-energy beams exhibited better OAR sparing and overal higher plan quality for deep-seated tumors.

The impact of intensity modulated radiotherapy on the skin dose for deep seated tumors

Objective: The purpose of this study was to investigate the impact of intensity modulated radiotherapy (IMRT) on surface doses for brain, abdomen and pelvis deep located tumors treated with 6 MV photon and to evaluate the skin dose calculation accuracy of the XIO 4.04 treatment planning system. Methods: More investigations for the influences of IMRT on skin doses would increase its applications for many treatment sites. Measuring skin doses in real treatment situations would reduce the uncertainty of skin dose prediction. In this work a pediatric human phantom was covered by a layer of 1 mm bolus at three treatment sites and thermoluminescent dosimeter (TLD) chips were inserted into the bolus at each treatment site before CT scan. Two different treatment plans [three-dimensional conformal radiation therapy (3DCRT) and IMRT] for each treatment sites were performed on XIO 4.04 treatment planning system using superposition algorism. Results: The results showed that the surface doses for 3DCRT were higher than the surface doses in IMRT by 1.6%, 2.5% and 3.2% for brain, abdomen and pelvis sites respectively. There was good agreement between measured and calculated surface doses, where the calculated surface dose was 15.5% for brain tumor calculated with 3DCRT whereas the measured surface dose was 12.1%. For abdomen site the calculated surface dose for IMRT treatment plan was 16.5% whereas the measured surface dose was 12.6%. Conclusion: The skin dose in IMRT for deep seated tumors is lower than that in 3DCRT which is another advantage for the IMRT. The TLD readings showed that the difference between the calculated and measured point dose is negligible. The superposition calculation algorism of the XIO 4.04 treatment planning system modeled the superficial dose well.

Applications of phototheranostic nanoagents in photodynamic therapy

Nanotherapeutics has an increasing role in the treatment of diseases such as cancer. In photodynamic therapy （PDT） a therapeutically inactive photosensitizer compound is selectively activated by light to produce molecules capable of killing diseased cells and pathogens. A phototheranostic agent can be defined as a single nanoentity with the capabilities for targeted delivery, optical imaging and photodynamic treatment of a disease. Malignant cells, tissue and microbial etiologic agents can be effectively targeted by PDT. Photodynamic therapy is noninvasive, or minimally invasive, and has few side effects as damage to healthy tissue is minimized and the killing effect is localized. Various forms of cancer, acne and other diseases may be treated. The in vivo efficacy of photosensitizers is further improved by attaching them to nanostructures capable of targeting the diseased site. Such photosensitizer-functionalized nanostructures, or nano- therapeutics, allow site-specific delivery of imaging and therapeutic agents for improved phototheranostic performance. This review explores the potential applications of phototheranostic nanostructures in diagnosis and therapy.

Self-assembled nanostructured photosensitizer with aggregation-induced emission for enhanced photodynamic anticancer therapy

Three nanostructured photosensitizers with aggregation-induced emission(AIE) characteristics based on2,3-bis(4?-(diphenylamino)-[1,1?-biphenyl]-4-yl) fumaronitrile(BDBF) were prepared for image-guided photodynamic therapy(PDT). BDBF was encapsulated with Pluronic F-127(F127) to form usual spherical nanoparticles(F127@BDBF NPs) with a red fluorescence emission and 9.8% fluorescence quantum yield(FQY). Moreover, BDBF self-assembled into nanorods(BDBF NRs) in water. Compared with F127@BDBF NPs, BDBF NRs exhibited stronger orange fluorescence with a higher FQY of 23.3% and similar singlet oxygen(1O2) generation capability. BDBF NRs were further modified with F127 to form BDBF@F127 NRs with the same 1O2 generation ability as BDBF NRs. The three nanostructures exhibited a higher 1O2 production capacity than BDBF molecule in dissolved state and favorable stability in an aqueous solution as well as under physiological condition. In vitro photocytotoxicity experiments indicated that the three nanostructures inhibited tumor cell proliferation effectively.Therefore, to construct eligible nanostructures with a high FQY and 1O2 generation ability, simple self-assembly can serve as a valuable method to prepare photosensitizers with enhanced PDT.

PEGylated carbon dot/MnO_2 nanohybrid: a new pH/H_2O_2-driven, turn-on cancer nanotheranostics

The effect of tumor-targeted photodynamic therapy（PDT） was improved by designing nanotheranostics to promote oxygenation in a tumor microenvironment（TME）wherein hypoxia, acidosis, and the elevated levels of H2O2 are three main characteristics. In this study, a carbon dot（CD）PDT agent recently developed by our group was firstly applied as reducing agent to react with potassium permanganate for fabricating CDs/manganese dioxide（CDs/MnO2） composites,which were in turn modified with polyethylene glycol（PEG） to form water-soluble CDs/MnO2-PEG nanohybrids. In a normal physiological environment, the as-prepared nanohybrids exhibited quenched fluorescence, weak singlet oxygen generation, and low magnetic resonance imaging（MRI） signal.However, given the high sensitivity of MnO2 to the TME, the CDs/MnO2-PEG nanohybrids changed from an ＂off＂ to an＂on＂ state with synchronously enhanced fluorescence, singlet oxygen generation, and MRI signal in the TME. In vitro and in vivo analyses have revealed that CDs/MnO2-PEG nanohybrids could be applied as TME-driven, turn-on nanotheranostics for the MR/fluorescence bimodal imaging-guided PDT of cancer.Moreover, complete clearance of CDs/MnO2-PEG nanohybrids from the body of mice was observed, indicating their low long-term toxicity and good biocompatibility. This work offers a new nanotheranostic candidate for modulating the unfavorable TME, particularly for the targeted PDT of cancer through precise positioning and oxygen generation.

New cyclometalated transition-metal based photosensitizers for singlet oxygen generation and photodynamic therapy

The aim of this review article is to introduce recent studies on an emergent class of singlet oxygen photosensitizers of potential applications to the photodynamic therapy,with a primary focus on the cyclometalated transition-metal complexes.Singlet oxygen photosensitization performances of various cyclometalated Ir and Pt scaffolds are reviewed,and the general photophysical properties of relevant systems and the mechanisms of singlet oxygen production via photo-sensitization are also briefly discussed.Thus far,investigations of singlet oxygen sensitization by such Ir and Pt complexes are mainly carried out in organic solvents and under non-physiological conditions,while some research efforts have been made at examining the feasibility of applying pertinent cyclometalated complexes to photodynamic 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.

Accelerated antibacterial red-carbon dots with photodynamic therapy against multidrug-resistant Acinetobacter baumannii

The emergence of antibiotic resistance in bacteria is a major public-health issue.Synthesis of efficient antibiotic-free material is very important for fighting bacterial infection-related diseases.Herein,red-carbon dots(R-CDs)with a broad range of spectral absorption(350–700 nm)from organic bactericides or intermediates were synthesized through a solvothermal route.The prepared R-CDs not only had intrinsic antibacterial activities,but also could kill multidrug-resistant bacteria(multidrug-resistant Acinetobacter baumannii(MRAB)and multidrug-resistant Staphylococcus aureus(MRSA))effectively by generating reactive oxygen species.Furthermore,R-CDs could eliminate and inhibit the formation of MRAB biofilms,while conferring few side effects on normal cells.A unique property of R-CDs was demonstrated upon in vivo treatment of antibiotic-sensitive MRABinduced infected wounds.These data suggested that this novel R-CDs-based strategy might enable the design of nextgeneration agents to fight drug-resistant bacteria.

Programmable starving-photodynamic synergistic cancer therapy

Synergistic therapy combines multiple therapeutic approaches in one shot,thus could significantly amplify the therapeutic effects.However,how to design the desirable combination to maximize the synergistic effect is still a big challenge in cancer management.Herein,a nanoagent composed of glucose oxidase(GOx)and upconversion nanoparticles(UCNPs)were constructed for programmable starving-photodynamic synergistic cancer therapy through cascade glucose oxidation and hydrogen peroxide photolysis.In this nanoagent,GOx modulated the tumor glucose metabolism and consumed the β-D-glucose to produce H2O2.The glucose depletion induced"starvation"in cancer cells and caused cell death.Afterwards,the generated H2O2 was photolyzed by the invisible ultraviolet emission of UCNPs under near-infrared light excitation at 980 nm.The toxic hydroxyl radicals produced by photolysis further induced cancer cell death.Both in vitro and in vivo experiments confirmed that this starving-photodynamic synergistic therapy significantly outran any single therapy.This study paves an avenue to design programmable starving-photodynamic synergistic therapy for cancer management.