靶向超声微泡在肿瘤诊断和治疗中的研究进展

近年来肿瘤的发病率有增高趋势,肿瘤的早期、无创、敏感而特异性的诊断和治疗对于降低死亡率及并发症的发生率至关重要。近年研究发现,靶向超声微泡造影剂有望成为一种新的安全有效的载体,从分子水平上介导肿瘤的靶向诊断和治疗。靶向超声微泡是利用微泡表面特有的生物学性质或通过特殊处理将靶向配体与微泡表面连接,使其能够持续、定向地蓄积于靶组织,实现靶向超声分子成像与靶向治疗。     

超声纳米微泡造影剂在肿瘤诊疗中的研究进展

随着分子生物学的快速发展,超声纳米微泡造影剂已成为研究热点之一。其作为一种新型的造影剂具有纳米级粒径,在成像方面有多种优势,容易实现对肿瘤的靶向性,在肿瘤诊疗中有一定意义。超声纳米微泡造影剂不仅可以结合超声成像、荧光探针及铁粒子等增强成像效果,还可以包裹肿瘤靶向药物进行药物靶向递送、作为载体和免疫增强剂携载目的基因进行基因转染、促进肿瘤的免疫治疗,为肿瘤的诊断和治疗提供了新方法。本文针对超声纳米微泡造影剂在肿瘤中的研究进展进行综述。     

靶向超声微泡在肿瘤诊断与治疗领域的研究进展

近年来靶向超声微泡在肿瘤诊断和治疗方面的研究进展十分迅速.实验研究表明,靶向超声微泡用于评价肿瘤血管新生和肿瘤血管内皮分子的变化,具有无创性的优势,并且能够大大提高肿瘤诊断的准确性.同时,靶向超声微泡作为一种新的基因或药物运载的有效工具,通过携带基因和药物对肿瘤组织实现靶向性释放,介导肿瘤细胞坏死、凋亡以及肿瘤微血管的栓塞和阻断,从而起到靶向治疗的作用.     

SonoVue 微泡瞬时均一性对新型绒癌细胞靶向造影剂结合特性的影响

背景与目的:超声微泡造影剂是目前的研究热点,通过其可提高超声扫描对肿瘤血管的检出率,但缺乏组织特异性.本研究目的是探讨在制备靶向造影剂之前SonoVue微泡瞬时均一性对绒癌细胞(choriocarcinoma cell, JAR)靶向造影剂的体外结合特性、结合率及稳定性的影响,为临床研究肿瘤细胞抗原的超声靶向定位显像、提高肿瘤的早期诊断率奠定基础.方法:研究分为微泡不均匀组(n=10),微泡均匀组(n=10),小微泡组(n=10) 3组;主要检测花环形成率、流式细胞计数及花环结合形态等.用均一性不同的SonoVue微泡与兔抗人绒毛膜促性腺激素(human chorionic gonadotrophin, HCG)抗体作用制成靶向造影剂,然后分别与绒癌细胞作用,比较各组的结合率及冲洗前后的结合率.结果:各组中不均一组的靶向造影剂微泡与绒癌细胞的结合率为(60.4±1.5)%,低于微泡均匀组及小微泡组[(84.3±5.5)%和(90.6±6.8)%],差异有统计学意义(P<0.05).冲洗前后比较,微泡均匀组靶向微泡与贴壁生长的绒癌细胞结合率变化最小,冲洗后结合率为(82.4±3.7)%(P>0.05).流式细胞检测结果显示:微泡不均匀组、微泡均匀组、小微泡组悬液中结合了荧光标记的靶向造影剂微泡与绒癌细胞的结合率分别为72.9%、81.03%、88.5%,3组间差异有统计学意义(P<0.05).结论:在体外制备靶向造影剂之前,SonoVu微泡瞬时均一性对绒癌细胞靶向造影剂微泡与绒癌细胞特异性结合能力有明显影响,而SonoVue微泡的均一性与适度振荡有关,SonoVue微泡瞬时不均一性直接影响靶向特异性结合率的数量.通过改善SonoVue微泡的均一性可望提高靶向造影剂结合率及靶向微泡稳定性,改善显影.     

超声分子成像技术定量评估肿瘤微血管生成的研究进展

 靶向超声造影剂微泡构建的方法主要有两种方式。靶向新生血管的超声微泡造影剂主要分为连接抗αVβ3抗体、连接αVβ3整合素抗体及连接血管内皮生长因子受体2(VEGFR2)等几种。目前通过靶向微泡黏附于肿瘤靶标的定量分析以及评估黏附于肿瘤新生血管内皮细胞上的靶向微泡与肿瘤局部病理微血管密度之间的相关性认为超声分子成像可以无创、快捷、反复、动态,定量评估肿瘤的微血管生成情况,间接反映恶性肿瘤组织增殖活性及其生物学特性     

超声微泡介导miRNAs在肿瘤治疗中的应用进展

随着超声治疗学的兴起及分子影像技术的深入发展,超声微泡不仅可以增强显像,还能作为一种新型的基因载体,能够靶向传递基因,促进基因转染,以达到治疗疾病的目的。超声微泡携带基因的靶向传递成为一种新型的肿瘤治疗技术,具有广阔的发展前景。人体单链非编码RNA（miRNAs）在肿瘤的发生发展中起着重要的作用,也是当前基因治疗研究的热点,本文针对超声微泡介导miRNAs在肿瘤治疗中的应用进展进行综述。     

超声造影在转移性肝癌和原发性肝细胞性 肝癌鉴别诊断中的应用

0 引言 自第二代超声微泡造影剂Sono Vue 2001年投入临床使用以来,超声造影在鉴别肝脏占位性病变性质上得到了广泛应用.到目前为止,肝脏良恶性质的占位性病变在超声造影上的鉴别要点已经比较明确,同时超声造影在肝脏肿瘤的继发和原发性质的鉴别方面的研究工作也正在开展.本文结合近3年发表的有关超声造影在鉴别诊断肝脏恶性肿瘤方面的文章,就超声造影在转移性肝癌和原发性肝细胞性肝癌的鉴别中的应用方面进行综述.     

超声微泡在肝癌治疗中的应用研究进展

随着超声治疗学的兴起及分子影像技术的深入发展，超声微泡除了可以增强病灶的显像，还能作为一种新型的药物或基因的载体，通过靶向传递药物或基因，以达到治疗疾病的目的。超声微泡载药物或基因的靶向传递，已成为一种新型的肿瘤治疗技术，它不仅具有无辐射、安全、高效、易重复使用的优点，还为药物或基因的靶向释放提供了技术支持，在肝癌的治疗研究中展现出良好的前景，有望为肝癌患者提供新的治疗思路。本文就超声微泡在肝癌治疗中的机制与应用，以及存在的问题进行综述。     

低频超声辐照联合微泡抑制兔VX_2肿瘤生长的实验研究

目的：探索低频超声辐照联合静脉注射微泡抑制肿瘤生长的非创伤性治疗肿瘤的新方法。方法：24只新西兰大白兔后腿肌肉内接种VX2肿瘤,瘤体长至1cm左右随机分为对照组、单纯微泡组、单纯超声组和超声微泡组。各组经相应处理后,超声检测肿瘤大小、观察瘤体内血流灌注情况,绘制肿瘤生长曲线,计算肿瘤增长百分率。病理学观察治疗后各组瘤体组织的病理学损伤。结果：治疗后2周结果显示超声微泡组瘤体体积和肿瘤增长百分率均明显小于其余各组（P〈0.01）,瘤体内血流灌注明显减少,瘤体组织大部分坏死;单纯微泡组、单纯超声组的瘤体体积和肿瘤增长百分率与对照组间均无显著性差异（P〉0.05）。结论：20kHz超声辐照联合微泡造影剂SonoVue可有效抑制兔VX2肿瘤的生长。     

低频超声辐照联合微泡抑制兔VX2肿瘤生长的实验研究

目的:探索低频超声辐照联合静脉注射微泡抑制肿瘤生长的非创伤性治疗肿瘤的新方法。方法:24只新西兰大白兔后腿肌肉内接种VX2肿瘤,瘤体长至1cm左右随机分为对照组、单纯微泡组、单纯超声组和超声微泡组。各组经相应处理后,超声检测肿瘤大小、观察瘤体内血流灌注情况,绘制肿瘤生长曲线,计算肿瘤增长百分率。病理学观察治疗后各组瘤体组织的病理学损伤。结果:治疗后2周结果显示超声微泡组瘤体体积和肿瘤增长百分率均明显小于其余各组(P<0.01),瘤体内血流灌注明显减少,瘤体组织大部分坏死;单纯微泡组、单纯超声组的瘤体体积和肿瘤增长百分率与对照组间均无显著性差异(P>0.05)。结论:20kHz超声辐照联合微泡造影剂SonoVue可有效抑制兔VX2肿瘤的生长。     

c-Met靶向成像在肿瘤诊断中的应用

肝细胞生长因子受体(c-Met)是一种酪氨酸激酶型受体，对于肿瘤的发生发展至关重要，c-Met靶向治疗已初步应用于临床，其对于癌症患者的治疗具有显著的益处。目前，由于无法对c-Met表达阳性的肿瘤患者进行有效的早期筛选，使得c-Met靶向治疗在肿瘤治疗中总体有效率偏低。c-Met靶向分子成像借助靶向分子成像探针能够实现肿瘤c-Met表达水平及活化状态的定量检测和直观揭示，对于肿瘤的早期诊断、治疗和预后具有重要意义和巨大的潜在价值。结合近年来c-Met靶向分子成像的研究，本文将深入分析、探讨c-Met靶向分子成像探针的构建及其在肿瘤诊断中的应用。     

Contrast-assisted destruction-replenishment ultrasound for the assessment of tumor microvasculature in a rat model

Angiogenesis, the development of new blood vessels, is necessary for tumor growth. Anti-angiogenic therapies have recently received attention as a possible cancer treatment. The purpose of this study was to monitor the vascularity of induced tumors in rats using contrast-enhanced ultrasound during anti-angiogenic therapy. Six rats with subcutaneously implanted R3230 murine mammary adenocarcinomas were treated with an orally administered anti-angiogenic agent (SU11657) beginning 28 days after tumor implantation (20 mg/kg BW once daily). Three additional tumor-bearing control rats were treated with an equivalent volume of vehicle alone. Sonographic evaluation of tumor blood flow was performed using a modified Siemens Sonoline Elegra equipped with a 5.0 MHz linear transducer prior to drug administration, during the first 51 hours following initial drug administration, and on days 8 and 15 after initiation of therapy. Tumor volumes were estimated at each time point using a prolate ellipsoid method from linear dimensions measured on the B-mode ultrasound image in the three major axes. A destruction-replenishment technique was used for tumor blood flow evaluation using a constant rate infusion of intravenously delivered ultrasound contrast media (Definity). A destructive pulse was fired first, followed by a chain of non-destructive pulses that allowed for visualization of vascular contrast agent replenishment. Parametric maps of the time required for contrast agent replenishment and the time-integrated intensity were generated for both the tumor and kidney. Following ultrasound examination, contrast-enhanced computed tomography of each tumor was performed in the same imaging plane as that used to acquire the ultrasound images. Fifteen days after the start of treatment, tumors were excised, preserved in 10% formalin, and sectioned in a plane approximating the ultrasound and CT imaging planes. Sections were prepared for light microscopy with H & E, CD31 and factor VIII immunostain to evaluate overall morphology and vessel distribution. Ultrasound measurements of tumor volume, the spatial extent of contrast enhancement, and the time required for contrast replenishment within control tumors were significantly different from those of treated tumors. The time-integrated ultrasound contrast enhancement decreases and the time required for replenishment of the contrast agent within the tumor volume increases over the course of anti-angiogenic therapy. Parametric maps of integrated intensity are shown to correlate with the regions of viable tumor demonstrated on H & E and regions of elevated contrast intensity on CT. Contrast-enhanced ultrasound imaging of implanted tumors provides a tool to assess differences in the microcirculation of treated and control tumors in studies of anti-angiogenic agents.     

Update: improvement strategies for peptide receptor scintigraphy and radionuclide therapy

Somatostatin receptor-targeting peptides are widely used for the imaging and therapy of neuroendocrine tumors. Peptide-receptor radionuclide therapy (PRRT) in neuroendocrine tumor patients with radiolabeled somatostatin analogs has resulted in symptomatic improvement, prolonged survival, and enhanced quality of life. The side-effects of PRRT are few and mostly mild, certainly when using kidney protective agents. If a more widespread use of PRRT is possible, such therapy might become the therapy of first choice in patients with metastasized or inoperable neuroendocrine gastroenteropancreatic tumors. Yet, much profit can be gained from improving the receptor-targeting strategies available and developing new strategies. This review presents an overview of several options to optimize receptor-targeted imaging and radionuclide therapy. These include the optimization of peptide analogs, increasing the number of receptors on the tumor site, and combining PRRT with other treatment strategies. The development of new peptide analogs with increased receptor-binding affinity and improved stability might lead to a higher accumulation of radioactivity inside tumor cells. Analogs of somatostatin have been widely studied. However, much profit can be gained in improving peptide analogs targeting other tumor-related receptors, including gastrin-releasing peptide (GRP) receptors, neurotensin (NT) receptors, cholecystokinin (CCK) receptors, and glucagon-like peptide-1 (GLP-1) receptors. Several peptide analogs targeting these receptors are well on their way to clinical utilization. The literature shows that it is possible to increase the receptor density on tumor cells by using different methods, which results in higher binding and internalization rates and thus a higher contrast during peptide-receptor scintigraphy. In PRRT treatment, this would enable the administration of higher therapeutic doses to tumors, which might lead to a higher cure rate in patients. Combinations of radionuclide therapy with other treatment modalities, such as chemotherapy or pretreatment with radiosensitizers, might increase the impact of the treatment. Further, the administration of higher dosages of radioactivity to the patient, enabled by combinations of PRRT with strategies reducing the radiation dose to healthy organs, will improve the outcome of tumor treatment. Also, targeting one or several tumor-specific receptors by using combinations of therapeutic agents, as well as by reducing nontarget uptake of radioactivity, will enlarge the therapeutic window of PRRT. Clinical studies will provide more insight in the effects of combining treatment strategies in cancer patients.     

Targeting cancer chemotherapeutic agents by use of lipiodol contrast medium

Arterially administered Lipiodol Ultrafluid contrast medium selectively remained in various malignant solid tumors because of the difference in time required for the removal of Lipiodol contrast medium from normal capillaries and tumor neovasculature. Although blood flow was maintained in the tumor, even immediately after injection Lipiodol contrast medium remained in the neovasculature of the tumor. To target anti-cancer agents to tumors by using Lipiodol contrast medium as a carrier, the characteristics of the agents were examined. Anti-cancer agents had to be soluble in Lipiodol, be stable in it, and separate gradually from it so that the anti-cancer agents would selectively remain in the tumor. These conditions were found to be necessary on the basis of the measurement of radioactivity in VX2 tumors implanted in the liver of 16 rabbits that received arterial injections of 14C-labeled doxorubicin. Antitumor activities and side effects of arterial injections of two types of anti-cancer agents were compared in 76 rabbits with VX2 tumors. Oily anti-cancer agents that had characteristics essential for targeting were compared with simple mixtures of anti-cancer agents with Lipiodol contrast medium that did not have these essential characteristics. Groups of rabbits that received oily anti-cancer agents responded significantly better than groups that received simple mixtures, and side effects were observed more frequently in the groups that received the simple mixtures. These results suggest that targeting of the anti-cancer agent to the tumor is important for treatment of solid malignant tumors.     

Biologic considerations for drug targeting in cancer patients

There is a great need for more specific targeting of chemotherapeutic agents, but development of specific therapy will be difficult in light of the barriers which separate a tumor from the vasculature, tumor cell heterogeneity and instability, technological advances necessary for drug delivery design and introduction into the clinic and mechanisms for assessment of efficacy (Table 5).While imposing, these problems are not insurmountable. A clearer understanding of the specific goal of a drug delivery/drug targeting approach will make the expectations more realistic and the chances for success greater. Primary to improving drug targeting is a better understanding of the biology of tumors. There are a number of limitations to drug targeting technology mentioned above, but, at present, the more difficult limitations are imposed by tumors themselves and the host's response to a tumor.Currently available technology does not offer Erlich's magic bullet and it does not appear that a single entity will suffice for cancer. Perhaps a mixture of drug delivery systems, each reducing the toxicity of a particular component of therapy will provide the first realistic goal in drug targeting. Each form of drug targeting is limited by biochemical and biophysical properties of the host, tumor cells, drug delivery system and interactions between them. Successes in vitro are moot without corresponding data in the (unfortunately) more complex organismic level. Development of drug targeting approaches will also require a critical, thorough evaluation of the ability to specifically deliver drug in vivo.     

New concepts of staging in gastrointestinal tumors as a basis of diagnosis and multimodal therapy

The therapy of gastrointestinal tumors is becoming more and more sophisticated and complex. This is due to an improved understanding of the pathogenesis of tumors, a more detailed classification and increasing therapeutic options. The basis of optimized therapeutic concepts is the exact evaluation of tumor spread and exact staging. The following review describes some of the most recent staging concepts in gastrointestinal tumors. Multislice computed tomography (CT), positron emission tomography (PET) and new supraparamagnetic iron oxide contrast agents for magnetic resonance imaging enable an increasing quality of the visualization of tumors and metastases. 3D imaging will be used for planning of surgical interventions in the future. Optical coherence tomography may contribute to an improved tumor staging and, thus, to the safety of limited interventions in early oesophageal- and gastric cancer patients. Laparoscopy and laparoscopic ultrasound become increasingly important for the identification of small metastases in the peritoneum, in lymph nodes and in the liver. The sentinel lymph node concept will contribute to an improved staging and individualized therapy as well.     

Vascular-targeting agents and radiation therapy in lung cancer: where do we stand in 2005?

With recent Food and Drug Administration approval of the anti-vascular endothelial growth factor (VEGF) antibody for the treatment of colon cancer, it may be possible to achieve similar progress in the treatment of locally advanced lung cancer. Antiangiogenic therapies in the clinic are a reality, and it is important to demonstrate that they can be used safely with conventional modalities, including radiation therapy (RT). Strategies under scrutiny in preclinical and clinical studies include the use of endogenous inhibitors of angiogenesis, use of agents that target VEGF and VEGF receptor signaling, targeting endothelial-related integrins during angiogenesis, and targeting the preexisting immature vessels growing within tumors (ie, vascular targeting). Regardless of the approach, it is necessary to address whether angiogenesis is a consistent phenomenon within the lung parenchyma around a cancer and a relevant target and whether inhibiting angiogenesis will improve current lung cancer therapies without increasing toxicity. Vascular-targeting agents (VTAs) are an interesting class of agents that have the potential to enhance RT, but their clinical promise has yet to be realized. In preclinical models, these agents selectively destroy the tumor vasculature, initiating a rapid centralized necrosis within established tumors. Characteristically, after treatment with VTAs, a rim of viable tumor cells remains at the periphery of the tumor, which remains well perfused and should therefore be relatively sensitive to radiation-induced cytotoxicity. This review will focus on VTAs in the treatment of lung cancer and includes a discussion of combination studies with RT in the laboratory and some of the hurdles in the clinical application of these agents.     

功能型复合生物材料用于肿瘤局部热疗的研究进展

肿瘤热疗不但具有杀伤广谱恶性肿瘤的能力,还可与化疗、放疗在临床治疗上相结合产生协同增敏的效果。同时又能减轻放、化疗治疗的毒副作用,因而被国际医学界称为“绿色疗法”。当前新型的热疗手段与传统的热疗手段相比较而言,能够提高治疗的适形性、有效性和靶向性,并且能够极大的减小热疗的毒副作用。但是新型的热疗手段需要借助于外界的能量源和热疗介质,即由安全、高效的热疗介质将外源的能量转化为热量并在肿瘤区域实现能量的“聚焦”,从而达到对肿瘤组织精确、高效的杀伤。所以,对基于功能型生物材料的热疗介质的开发和选择就成为了决定新型热疗治疗效果的关键因素。目前,针对肿瘤局部热疗的功能型复合生物材料的综述鲜有报道,因此,本文就目前肿瘤热疗领域中光热治疗、磁感应热疗和微波热疗的相关复合介质材料进行总结阐述,为功能型复合生物材料在未来肿瘤热疗领域提供借鉴。     

Antitumor effects of combining metronomic chemotherapy with the antivascular action of ultrasound stimulated microbubbles

Considerable effort is being directed toward investigating the use of ultrasound (US) stimulated microbubbles (MB) to promote the uptake of anticancer agents in tumors. In this study we propose and investigate a new method for combining therapeutic ultrasound with anticancer agents, which is to induce antivascular effects and combine these with an antiangiogenic treatment strategy, in this case metronomic chemotherapy. This is effectively a vascular targeting rather than a drug delivery approach. Experiments were conducted on MDA‐MB‐231 breast cancer tumors implanted in athymic mice. Metronomic cyclophosphamide (MCTX) was employed as an antiangiogenic therapy and was administered through the drinking water. Ultrasound stimulated microbubble treatments (USMB) were conducted at 1 MHz employing short bursts (0.00024 duty cycle) at 1.6 MPa in combination with the commercial microbubble agent Definity. USMB treatments were performed on a weekly basis for 4 weeks and MCTX was administered for 10 weeks. The USMB induced an acute reduction of blood flow as confirmed with US contrast imaging and DiOC₇ perfusion staining. Longitudinal experiments demonstrated that significant growth inhibition occurred in MCTX‐only and USMB‐only treatment groups relative to control tumors. The combined USMB and MCTX treatment group showed significant growth inhibition and survival prolongation relative to the USMB‐only (p < 0.01) and MCTX‐only treatment groups (p < 0.01). These results indicate the feasibility of a new approach to combining therapeutic ultrasound with an anticancer agent.