靶向纳米材料在肿瘤诊断和治疗中的研究进展

肿瘤是困扰人类健康的世界难题,当今肿瘤治疗面临的主要问题是不能在肿瘤发生早期做出精确诊断,从而失去治疗的最佳时机,导致肿瘤患者的死亡率逐年增高;此外,肿瘤治疗药物的靶向性差,严重的毒副作用限制了临床应用.因此,设计并开发新型靶向肿瘤的药物载体迫在眉睫.研究表明,靶向纳米材料在肿瘤特异性诊断和治疗方面有极大的优越性.就靶向纳米材料、在肿瘤特异性诊断和靶向治疗方面的研究进展作一综述,并展望其发展前景.     

肿瘤的靶向治疗不同途径的研究进展

肿瘤的靶向治疗是一种恶性肿瘤的生物治疗方法之一，其原理是借助高度特异的亲肿瘤物质作为载体，以有细胞毒作用的物质如放射性核素、化疗药、毒素等与载体结合，依靠载体的特异性和肿瘤的亲和力，将细胞毒物质尽量集中在肿瘤部位发挥稳定地杀伤作用，而对宿主正常组织无害。近20多年来的研究已取得了很大的进展。开辟了多条不同的靶向治疗途径。本文就此方面的研究进展作一综述。     

肿瘤干细胞与肿瘤耐药

肿瘤细胞对化疗药物耐药是肿瘤治疗的主要障碍,肿瘤干细胞(CSC)是造成肿瘤耐药的最根本原因,故肿瘤治疗的关键应以CSC为治疗靶点。CSC概念的提出为癌症靶向治疗的研究带来了新的思路,提供了选择性杀伤CSC的靶向分子疗法,即新的药物应有选择的杀伤CSC而不损伤正常的干细胞,克服肿瘤耐药、防止治疗后的复发与转移,达到真正的治愈肿瘤。     

靶向药物治疗肿瘤降低死亡率

靶向治疗和靶向药物是近年来肿瘤治疗的新理念和新措施。日前在亚特兰大召开的美国临床肿瘤学会年会上，又有多个靶向药物的研究成果在大会上公布，表明了人类攻克癌症又向前迈进了一大步。     

主动靶向载药脂质体在肿瘤治疗中的研究进展

脂质体是理想的药物载体,具有生物相容性好、无免疫原性、表面易功能化等众多优点,并已在肿瘤等疾病的临床治疗中得到应用。对于肿瘤治疗来说,脂质体本身虽然具有一定的被动靶向能力,但单一的被动靶向对提高药物在肿瘤组织的富集率的作用非常有限,主动靶向是提高药物富集率的有效措施。因此几十年来,主动靶向脂质体药物载体获得广泛研究。本文综述了基于载体与肿瘤细胞表面特异性结合的主动靶向脂质体药物载体的研究进展,并总结了该领域存在的机遇、挑战和未来前景。     

肿瘤相关巨噬细胞作为抗肿瘤靶点的研究进展

肿瘤相关巨噬细胞（TAMs）是肿瘤间质的重要成分,受肿瘤微环境影响表现出强烈的可塑性,在肿瘤的增殖、侵袭、转移、血管生成等方面发挥重要作用。近年来调控肿瘤微环境、靶向TAMs已成为肿瘤免疫治疗中重要的研究方向,本文系统地介绍了TAMs的促肿瘤作用及靶向TAMs治疗的研究进展。     

肿瘤免疫代谢靶向治疗的研究进展

肿瘤免疫疗法的出现改变了许多肿瘤的治疗格局，是肿瘤治疗领域的重大突破。虽然其在一些肿瘤类型中显示出良好疗效，然而，总体反应率仍然偏低，因此需要开发新型的免疫治疗药物及治疗策略。代谢重编程是肿瘤细胞的一大特征，肿瘤微环境中免疫代谢的复杂性是影响肿瘤免疫治疗疗效的重要因素。近年来的研究表明，靶向免疫代谢可以减少免疫抑制，增强抗肿瘤免疫，提高现有肿瘤免疫疗法的疗效甚至克服耐药。文章综述了靶向肿瘤免疫代谢途径治疗的最新进展，包括靶向糖代谢、氨基酸代谢、核苷酸代谢和脂质代谢等，为开发免疫代谢靶向治疗潜力，寻找新靶点提供新思路。     

靶向肿瘤微环境免疫治疗新进展

肿瘤的发生发展涉及到肿瘤细胞和细胞外基质、脉管系统和免疫细胞的共同进化,不单单是肿瘤细胞遗传学的改变,还有肿瘤微环境的共同改变以适应肿瘤的生长。肿瘤微环境的异质性导致同一从属的肿瘤对相同药物的效应及耐受性不同,本文就肿瘤微环境的免疫耐受及其免疫靶向治疗等方面进行综述。     

恶性肿瘤的分子靶点检测和靶向治疗

随着肿瘤分子生物学的发展,分子靶向治疗作为肿瘤治疗的新手段逐渐成为热点.靶向治疗具有特异性强、疗效明显、对正常组织损伤较小等优点.该文对常用的分子靶向治疗药物及其靶点检测做一综述.     

静磁场靶向药物递送系统在肿瘤诊疗中的研究进展

化疗是治疗肿瘤的传统手段之一,但其具有组织非特异性,在抑制肿瘤细胞生长的同时也会对正常细胞产生毒副作用.磁靶向药物递送系统可通过具有生物相容性的、稳定的磁性纳米颗粒载体将抗癌药物在外磁场的引导下,靶向运输和浓聚在肿瘤组织.该技术不仅提高了药物运输的效率和药物的抗癌活性,还能降低药物用量和减轻毒副作用.载药磁性纳米颗粒和所应用的外磁场的性质是影响磁性纳米颗粒靶向肿瘤组织的重要影响因素.载药磁性纳米颗粒的靶向递送是否有效,主要依赖靶向目标位置处所应用的磁场和磁场强度是否足够吸引束缚载药磁性纳米颗粒在肿瘤组织中停留以及释放.对静磁场在引导磁性纳米颗粒靶向肿瘤组织研究的新进展进行综述,为静磁场在靶向肿瘤治疗方面提供一定的科研基础支持.     

A new probe for targeting drug delivery system

Recently, TDDS (Targeting drug delivery system) plays an important role in enhancing the bioavailability and targeting of anti-tumor drugs. How to transport drugs quickly and precisely to their target sites of action has not been solved fundamentally. A large number of researches have identified artemisinin and its analogs have the merit of precisely targeting to cancer cell, and low side effects to healthy tissue. Thus, if these compounds could be attached to established anti-tumor drugs with probe, a novel targeting anti-tumor drugs will be put into practice in the future. The novel drugs delivery system will be a powerful weapon against cancer disease for their unique targeting.     

Embryonic stem cells and gene targeting

The development of gene targeting technology, the exchange of an endogenous allele of a target gene for a mutated copy via homologous recombination, and the application of this technique to murine embryonic stem cells has made it possible to alter the germ-line of mice in a predetermined way. Gene targeting has enabled researchers to generate mouse strains with defined mutations in their genome allowing the analysis of gene function in vivo. This review presents the essential tools and methodologies used for gene targeting that have been developed over the past decade. Special emphasis has been laid on the available embryonic stem cell lines and the importance of the genetic background. Also, the state-of-the art of gene targeting approaches in species other than mice will be discussed.     

Extracellular targeting of synthetic therapeutic nucleic acid formulations

Success of nucleic acid based therapies often depends on target-cell specific delivery of genetic materials such as plasmid DNA, antisense oligonucleotides or small interfering RNA. Such extracellular targeting strategies include the incorporation of hydrophilic shielding domains into nucleic acid carriers which protects them from unspecific interactions with non-target tissues (passive targeting), and the inclusion of targeting moieties which allows recognition of target-specific cellular receptors (active targeting). Furthermore physical targeting methods such as magnetofection, electroporation or by photochemical means have been used to enhance efficiency of nucleic acid transfer. For optimum efficacy, extracellular targeting concepts are combined with programmed bioresponsive carrier chemistry which confers to the formulation stability during extracellular delivery but controlled disassembly and nucleic acid release after reaching the target cell.     

Get into the groove! Targeting antigens to MHC class II

Summary: The activation of MHC class Il-restricted helper T cells is paramount to adaptive immune responses. Vaccine development could therefore benefit from improved ways of targeting antigens into MHC class II molecules. In recent years, the natural pathways of MHC class II antigen presentation have been exploited to achieve this goal, First, antigenic proteins and peptides have been modified to facilitate receptor-mediated uptake by professional antigen-presenting cells. Second, DNA constructs containing specific targeting seqtiences have been used to direct endogenously synthesized antigens to the MHC dass II compartments. Both strategies proved to be highly effective. We review these data and describe how this knowledge is currently applied to the design of vaccines that activate helper T cells in vivo.     

The function and specificity of the C-terminal tripeptide glyoxysomal targeting signal in Neurospora crassa

The function of the C-terminal tripeptide targeting signal responsible for microbody targeting in many eukaryotes has been investigated in the filamentous fugus Neurospora crassa. Using an in-vivo targeting assay that employs transformants carrying C-terminally-modified versions of the bacterial enzyme chloramphenicol acetyltransferase (CAT), it has been demonstrated that C-terminal tripeptide-dependent import occurs most efficiently in response to nutritional acetate-induction. Under these conditions Neurospora generates a specialized organelle, the glyoxysome, which carries the enzymes responsible for the glyoxylate cycle and can be distinguished from peroxisome-like microbodies that contain catalase. Moreover, several C-terminal peptides have been tested in this system to extend the tripeptide targeting consensus to A/C/G/S-H/K/Q/R-I/L/V. However, the tripeptide analogue, ARM, found at the C-terminus of the glyoxylate cycle enzyme isocitrate lyase in higher plants, does not apparently function here.     

Smarter Drugs

Antibodies capable of targeting more than one antigen are envisioned to expand therapeutic efficacy in complex disease settings. Several strategies have been developed to achieve multiple targeting, including antibody mixtures and bispecific formats. In recent years, several dual- and pan-specific antibodies have been described and represent an alternative approach. These antibodies bind to different targets using a single antigen-combining site while maintaining high affinity and specificity, thus challenging the 'one antibody, one antigen' dogma. Despite certain drawbacks, the simple IgG format of this drug class enables rapid progression into the clinic.     

Vascular and cellular targeting for photodynamic therapy

Photodynamic therapy (PDT) involves the combination of photosensitizers (PS) with light as a treatment, and has been an established medical practice for about 10 years. Current primary applications of PDT are age-related macular degeneration (AMD) and several types of cancer and precancer. Tumor vasculature and parenchyma cells are both potential targets of PDT damage. The preference of vascular versus cellular targeting is highly dependent upon the relative distribution of photosensitizers in each compartment, which is governed by the photosensitizer pharmacokinetic properties and can be effectively manipulated by the photosensitizer drug administration and light illumination interval (drug-light interval) during PDT treatment, or by the modification of photosensitizer molecular structure. PDT using shorter PS-light intervals mainly targets tumor vasculature by confining photosensitizer localization within blood vessels, whereas if the sensitizer has a reasonably long pharmacokinetic lifetime, then PDT at longer PS-light intervals can induce more tumor cellular damage, because the photosensitizer has then distributed into the tumor cellular compartment. This passive targeting mechanism is regulated by the innate photosensitizer physicochemical properties. In addition to the passive targeting approach, active targeting of various tumor endothelial and cellular markers has been studied extensively. The tumor cellular markers that have been explored for active photodynamic targeting are mainly tumor surface markers, including growth factor receptors, low-density lipoprotein (LDL) receptors, transferrin receptors, folic acid receptors, glucose transporters, integrin receptors, and insulin receptors. In addition to tumor surface proteins, nuclear receptors are targeted, as well. A limited number of studies have been performed to actively target tumor endothelial markers (ED-B domain of fibronectin, VEGF receptor-2, and neuropilin-1). Intracellular targeting is a challenge due to the difficulty in achieving sufficient penetration into the target cell, but significant progress has been made in this area. In this review, we summarize current studies of vascular and cellular targeting of PDT after more than 30 years of intensive efforts.     

Nanofacilitated synergistic treatment for rheumatoid arthritis: A ‘three-pronged’ approach

Rheumatoid arthritis (RA) is a chronic, inflammatory, autoimmune disease of unidentified etiology that affects the joints and causes pain, swelling, stiffness and redness in the joints. The exact cause of rheumatoid arthritis has not yet been discovered and, consequently, treatment methods have not been optimally effective. It has long been treated with anti-inflammatory and immunosupressants including modern biologics either alone or in combination but all of the drugs have severe life threatening consequences with impaired immune function due to nonspecific targeting. Therefore, a three-pronged approach of local, active and synergistic targeting can be used to optimize delivery of therapeutic agents to reduce toxicity and patient outcome without compromising patient’s immunity.     

Targeting of cancer with radiolabeled antibodies. Prospects for imaging and therapy

This article reviews the current status, including problems and some proposed solutions, of the targeting of cancer with radioactive antibodies for use in antibody imaging (radioimmunodetection) and radioimmunotherapy. The problems and results are similar for purified polyclonal and murine monoclonal antibodies. Foremost among the problems are the low accretion of antibody (0.01% to 0.001% of injected dose per gram) in tumor and the nonspecific deposition of radiometals that are more ideal for imaging or therapy after antibody conjugation. Despite these limitations, radioimmunodetection appears to be a safe and useful method, even at this early stage of development. Sensitivity, specificity, and accuracy rates of 80% to 90% have been achieved in some studies involving radioiodine labels and polyclonal or monoclonal antibodies, whereas lower percentages have been achieved with indium 111 or technetium Tc 99m radioconjugates. Even at a usual tumor resolution of 1.5 to 2.0 cm, occult cancers have been disclosed by radioimmunodetection when missed by traditional detection measures, including computed tomography and magnetic resonance imaging. Radioimmunotherapy is somewhat less developed as a treatment modality, but encouraging remissions have been observed, thus stimulating further active pursuit of this technology. These targeting results have been achieved with antibodies that are not truly cancer specific, but only exploit quantitative differences in antigen expression between tumor and adjacent normal tissues. Circulating target tumor antigens do not appear to prevent successful tumor targeting of the radioactive antibodies.     

A review of NIR dyes in cancer targeting and imaging

The development of multifunctional agents for simultaneous tumor targeting and near infrared (NIR) fluorescence imaging is expected to have significant impact on future personalized oncology owing to the very low tissue autofluorescence and high tissue penetration depth in the NIR spectrum window. Cancer NIR molecular imaging relies greatly on the development of stable, highly specific and sensitive molecular probes. Organic dyes have shown promising clinical implications as non-targeting agents for optical imaging in which indocyanine green has long been implemented in clinical use. Recently, significant progress has been made on the development of unique NIR dyes with tumor targeting properties. Current ongoing design strategies have overcome some of the limitations of conventional NIR organic dyes, such as poor hydrophilicity and photostability, low quantum yield, insufficient stability in biological system, low detection sensitivity, etc. This potential is further realized with the use of these NIR dyes or NIR dye-encapsulated nanoparticles by conjugation with tumor specific ligands (such as small molecules, peptides, proteins and antibodies) for tumor targeted imaging. Very recently, natively multifunctional NIR dyes that can preferentially accumulate in tumor cells without the need of chemical conjugation to tumor targeting ligands have been developed and these dyes have shown unique optical and pharmaceutical properties for biomedical imaging with superior signal-to-background contrast index. The main focus of this article is to provide a concise overview of newly developed NIR dyes and their potential applications in cancer targeting and imaging. The development of future multifunctional agents by combining targeting, imaging and even therapeutic routes will also be discussed. We believe these newly developed multifunctional NIR dyes will broaden current concept of tumor targeted imaging and hold promise to make an important contribution to the diagnosis and therapeutics for the treatment of cancer.