生物靶向治疗

生物靶向治疗是指应用一定的医学生物学技术,将治疗药物和一定的靶向载体交联,特异性地将治疗药物运送到靶器官或靶细胞,以达到高效治疗的目的。这一治疗方法特异性好,选择性强,能减少药物用量和给药次数,     

纳米粒体内靶向性的研究进展

纳米粒（Nanoparticle）一般指由天然或合成的高分子材料制成的、粒度为纳米级的（1～1000nm）固态胶体微粒。靶向给药指运用载体将药物选择性地浓集定位于靶器官、靶组织或靶细胞，使其药物浓度高于其他正常组织。纳米粒的体内靶向性一般分为被动靶向性和主动靶向性。被动靶向性是利用纳米粒的大小、质量、表面疏水性、静电作用、磁力作用等物理因素实现靶向给药。主动靶向性是指对纳米粒进行表面修饰，如在其表面耦联特异性的靶向分子（特异性的配体、单克隆抗体等），通过靶向分子与细胞表面特异性受体结合，实现主动靶向治疗。自20世纪90年代以来．纳米粒作为靶向给药的载体一直是药物制剂研究的热点之一。现将纳米粒在肝脏、脑、骨髓和肿瘤中的药物靶向性研究进展综述如下。     

心血管疾病靶向治疗-定位给药仪的研制原理及发展现状

<正>心血管疾病多以化学药物治疗为主,然而有些药物缺乏选择性,导致出现严重副作用,如尿激酶溶栓时会导致重要器官出血。而定位给药仪则利用脉冲电场使带电药物靶向、快速、高效作用于病变处。本文就用于靶向治疗心血管疾病的新型定位给药仪的研制原理、技术难点、发展现状与趋势作一综述。1定位给药仪研制原理心血管大多数疾病急性发作严重威胁生命,使药物靶向、高效、迅速到达病变处是定位给药仪研制宗旨。定位给药仪技     

抗乙型肝炎病毒靶向药物研究进展

乙型肝炎治疗的关键是清除乙型肝炎病毒,多数抗病毒药物均有不同程度的不良反应,从而限制了其临床价值。人们试图通过制备靶向药物来提高抗病毒效果并降低其不良反应。自从 Ehrlich 提出靶向药物概念以来,这一领域的研究已不断取得突破。所谓靶向药物(Targeted Drug)是指能选择性地达到特定生理部位、器官、组织或细胞,并在该靶位发挥治疗作用的药物。靶向药物最大的优点是它可以增强药物在靶部位的活性并减少其在非靶部位的毒副作用,提高药物治疗指数。已有的研究成果显示,抗病毒靶向药物特异性好,选择性强,能减少药物用量和给药次数,以及有降低     

靶向载药脂质体在肿瘤治疗中的应用研究进展

脂质体是最早被批准应用于临床的肿瘤治疗纳米载药系统，具有易于制备、高生物相容性、低不良反应、高度靶向性等优势。脂质体能够作为载体通过被动及主动靶向机制将药物通过全身或局部给药选择性地定位于靶组织、靶器官、靶细胞或细胞内结构，从而发挥对肿瘤的治疗作用。深入探讨靶向载药脂质体在肿瘤治疗中的应用，或可为靶向载药脂质体的临床应用提供进一步参考。     

载药电纺纳米纤维膜用于局部化疗治疗癌症研究进展

<正>高分子材料的局部挖释给药系统是将在过去几十年里,以高分子聚合物为药物载体,提高癌症患者的恶性病灶处药物浓度的相关研究获得了广泛的发展。为了提高生存率和生存质量,人们致力于提高药物在病灶处的生物利用度、药物浓度和溶解度,以减少全身副反应〔1,2〕。1高分子载药体系根据给药模式和作用机制高分子载药体系根据给药模式和作用机制分为两类〔3〕:(1)是通过系统给药体系(包括被动靶向和主动靶向)。所谓     

非小细胞肺癌分子靶向治疗药物的研究进展

分子靶向治疗是肺癌治疗的新方法.分子靶向治疗药物包括表皮生长因子受体抑制药、肿瘤新生血管生成抑制药和凋亡诱导药等.与传统细胞毒性化疗药物相比,分子靶向治疗能更特异地作用于肿瘤而毒副反应显著减少.虽然目前多数分子靶向治疗药物对肺癌的疗效不佳,但是厄罗替尼、贝伐单抗等对某些非小细胞肺癌(NSCLC)患者的良好疗效展示了这一研究领域的美好前景.本文对近年来NSCLC分子靶向治疗药物的研究进展作一综述.     

晚期结直肠癌抗血管生成靶向治疗的若干热点

氟尿嘧啶类药物、伊立替康与奥沙利铂在晚期结直肠癌化学治疗(以下简称化疗)中呈三足鼎立之势,单药(除奥沙利铂)、两药乃至三药组合在临床均有尝试,核心在于高效低毒.随着表皮生长因子受体(epidermal growthfactor receptor,EGFR)单克隆抗体和血管内皮生长因子(vascularendothelial growth factor,VEGF)单克隆抗体等分子靶向治疗药物的出现,合理有效地布局总体治疗策略和选择合适的分子靶向药物,在目前可选药物不多的前提下使所用药物的效应最大化,分子靶向药物与化疗药物发挥协同增效作用以及在分子标志物指导下的个体化治疗等问题,已逐渐成为该领域的研究热点.现以抗血管生成靶向治疗为例,剖析晚期结直肠癌抗血管生成靶向治疗的若干进展.     

肿瘤血管靶向治疗新策略——选择性肿瘤血管血栓栓塞的研究进展

以肿瘤血管靶向分子(多肽、抗体和配体)为载体,以截短组织因子为效应分子的选择性诱发肿瘤血管血栓栓塞的抗肿瘤治疗是一种新颖的肿瘤血管靶向策略.本文就其临床前研究进展、治疗原理、治疗评价,3类肿瘤血管靶向治疗的区别、影响因素以及现存问题等作一综述.     

药物的靶向治疗（83）

抗肿瘤药物的靶向治疗：药物的靶向治疗又称选择性治疗,其不仅能减少药物的不良作用,还能使药物更加集中作用在病变部位而提高疗效。药物的靶向治疗是肿瘤药物治疗理念的一次革命,传统的抗肿瘤药物除了对肿瘤细胞和组织有抑制、破坏和杀伤作用外,对机体正常组织也有同样作用。     

Peptide-Based Technologies to Alter Adenoviral Vector Tropism: Ways and Means for Systemic Treatment of Cancer

Due to the fundamental progress in elucidating the molecular mechanisms of human diseases and the arrival of the post-genomic era, increasing numbers of therapeutic genes and cellular targets are available for gene therapy. Meanwhile, the most important challenge is to develop gene delivery vectors with high efficiency through target cell selectivity, in particular under in situ conditions. The most widely used vector system to transduce cells is based on adenovirus (Ad). Recent endeavors in the development of selective Ad vectors that target cells or tissues of interest and spare the alteration of all others have focused on the modification of the virus broad natural tropism. A popular way of Ad targeting is achieved by directing the vector towards distinct cellular receptors. Redirecting can be accomplished by linking custom-made peptides with specific affinity to cellular surface proteins via genetic integration, chemical coupling or bridging with dual-specific adapter molecules. Ideally, targeted vectors are incapable of entering cells via their native receptors. Such altered vectors offer new opportunities to delineate functional genomics in a natural environment and may enable efficient systemic therapeutic approaches. This review provides a summary of current state-of-the-art techniques to specifically target adenovirus-based gene delivery vectors.     

Targeted retroviral transduction of c-kit+ hematopoietic cells using novel ligand display technology

Gene therapy for a wide variety of disorders would be greatly enhanced by the development of vectors that could be targeted for gene delivery to specific populations of cells. We describe here high-efficiency targeted transduction based on a novel targeting strategy that exploits the ability of retroviruses to incorporate host cell proteins into the surface of the viral particle as they bud through the plasma membrane. Ecotropic retroviral particles produced in cells engineered to express the membrane-bound form of stem cell factor (mbSCF) transduce both human cell lines and primary cells with high efficiency in a strictly c-kit (SCF receptor)-dependent fashion. The availability of efficient targeted vectors provides a platform for the development of a new generation of therapies using in vivo gene delivery.     

Upgraded CRISPR/Cas9 tools for tissue-specific mutagenesis in Drosophila

CRISPR/Cas9 has emerged as a powerful technology for tissue-specific mutagenesis. However, tissue-specific CRISPR/Cas9 tools currently available in Drosophila remain deficient in three significant ways. First, many existing gRNAs are inefficient, such that further improvements of gRNA expression constructs are needed for more efficient and predictable mutagenesis in both somatic and germline tissues. Second, it has been difficult to label mutant cells in target tissues with current methods. Lastly, application of tissue-specific mutagenesis at present often relies on Gal4-driven Cas9, which hampers the flexibility and effectiveness of the system. Here, we tackle these deficiencies by building upon our previous CRISPR-mediated tissue-restricted mutagenesis (CRISPR-TRiM) tools. First, we significantly improved gRNA efficiency in somatic tissues by optimizing multiplexed gRNA design. Similarly, we also designed efficient dual-gRNA vectors for the germline. Second, we developed methods to positively and negatively label mutant cells in tissue-specific mutagenesis by incorporating co-CRISPR reporters into gRNA expression vectors. Lastly, we generated genetic reagents for convenient conversion of existing Gal4 drivers into tissue-specific Cas9 lines based on homology-assisted CRISPR knock-in. In this way, we expand the choices of Cas9 for CRISPR-TRiM analysis to broader tissues and developmental stages. Overall, our upgraded CRISPR/Cas9 tools make tissue-specific mutagenesis more versatile, reliable, and effective in Drosophila. These improvements may be also applied to other model systems.

The ability to characterize gene function in a tissue-specific manner has been critical for studying developmental and disease mechanisms of essential genes. The CRISPR/Cas9 system has recently provided powerful tools for inducing tissue-specific gene loss of function (LOF). In this system, the endonuclease Cas9 is directed by a small guide RNA (gRNA) to a specific DNA sequence to create double-strand breaks (DSBs) (1). In the absence of homologous repair templates, DSBs are primarily repaired by nonhomologous end joining, an error-prone process that often introduces mutations in the form of insertions or deletions (indels) (2, 3). Because the protospacer adjacent motif required for Cas9 action is ubiquitous in genomes (1, 4), by targeting the expression of Cas9 and gRNAs to specific tissues, mutations can be induced at virtually any gene in a tissue-specific manner. However, current tissue-specific CRISPR/Cas9 tools in Drosophila are still deficient in three areas, limiting the power of CRISPR/Cas9 in analyzing gene functions in broad tissues and biological processes.     

Tumor vascular targeting therapy with viral vectors

Tumor angiogenesis is crucial for the progression and metastasis of cancer. The vasculature of tumor tissue is different from normal vasculature. Therefore, tumor vascular targeting therapy could represent an effective therapeutic strategy with which to suppress both primary tumor growth and tumor metastasis. The use of viral vectors for tumor vascular targeting therapy is a promising strategy based on the unique properties of viral vectors. In order to circumvent the potential problems of antiviral neutralizing antibodies, poor access to extravascular tumor tissue, and toxicities to normal tissue, viral vectors need to be modified to target the tumor endothelial cells. Viral vectors that could be used for tumor vascular targeting therapy include adenoviral vectors, adeno-associated viral vectors, retroviral vectors, lentiviral vectors, measles virus, and herpes simplex viral vectors. In this review, we will summarize the strategies available for targeting viral vectors for tumor vascular targeting therapy.     

Screening phage display libraries for organ-specific vascular immunotargeting in vivo

The molecular diversity of the luminal endothelial cell surface arising in vivo from local variations in genetic expression and tissue microenvironment may create opportunities for achieving targeted molecular imaging and therapies. Here, we describe a strategy to identify probes and their cognate antigens for targeting vascular endothelia of specific organs in vivo. We differentially screen phage libraries to select organ-targeting antibodies by using luminal endothelial cell plasma membranes isolated directly from tissue and highly enriched in natively expressed proteins exposed to the bloodstream. To obviate liver uptake of intravenously injected phage, we convert the phage-displayed antibodies into scFv-Fc fusion proteins, which then are able to rapidly target select organ(s) in vivo as visualized directly by gamma-scintigraphic whole-body imaging. Mass spectrometry helps identify the antigen targets. This comprehensive strategy provides new promise for harnessing the power of phage display for mapping vascular endothelia natively in tissue and for achieving vascular targeting of specific tissues in vivo.     

Selective esterase-ester pair for targeting small molecules with cellular specificity

Small molecules are important tools to measure and modulate intracellular signaling pathways. A longstanding limitation for using chemical compounds in complex tissues has been the inability to target bioactive small molecules to a specific cell class. Here, we describe a generalizable esterase-ester pair capable of targeted delivery of small molecules to living cells and tissue with cellular specificity. We used fluorogenic molecules to rapidly identify a small ester masking motif that is stable to endogenous esterases, but is efficiently removed by an exogenous esterase. This strategy allows facile targeting of dyes and drugs in complex biological environments to label specific cell types, illuminate gap junction connectivity, and pharmacologically perturb distinct subsets of cells. We expect this approach to have general utility for the specific delivery of many small molecules to defined cellular populations.     

Adenovirus-mediated gene transfer

The introduction of foreign genetic material into somatic cells in intact organisms is an important investigational technique that holds considerable promise as a therapeutic tool. Although successful gene transfer has been achieved by the use of both cell-mediated and direct techniques, most strategies have been limited either by constraints on the type, accessibility, and growth state of the target cell population, or by the low efficiency of genetic modification. Among the available vectors for somatic cell gene transfer, recombinant adenoviruses have several properties that make them particularly attractive for direct, in vivo introduction of foreign genes into adult animals and people. Simple techniques for the efficient generation and propagation of recombinant adenoviruses have been developed, and early studies employing recombinant adenoviral vectors demonstrate their potential for broad experimental and eventual clinical application. To exploit this potential properly, a number of important issues, including the efficiency of genetic modification of a targeted cell population, stability of foreign gene expression, effects of host immune response, and cell-type specific targeting of gene transfer, remain to be addressed.     

Nanoparticle delivery systems,general approaches,and their implementation in multiple myeloma

Multiple myeloma (MM) is a hematological malignancy that remains incurable, with relapse rates >90%. The main limiting factor for the effective use of chemotherapies in MM is the serious side effects caused by these drugs. The emphasis in cancer treatment has shifted from cytotoxic, non‐specific chemotherapies to molecularly targeted and rationally designed therapies showing greater efficacy and fewer side effects. Traditional chemotherapy has shown several disadvantages such as lack of targeting capabilities, systemic toxicity, and side effects; low therapeutic index, as well as most anticancer drugs, has poor water solubility. Nanoparticle delivery systems (NPs) are capable of targeting large doses of chemotherapies into the target area while sparing healthy tissues, overcoming the limitations of traditional chemotherapy. Here, we review the current state of the art in nanoparticle‐based strategies designed to treat MM. Many nanoparticle delivery systems have been studied for myeloma using non‐targeted NPs (liposomes, polymeric NPs, and inorganic NPs), triggered NPs, as well as targeted NPs (VLA‐4, ABC drug transporters, bone microenvironment targeting). The results in preclinical and clinical studies are promising; however, there remains much to be learned in the emerging field of nanomedicine in myeloma.     

Design of Nano Vectors for Therapy and Imaging of Cardiovascular Diseases

Cardiovascular diseases are widely prevalent in western societies, and their associated costs number in the billions of dollars and affect millions of patients each year. Nanovectors targeted to tissues involved in cardiovascular diseases offer great opportunities to improve cardiovascular treatment through their imaging and drug delivery capabilities. Vascular-targeted imaging particles may permit the early identification of atherosclerosis, discriminate between stable and vulnerable atherosclerotic plaques, or guide surgeons as they work on fragile vasculature. Tailored therapeutic nanoparticles may provide safer, more efficient and effective intervention through localization and release of encapsulated therapeutics. Nanovector design involves numerous considerations such as fabrication material, particle size, and surface-modification with ligands for targeting and increasing blood circulation times. Complex blood rheology may affect the efficiency with which dissimilarsized particles target ligand receptors associated with disease. Additionally, the intended use of a nanovector is a critical factor in its design as some materials with poor drug-loading qualities or release kinetics may be suitable for imaging purposes only. Overall, vectors targeted to the vasculature will need to be efficient in avoiding blood clearance, honing to the target location, and binding at the desired site.