Nanotechnology for targeted cancer therapy

Cancer nanotechnology is currently under intense development for applications in cancer imaging, molecular diagnosis and targeted therapy. The basic rationale is that nanometer-sized particles, such as biodegradable micelles, semiconductor quantum dots and iron oxide nanocrystals, have functional or structural properties that are not available from either molecular or macroscopic agents. When linked with biotargeting ligands, such as monoclonal antibodies, peptides or small molecules, these nanoparticles are used to target malignant tumors with high affinity and specificity. In the 'mesoscopic' size range of 5-100 nm in diameter, nanoparticles also have large surface areas and functional groups for conjugating to multiple diagnostic (e.g., optical, radioisotopic or magnetic) and therapeutic (e.g., anticancer) agents. Recent advances have led to multifunctional nanoparticle probes for molecular and cellular imaging, nanoparticle drugs for targeted therapy, and integrated nanodevices for early cancer detection and screening. These developments have opened exciting opportunities for personalized oncology in which cancer detection, diagnosis and therapy are tailored to each individual's molecular profile, and also for predictive oncology, in which genetic/molecular information is used to predict tumor development, progression and clinical outcome.     

Vascular targeted nanoparticles for imaging and treatment of brain tumors.

PURPOSE: Development of new therapeutic drug delivery systems is an area of significant research interest. The ability to directly target a therapeutic agent to a tumor site would minimize systemic drug exposure, thus providing the potential for increasing the therapeutic index. EXPERIMENTAL DESIGN: Photodynamic therapy (PDT) involves the uptake of a sensitizer by the cancer cells followed by photoirradiation to activate the sensitizer. PDT using Photofrin has certain disadvantages that include prolonged cutaneous photosensitization. Delivery of nanoparticles encapsulated with photodynamic agent specifically to a tumor site could potentially overcome the drawbacks of systemic therapy. In this study, we have developed a multifunctional polymeric nanoparticle consisting of a surface-localized tumor vasculature targeting F3 peptide and encapsulated PDT and imaging agents. RESULTS: The nanoparticles specifically bound to the surface of MDA-435 cells in vitro and were internalized conferring photosensitivity to the cells. Significant magnetic resonance imaging contrast enhancement was achieved in i.c. rat 9L gliomas following i.v. nanoparticle administration. Serial magnetic resonance imaging was used for determination of pharmacokinetics and distribution of nanoparticles within the tumor. Treatment of glioma-bearing rats with targeted nanoparticles followed by PDT showed a significant improvement in survival rate when compared with animals who received PDT after administration of nontargeted nanoparticles or systemic Photofrin. CONCLUSIONS: This study reveals the versatility and efficacy of the multifunctional nanoparticle for the targeted detection and treatment of cancer.     

Nanomedicine for drug delivery and imaging: a promising avenue for cancer therapy and diagnosis using targeted functional nanoparticles

The diagnosis and treatment of cancer or tumor at the cellular level will be greatly improved with the development of techniques that enable the delivery of analyte probes and therapeutic agents into cells and cellular compartments. Organic and inorganic nanoparticles that interface with biological systems have recently attracted widespread interest in the fields of biology and medicine. The new term nanomedicine has been used recently. Nanoparticles are considered to have the potential as novel intravascular or cellular probes for both diagnostic (imaging) and therapeutic purposes (drug/gene delivery), which is expected to generate innovations and play a critical role in medicine. Target-specific drug/gene delivery and early diagnosis in cancer treatment is one of the priority research areas in which nanomedicine will play a vital role. Some recent breakthroughs in this field recently also proved this trend. Nanoparticles for drug delivery and imaging have gradually been developed as new modalities for cancer therapy and diagnosis. In this article, we review the significance and recent advances of gene/drug delivery to cancer cells, and the molecular imaging and diagnosis of cancer by targeted functional nanoparticles.     

Recent advances in nanooncology

Nanobiotechnology is playing an important role in advances in oncology and currently nanooncology is the most important chapter of nanomedicine. Nanobiotechnologies have refined molecular diagnostics and enabled early detection of tumors and discovery of biomarkers of cancer. Various nanoparticles are the basis of diagnostic assays for cancer as well as contrast materials for MRI. Nanobiotechnology is facilitating the discovery and development of drugs for cancer. Several nanobiotechnologies, mostly based on nanoparticles, have been described to facilitate drug delivery in cancer, which is important for optimizing the effect of drugs and reducing toxic side effects. Nanoparticles for targeted drug delivery in cancer enable combination of diagnostics and therapeutics and act as adjuncts to hyperthermia and photodynamic therapy. Several applications of nanobiotechnology in cancer surgery include use of nanoparticles to visualize tumor during surgery as aid to proper removal, and nanorobotics for remotely controlled diagnostics combined with therapeutics. Selected new developments in nanooncology have been highlighted in this review and these point to an important role in development of personalized oncology.     

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。     

Emerging use of nanoparticles in diagnosis and treatment of breast cancer

The biological application of nanoparticles is a rapidly developing area of nanotechnology that raises new possibilities in the diagnosis and treatment of human cancers. In cancer diagnostics, fluorescent nanoparticles can be used for multiplex simultaneous profiling of tumour biomarkers and for detection of multiple genes and matrix RNA with fluorescent in-situ hybridisation. In breast cancer, three crucial biomarkers can be detected and accurately quantified in single tumour sections by use of nanoparticles conjugated to antibodies. In the near future, the use of conjugated nanoparticles will allow at least ten cancer-related proteins to be detected on tiny tumour sections, providing a new method of analysing the proteome of an individual tumour. Supermagnetic nanoparticles have exciting possibilities as contrast agents for cancer detection in vivo, and for monitoring the response to treatment. Several chemotherapy agents are available as nanoparticle formulations, and have at least equivalent efficacy and fewer toxic effects compared with conventional formulations. Ultimately, the use of nanoparticles will allow simultaneous tumour targeting and drug delivery in a unique manner. In this review, we give an overview of the use of clinically applicable nanoparticles in oncology, with particular focus on the diagnosis and treatment of breast cancer.     

Utility of MRI contrast agents for diagnosis and treatment follow-up in cancer

Numerous and diverse contrast agents are available in MRI. Their use is focused on two directions : microcirculation imaging and cell capture imaging. Microcirculation imaging uses gadolinium chelates and technical advances in MRI. It quantifies perfusion and capillary permeability applying a physiological analysis to the tissue enhancement curve. Cellular imaging uses labeled cells as contrast agents ; the cells can be labeled in vitro or in vivo. The roles of imaging in cancer are numerous. For diagnosis, detection is improved, particularly for liver metastases with the development of cellular imaging and liver-specific contrast agents. Cellular imaging opens promising perspectives for cellular therapy. Microcirculation imaging characterizes tumors more specifically, particularly in breast imaging. Regarding treatment follow-up, the impact of imaging is considerable. Microcirculation imaging predicts treatment response even before initiation of therapy. During treatment, it allows a more complete evaluation taking into account physiological parameters, better adapted to monitor therapies currently in development, such as anti-angiogenic drugs. Therapeutic effects can be detected earlier, before morphological changes. Cellular imaging offers new prospects to monitor cellular therapy. The use of MRI contrast agents is moving towards the coupling of functional to morphological analysis. This constitutes a new approach perfectly adapted to diagnosis and therapy follow-up in oncology.     

Will nanotechnology influence targeted cancer therapy?

The rapid development of techniques that enable synthesis (and manipulation) of matter on the nanometer scale and the development of new nanomaterials will play a large role in disease diagnosis and treatment, specifically in targeted cancer therapy. Targeted nanocarriers are an intriguing means to selectively deliver high concentrations of cytotoxic agents or imaging labels directly to the cancer site. Often, solubility issues and an unfavorable biodistribution can result in a suboptimal response of novel agents even though they are very potent. New nanoparticulate formulations allow simultaneous imaging and therapy ("theranostics"), which can provide a realistic means for the clinical implementation of such otherwise suboptimal formulations. In this review, we did not attempt to provide a complete overview of the rapidly enlarging field of nanotechnology in cancer; rather, we presented properties specific to nanoparticles and examples of their uses, which show their importance for targeted cancer therapy.     

Targeted therapy in non-small cell lung cancer: myth or reality

In oncology, the term 'targeted therapy' is used to describe drugs that target only the cancer cells and spare normal cells thereby reducing host toxicity while simultaneously increasing the eradication of cancer. Trastuzumab and imatinib are well known examples of successful targeted therapy. Newer agents like gefitinib and cetuximab offer hope that targeted therapy also may yield therapeutic benefit for such refractory malignancies as lung and colon cancers. One of many remaining challenges is to identify markers, molecular or clinical, that predict for responsiveness to a specific targeted therapy (e.g. HER2/neu positivity and trastuzumab responsiveness). However, using emerging technologies such as gene or protein profiling, it may be possible to predict a tumor's responsiveness to a particular targeted therapy based on its molecular signature. If true, clinicians might then possess the ability to predict a tumor's clinical behavior and shape its density through specific, targeted interventions.     

Molecular imaging and personalized medicine: an uncertain future

The Food and Drug Administration has described their view of the role that imaging will play in the approval, and perhaps postapproval, use of new therapeutic drugs. The therapeutic drug industry and regulatory authorities have turned to imaging to help them achieve better efficiency and efficacy. We must extend this initiative by demonstrating that molecular imaging can also improve the efficiency and efficacy of routine treatment with these same drugs. The role of molecular imaging in personalized medicine, using targeted drugs in oncology, is very attractive because of the regional information that it provides (in many cases, with a functional or dynamic component), which cannot be provided by in vitro methods ("regional proteomics"). There is great potential for molecular imaging to play a major role in selecting appropriate patients and providing early proof of response, which is critical to addressing the conflict between the high price of treatment and limited reimbursement budgets. This is a new venture in both molecular imaging and targeted drugs. However, there are various regulatory, financial, and practical barriers that must be overcome to achieve this aim, in addition to the normal scientific challenges of drug discovery. There is an urgent need to reduce the cost (i.e., time and money) of developing imaging agents for routine clinical use. The mismatch between the current regulations and personalized medicine includes molecular imaging and requires the engagement of the regulatory authorities to correct. Therapeutic companies must be engaged early in the development of new targeted drugs and molecular imaging agents to improve the fit between the two drug types. Clinical trials must be performed to generate data that not only shows the efficacy of imaging plus therapy in a medical sense, but also in a financial sense. Molecular imaging must be accepted as not just good science but also as central to routine patient management in the personalized medicine of the future.     

Nanooncology: The future of cancer diagnosis and therapy

In recent years, there has been an unprecedented expansion in the field of nanomedicine with the development of new nanoparticles for the diagnosis and treatment of cancer. Nanoparticles have unique biological properties given their small size and large surface area‐to‐volume ratio, which allows them to bind, absorb, and carry compounds such as small molecule drugs, DNA, RNA, proteins, and probes with high efficiency. Their tunable size, shape, and surface characteristics also enable them to have high stability, high carrier capacity, the ability to incorporate both hydrophilic and hydrophobic substances and compatibility with different administration routes, thereby making them highly attractive in many aspects of oncology. This review article will discuss how nanoparticles are able to function as carriers for chemotherapeutic drugs to increase their therapeutic index; how they can function as therapeutic agents in photodynamic, gene, and thermal therapy; and how nanoparticles can be used as molecular imaging agents to detect and monitor cancer progression. CA Cancer J Clin 2013;63:395‐418 . ^© 2013 American Cancer Society, Inc.     

New science-based endpoints to accelerate oncology drug development

Although several new oncology drugs have reached the market, more than 80% of drugs for all indications entering clinical development do not get marketing approval, with many failing late in development often in Phase III trials, because of unexpected safety issues or difficulty determining efficacy, including confounded outcomes. These factors contribute to the high costs of oncology drug development and clearly show the need for faster, more cost-effective strategies for evaluating oncology drugs and better definition of patients who will benefit from treatment. Remarkable advances in the understanding of neoplastic progression at the cellular and molecular levels have spurred the discovery of molecularly targeted drugs. This progress along with advances in imaging and bioassay technologies are the basis for describing and evaluating new biomarker endpoints as well as for defining other biomarkers for identifying patient populations, potential toxicity, and providing evidence of drug effect and efficacy. Definitions and classifications of these biomarkers for use in oncology drug development are presented in this paper. Science-based and practical criteria for validating biomarkers have been developed including considerations of mechanistic plausibility, available methods and technology, and clinical feasibility. New promising tools for measuring biomarkers have also been developed and are based on genomics and proteomics, direct visualisation by microscopy (e.g., confocal microscopy and computer-assisted image analysis of cellular features), nanotechnologies, and direct and remote imaging (e.g., fluorescence endoscopy and anatomical, functional and molecular imaging techniques). The identification and evaluation of potential surrogate endpoints and other biomarkers require access to and analysis of large amounts of data, new technologies and extensive research resources. Further, there is a requirement for a convergence of research, regulatory and drug developer thinking - an effort that will not be accomplished by individual scientists or research institutions. Research collaborations are needed to foster development of these new endpoints and other biomarkers and, in the United States (US), include ongoing efforts among the Food and Drug Administration (FDA), National Cancer Institute (NCI), academia, and industry.     

Biological agents alone or in combination as second-line therapy in advanced non-small-cell lung cancer: systematic review of randomized studies

The only approved agents for second-line therapy in unselected non-small-cell lung cancer are docetaxel and pemetrexed (chemotherapies) and erlotinib (targeted therapies). Several new molecular drugs have now entered clinical trials and are being compared with approved agents (e.g., vandetanib). Alternative pathways are also being explored to overcome resistance to established agents (c-MET and ALK inhibitors), and predictive factors are now crucial for the selection of drug and of patients (e.g., EGFR mutations). Better patient selection permits second-line treatment to be tailored according to disease identity, which confers a particular benefit in certain subgroups of patients. In this review, the authors examine existing trials comparing targeted therapies with the standard of care as second-line therapy for advanced non-small-cell lung cancer.     

纳米粒作为抗肿瘤药物载体的研究进展

纳米粒载药系统可以改变药物的体内分布特征, 具有缓控释和靶向给药特性, 增加药物的稳定性, 提高药物的生物利用度。纳米粒的靶向选择性可以通过增强渗透滞留效应(EPR)、偶联特定的配体, 或由于生理条件如pH值、温度等的改变实现。纳米粒可以由多种材料制备并且用于包合各种化学治疗药物以降低药物不良反应, 其中, 磁性纳米粒作为抗肿瘤药物载体不仅可以用来治疗还能用于成像诊断。本文综述了纳米粒被动靶向、主动靶向、物理化学靶向给药系统用于抗肿瘤药物载体的研究进展。      

The diverse and complex roles of radiation on cancer treatment: therapeutic target and genome maintenance

Cancer is a genetic disease, grows exponentially with the development of intrinsic and acquired treatment resistance. Past decade has witnessed a considerable progress towards the treatment and understanding of proposed hallmarks of cancer and together with advances in early detection and various treatment modalities. Radiation therapy is an integral part of cancer treatment armamentarium. In developed countries more than half of all cancer patients receive radiation therapy during their course of illness. Although radiation damages both cancer and normal cells, the goal of radiation therapy is to maximize the radiation dose to abnormal cancer cells while minimizing exposure to normal cells, which is adjacent to cancer cells or in the path of radiation. In recent years, life expectancy increases among cancer patients and this increase is due to the results of early diagnosis, screening efforts, improved treatments and with less late effects mostly secondary cancer development. Therefore, cancer survivorship issues have been gaining prominence in the area of radiation oncology research. Understanding the tradeoff between the expected decreases in normal tissue toxicity resulting from an improved radiation dose distribution to the targeted site is an increasingly pertinent, yet needed attention and research in the area of radiation oncology. In recent years, a number of potential molecular targets that involve either with radiation increased tumor cell killing or protecting normal cells have been identified. For clinical benefits, translating these findings to maximize the toxicity of radiation on tumor cells while safeguarding early or late normal cell toxicities using molecular targeted radioprotectors will be useful in radiation treatment.     

Personalized therapy in endometrial cancer: challenges and opportunities

Early stage endometrial cancer is generally curable. However, progress in the treatment of advanced and recurrent endometrial cancer has been limited. This has led to a shift from the use of traditional chemotherapeutic agents and radiotherapy regimens to the promising area of targeted therapy, given the large number of druggable molecular alterations found in endometrial cancer. To maximize the effects of directed targeted therapy, careful molecular characterization of the endometrial tumor is necessary. This represents an important difference in the use of targeted therapy vs. traditional chemotherapy or radiation treatment. This review will discuss relevant pathways to target in endometrial cancer as well as the challenges that arise during development of a personalized oncology approach.     

MR and iron magnetic nanoparticles. Imaging opportunities in preclinical and translational research

Ultrasmall superparamagnetic iron oxide nanoparticles and magnetic resonance imaging provide a non-invasive method to detect and label tumor cells. These nanoparticles exhibit unique properties of superparamagnetism and can be utilized as excellent probes for magnetic resonance imaging. Most work has been performed using a magnetic resonance scanner with high field strength up to 7 T. Ultrasmall superparamagnetic iron oxide nanoparticles may represent a suitable tool for labeling molecular probes that target specific tumor-associated markers for in vitro and in vivo detection by magnetic resonance imaging. In our study, we demonstrated that magnetic resonance imaging at 1.5 T allows the detection of ultrasmall superparamagnetic iron oxide nanoparticle conjugated antibody specifically bound to human tumor cells in vitro and in vivo, and that the magnetic resonance signal intensity correlates with the concentration of ultrasmall superparamagnetic iron oxide nanoparticle antibody used and with the antigen density at the cell surface. The experiments were performed using two different means of targeting: direct and indirect magnetic tumor targeting. The imaging of tumor antigens using immunospecific contrast agents is a rapidly evolving field, which can potentially aid in early disease detection, monitoring of treatment efficacy, and drug development. Cell labeling by iron oxide nanoparticles has emerged as a potentially powerful tool to monitor trafficking of a large number of cells in the cell therapy field. We also studied the labeling of natural killer cells with iron nanoparticles to a level that would allow the detection of their signal intensity with a clinical magnetic resonance scanner at 1.5 T. Magnetic resonance imaging and iron magnetic nanoparticles are able to increase the accuracy and the specificity of imaging and represent new imaging opportunities in preclinical and translational research.     

Molecular targeting of the lymphovascular system for imaging and therapy

Progress toward targeting cancer cells is a multi-disciplinary endeavor. In addition to the surgical and oncology specialties, radiologists collaborate with mathematicians, computer scientists, and physicists, in a constant effort to incrementally improve upon the current imaging modalities. Recently, radiologists have formed collaborations with molecular biologists and chemists in order to develop molecular agents that target cancer cells via receptor-substrate or specific physiochemical interactions. In this review, we summarize selected efforts toward molecular targeting of the lymphovascular system. Standard imaging modalities, positron emission tomography, single photon emission tomography, and ultrasound, are reviewed as well as, the targeted introduction of substances for endolymphatic therapy. We also review the current status of sentinel lymph node mapping with radiocolloids and the application of molecular targeting for the development of a radiopharmaceutical specifically designed for sentinel lymph node mapping. Presented as Session II of the First International Symposium on Cancer Metastasis and the Lymphovascular System. April 28–30, 2005, San Francisco, CA; Chaired by by David R. Vera.     

Novel challenges in exploring peptide ligands and corresponding tissue-specific endothelial receptors

The structural and molecular diversity of vascular endothelium may depend on the functional state and tissue localisation of its cells. Tumour vasculature expresses a number of molecular markers that distinguish it from normal vasculature. In cancer, the determinant of specific tumour vasculature heterogeneity is, in part, dictated by dysregulated expression of tumour-derived angiogenic factors. The identification of molecular 'addresses' on the surface of tumour vasculature has significantly contributed to the selection of targets, which have been used for delivering therapeutic and imaging agents in cancer. Cytotoxic drug, pro-apoptotic peptides, protease inhibitors, and gene therapy vectors have been successfully linked to peptides and delivered to tumour sites with an improved experimental therapy. Different diagnostic and therapeutic compounds can be efficiently targeted to specific receptors on vascular endothelial cells; the development of ligand-directed vector tools may promote systemic targeted gene delivery. Here, we review the very recent advances in the identification of peptide ligands and their corresponding tissue-specific endothelial receptors through the phage display technology with emphasis on ligand-directed delivery of therapeutic agents and targeted gene therapy.     

肾细胞癌靶向治疗的临床研究进展

肾细胞癌（RCC ）是难治的恶性肿瘤之一,对放化疗不敏感,免疫治疗方式有效率一直徘徊于10% ～15% 。随着对肿瘤分子机制的深入以及多种分子靶向药物的深入研究,靶向治疗取得了重大进展。肾癌的发病机制与VHL 、Ras、PTEN等抑癌基因的突变有关,可诱导其下游的蛋白激酶受体表达异常。而蛋白激酶抑制剂可以通过干扰细胞内信号传导通路及改变肿瘤细胞微环境而影响肿瘤细胞的存活和增殖,是当前研发最集中的靶向治疗药物之一。近年来,多项靶向药物临床试验的可喜结果为转移性肾细胞癌（mRCC）治疗带来了新希望。本文就2009年NCCN 肿瘤治疗指南中介绍的舒尼替尼、索拉非尼、Temsirolimus、贝伐单抗等四种药物在肾细胞癌靶向治疗方面的临床研究最新进展展开综述。