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Human CIK Cells Loaded with Au Nanorods as a Theranostic Platform for Targeted Photoacoustic Imaging and Enhanced Immunotherapy and Photothermal Therapy
Abstract
How to realize targeted photoacoustic imaging, enhanced immunotherapy, and photothermal therapy of gastric cancer has become a great challenge. Herein, we reported for the first time that human cytokine-induced killer cells (CIK) loaded with gold nanorods were used for targeted photoacoustic imaging, enhanced immunotherapy, and photothermal therapy of gastric cancer. Silica-modified gold nanorods were prepared; then incubated with human cytokine-induced killer cells (CIK), resultant human CIK cells loaded with Au nanorods were evaluated for their cytotoxicity, targeted ability of gastric cancer in vitro and in vivo, immunotherapy, and photothermal therapy efficacy. In vitro cell experiment shows that human CIK cells labeled with gold nanorods actively target gastric cancer MGC803 cells, inhibit growth of MGC803 cells by inducing cell apoptosis, and kill MGC803 cells under low power density near-infrared (NIR) laser treatment (808-nm continuous wave laser, 1.5 W/cm(2), 3 min). In vivo experiment results showed that human CIK cells labeled with gold nanorods could target actively and image subcutaneous gastric cancer vessels via photoacoustic imaging at 4 h post-injection, could enhance immunotherapy efficacy by up-regulating cytokines such as IL-1, IL-12, IL-2, IL-4, IL-17, and IFN-γ, and kill gastric cancer tissues by photothermal therapy via direct injection into tumor site under near-infrared (NIR) laser irradiation. High-performance human CIK cells labeled with Au nanorods are a good novel theranostic platform to exhibit great potential in applications such as tumor-targeted photoacoustic imaging, enhanced immunotherapy, and photothermal therapy in the near future.
... Any substance endogenous or exogenous that can suppress an immune response or boost it, is known as biological response modifier such as interferon, interleukin (IL), colony-stimulating factors (erythropoietin, thrombopoietin, GM-CSF), TNF-α, antibodies, differentiating agents (tretinoin, bexarotene), angiogenic inhibitors, vaccines, thalidomide and its congeners [4]. Cancer immunotherapy can be enhanced using nanocarriers by: delivering supportive drugs to T cells in circulation, concentrating immunostimulatory compounds in the immunosuppressive tumor microenvironment, stimulating T cells directly as artificial antigen-presenting cells, and delivering adjuvants and cancer vaccine antigens to dendritic cells [5][6][7]. ...
... They first prepared silica-modified Au nanorods and then incubated with human CIK cells that resulted in formation of human CIK cells loaded with Au nanorods. Those human CIK cells loaded with Au nanorods were further evaluated for their immunotherapy, photothermal therapy efficacy, cytotoxicity and targeted ability of gastric cancer in vitro and in vivo [6]. Cancer nanomedicine has provided solution to the number of problems that researchers were experiencing in traditional immunotherapy [6]. ...
... Those human CIK cells loaded with Au nanorods were further evaluated for their immunotherapy, photothermal therapy efficacy, cytotoxicity and targeted ability of gastric cancer in vitro and in vivo [6]. Cancer nanomedicine has provided solution to the number of problems that researchers were experiencing in traditional immunotherapy [6]. Likewise, another study observed enhanced immunotherapy and photothermal therapy efficacy of human CIK cells labeled with PEGylated gold nanoprisms (Au NPRs) in vivo [7]. ...
Artificially boosting body's immune response is one of the most exciting, effective and promising advancement in the treatment of cancers. Cancer immunotherapeutics consist of variety of treatment approaches such as cytokine therapy, adoptive T-cell transfer therapy, and antibodies that stimulate innate and adoptive immune responses. In addition to this, Development of HPV vaccine has paved way towards the development of other cancer vaccines. Checkpoint blockade inhibitors e.g, anti-PD-1 and anti-CTLA-4, CAR-T cell therapy, and monoclonal antibodies are emerging as other major breakthroughs that are highly effective against cancer. This review addresses the current status of immunotherapeutic strategies against cancer and provides baseline data for future research.
... And the targeting characteristic of CIK cells has an extensive adaptability feature, which can be applied to clinical therapies of many kinds of cancers. However, up to date, few reports have demonstrated that tumor patients with middle and late stages can be cured completely by using DCs and CIK immunotherapies [17]- [22]. How to enhance CIK therapeutic effects has become a challengeable problem. ...
... Human CIK cells were expanded from peripheral blood collected from the healthy people in our Laboratory [17]- [22]. All individuals provided informed consent for blood donation according to a protocol approved by the internal review board and ethic committee. ...
... Some reports show that human CIK cells can target in vivo tumor tissues [17]- [22]. However, a lot of reports showed that CIK cells kill tumor cells via releasing some special factors [47,48]. ...
How to enhance the therapeutic efficacy of human cytokine induced killers cell (CIK) has become a great challenge. Herein, we report for the first time that human CIK cells loaded with gold nanoprisms were successfully used for targeted photoacoustic imaging, enhanced immunotherapy and photothermal therapy of gastric cancer in vivo. Gold nanoprisms were synthesized and modified with PEG; human CIK cells were prepared and incubated with PEGylated gold nanoprisms (Au GNPrs), and then the effects of human CIK cells labeled with Au NPrs on gastric cancer MGC 803 cells were evaluated and further used for targeted photoacoustic imaging, immunotherapy and photothermal therapy of gastric cancer in vivo in mice models. Results showed that PEGylated Au NPrs could be uptaken high-efficiently by human CIK cells, resultant human CIK cells labeled with AuNPrs could inhibit the growth of gastric cancer MGC 803 cells actively by induced apoptosis and G1 phase arrest, and actively target and accumulate the tumor sites in gastric cancer-bearing nude mice. Enhanced synergistic therapeutic efficacy was demonstrated with the maximal inhibition of tumor through a combination of CIK cells-based immunotherapy for three days and then a continuous gold nanoprisms-based photothermal therapy. In conclusion, human CIK cells labeled with PEGylated Au NPrs can target gastric cancer cells in vivo, enhance immunotherapy and photothermal therapy efficacy, and have a great potential in applications such as targeted imaging, immunotherapy and photothermal therapy of gastric cancer in the near future. © 2016 Jingjing Zhang, Fangfang Xia, Yao Yang, Caixia Yue, Chunlei Zhang, Yuming Yang, Lijun Ma, Gabriel Alfranca, Yanlei Liu, Yafei Hou, Weilin Jin, Jian Ni, Jesus Martinez de la Fuente and Daxiang Cui.
... Irradiation of suspensions (5-160 µg/mL of Au-PEG-glucose for 10 min) with 808 nm (P = 0.5 W/cm 2 ) led to a maximum temperature increase of 20 • C. Next, Ma et al. [25] reported CTAC-capped AuNTrs with mPEG-SH coating (edge length 55 nm and thickness: 20 nm) and absorption peak at 669 nm. Laser irradiation with 650 nm-laser at P = 2 W/cm 2 and nanoparticles concentration 5-40 µg/mL yield ∆T max = 40 • C. Zhang et al. [26] prepared 110 nm AuNTrs, functionalized with HS-PEG-Nanomaterials 2021, 11, 912 7 of 11 COOH with absorption peaks at 530 and 800-900 nm. Irradiation with 808 nm laser (P = 1 W/cm 2 , t = 750 s) and nanoparticles concentration 50 µg/mL resulted in ∆T =30 • C. All three articles reported AuNTrs with size > 50 nm and heating rates similar to our ultra-small AuAgNTrs. ...
... Laser irra 650 nm-laser at P = 2 W/cm 2 and nanoparticles concentration 5-40 μg/mL yiel °C. Zhang et al. [26] prepared 110 nm AuNTrs, functionalized with HS-PEGabsorption peaks at 530 and 800-900 nm. Irradiation with 808 nm laser (P = 750 s) and nanoparticles concentration 50 μg/mL resulted in ΔT =30 °C. ...
Photothermal therapy has always been a very attractive anti-cancer strategy, drawing a lot of attention thanks to its excellent performance as a non-invasive and pretty safe technique. Lately, nanostructures have become the main characters of the play of cancer therapy due to their ability to absorb near-infrared radiation and efficient light-to-heat conversion. Here we present the synthesis of polyethylene glycol (PEG)-stabilized hybrid ultrasmall (<20 nm) gold–silver nanotriangles (AuAgNTrs) and their application in photothermal therapy. The obtained AuAgNTrs were deeply investigated using high-resolution transmission electron microscopy (HR-TEM). The cell viability assay was performed on U-87 glioblastoma multiforme cell model. Excellent photothermal performance of AuAgNTrs upon irradiation with NIR laser was demonstrated in suspension and in vitro, with >80% cell viability decrease already after 10 min laser irradiation with a laser power P = 3W/cm2 that was proved to be harmless to the control cells. Moreover, a previous cell viability test had shown that the nanoparticles themselves were reasonably biocompatible: without irradiation cell viability remained high. Herein, we show that our hybrid AuAgNTrs exhibit very exciting potential as nanostructures for hyperthermia cancer therapy, mostly due to their easy synthesis protocol, excellent cell compatibility and promising photothermal features.
... In 1983, William Coley used live bacteria as an adjuvant to target cancer successfully, highlighting the importance of the immune systems relevant to cancer recognition and clearance. Furthermore, the immune system plays an important role in cancer [64]. Tumors can escape immune surveillance through various strategies, such as the secretion of cytokines like vascular endothelial growth factor (VEGF) and Fas-L expression. ...
The management of metastatic cancer is complicated by chemotherapy resistance. This manuscript provides a comprehensive academic review of strategies to overcome chemotherapy resistance in metastatic cancer. The manuscript presents background information on chemotherapy resistance in metastatic cancer cells, highlighting its clinical significance and the current challenges associated with using chemotherapy to treat metastatic cancer. The manuscript delves into the molecular mechanisms underlying chemotherapy resistance in subsequent sections. It discusses the genetic alterations, mutations, and epigenetic modifications that contribute to the development of resistance. Additionally, the role of altered drug metabolism and efflux mechanisms, as well as the activation of survival pathways and evasion of cell death, are explored in detail. The strategies to overcome chemotherapy resistance are thoroughly examined, covering various approaches that have shown promise. These include combination therapy approaches, targeted therapies, immunotherapeutic strategies, and the repurposing of existing drugs. Each strategy is discussed in terms of its rationale and potential effectiveness. Strategies for early detection and monitoring of chemotherapy drug resistance, rational drug design vis-a-vis personalized medicine approaches, the role of predictive biomarkers in guiding treatment decisions, and the importance of lifestyle modifications and supportive therapies in improving treatment outcomes are discussed. Lastly, the manuscript outlines the clinical implications of the discussed strategies. It provides insights into ongoing clinical trials and emerging therapies that address chemotherapy resistance in metastatic cancer cells. The manuscript also explores the challenges and opportunities in translating laboratory findings into clinical practice and identifies potential future directions and novel therapeutic avenues. This comprehensive review provides a detailed analysis of strategies to overcome chemotherapy resistance in metastatic cancer. It emphasizes the importance of understanding the molecular mechanisms underlying resistance and presents a range of approaches for addressing this critical issue in treating metastatic cancer.
... Various types of stem cells have been reported for specific targeting abilities to cancer cells because of their property of cancer homing. The developed immune cells loaded with therapeutic agents can potentially pass into the tumor microenvironment through the blood vessels, and attain combined therapeutic efficiency [216,217]. Currently, gold nanostructures-based theranostics applications had reached a peak in the area of cancer imaging, PTT, and PDT [218]. In recent years, multiple research work has been reported based on the combination of immune therapy with other therapies using various nanoparticles for cancer theranostics. ...
Cancer is one of the most dangerous health problems in the millennium and it is the third foremost human cause of death in the universe. Traditional cancer treatments face several disadvantages and cannot often afford adequate outcomes. It has been exhibited that the outcome of several therapies can be improved when associated with nanostructures. In addition, a modern tendency is being developed in cancer therapy to convert single-modal into multi-modal therapies with the help of existing various nanostructures. Among them, gold is the most successful nanostructure for biomedical applications due to its flexibility in preparation, stabilization, surface modifications, less cytotoxicity, and ease of bio-detection. In the past few decades, gold-based nanomaterials rule cancer treatment applications, currently, gold nanostructures were the leading nanomaterials for synergetic cancer therapies. In this review article, the synthesis, stabilization, and optical properties of gold nanostructures have been discussed. Then, the surface modifications and targeting mechanisms of gold nanomaterials will be described. Recent signs of progress in the application of gold nanomaterials for synergetic cancer therapies such as photodynamic and photo-thermal therapies in combination with other common interventions such as radiotherapy, chemotherapy, and will be reviewed. Also, a summary of the pharmacokinetics of gold nanostructures will be delivered. Finally , the challenges and outlooks of the gold nanostructures in the clinics for applications in cancer treatments are debated. Citation: Sekar, R.; Basavegowda, N.; Thathapudi, J.J.; Sekhar, M.R.; Joshi, P.; Somu, P.; Baek, K.-H.
... SiO 2 -AuNRs were loaded on human cytokineinduced killer (CIK) cells; in vitro and in vivo experiments showed that they targeted gastric cancer cells, enhanced gastric cancer tissue fluorescence and PAI, and improved immuno and photothermal therapies. As a "carrier, " CIK precisely carries functional nanoparticles or drugs to the tumor site to treat various tumors [116]. Amphiphilic poly-TLR7/8a and MMP-2-sensitive R9-PEG form AuNRs-IMQD-R9-PEG that effectively absorb tumorderived protein antigens and directly from nanovaccines in vivo, enhancing the activation of host DCs, thereby amplifying adaptation anti-tumor T cell responses, triggering effector memory immune responses, and activating innate anti-tumor immunity [117]. ...
Gold nanorods (AuNRs) are ideal inorganic nanophotothermal agents with unique characteristics, including local surface plasmon resonance effects, easy scale preparation and functional modification, and good biocompatibility. This review summarizes several recent advances in AuNRs-based photothermal therapy (PTT) research. Functionalized AuNRs photothermal agents have optimized biocompatibility and targeting properties. The multifunctional AuNRs nanoplatform composite structure meets the requirements for synergistic effects of PTT, photoacoustic imaging, and other therapeutic methods. Photothermal therapy with AuNRs (AuNRs-PTT) is widely used to treat tumors and inflammatory diseases; its tumor-targeting, tumor metastasis inhibition, and photothermal tumor ablation abilities have remarkable curative effects. An in-depth study of AuNRs in living systems and the interactions between biological structure, nanomaterial, and near-infrared irradiation could lay the foundation for further clinical research and the broad application of AuNRs in PTT.
... The results also showed CIKAuNR can actively target and image subcutaneous gastric cancer vessels via PIA after 4 h of injection. It can also enhance immunotherapy by regulating cytokines and kill gastric cancer cells by PTT [203]. SPIONs have high and relativities and they can be completely eliminated from the body. ...
Nanomaterials, such as nanoparticles, nanorods, nanosphere, nanoshells, and nanostars, are very commonly used in biomedical imaging and cancer therapy. They make excellent drug carriers, imaging contrast agents, photothermal agents, photoacoustic agents, and radiation dose enhancers, among other applications. Recent advances in nanotechnology have led to the use of nanomaterials in many areas of functional imaging, cancer therapy, and synergistic combinational platforms. This review will systematically explore various applications of nanomaterials in biomedical imaging and cancer therapy. The medical imaging modalities include magnetic resonance imaging, computed tomography, positron emission tomography, single photon emission computerized tomography, optical imaging, ultrasound, and photoacoustic imaging. Various cancer therapeutic methods will also be included, including photothermal therapy, photodynamic therapy, chemotherapy, and immunotherapy. This review also covers theranostics, which use the same agent in diagnosis and therapy. This includes recent advances in multimodality imaging, image-guided therapy, and combination therapy. We found that the continuous advances of synthesis and design of novel nanomaterials will enhance the future development of medical imaging and cancer therapy. However, more resources should be available to examine side effects and cell toxicity when using nanomaterials in humans.
... Human cytokine-induced killer (CIK) cells loaded with gold nanorods (AuNRs) were used in a nano-immunotheranostic approach which paired photoacoustic imaging with photothermal therapy to diagnose/treat gastric cancer. 130 Human CIKs were labeled with silica-modified AuNRs by incubation. Labeled CIK cells inhibited the growth of gastric cancer MGC803 cells in vitro by inducing cell apoptosis and killed MGC803 cells under low power density near-infrared (NIR) laser treatment. ...
Immunoimaging is a rapidly growing field stoked in large part by the intriguing triumphs of immunotherapy. On the heels of immunotherapy's successes, there exists a growing need to evaluate tumor response to therapy particularly immunotherapy, stratify patients into responders vs. non-responders, identify inflammation, and better understand the fundamental roles of immune system components to improve both immunoimaging and immunotherapy. Innovative nanomaterials have begun to provide novel opportunities for immunoimaging, in part due to their sensitivity, modularity, capacity for many potentially varied ligands (high avidity), and potential for multifunctionality/multimodality imaging. This review strives to comprehensively summarize the integration of nanotechnology and immunoimaging, and the field's potential for clinical applications.
... Since the high pressure of blood vessel inside tumors, anticancer agents (such as nanoparticles, chemotherapy drugs) are very difficult to enter into the internal tumor. When cells are designed to deliver nanoparticles, RNA, or therapeutic agents as cargos, these bioactive cargos can effectively migrate to the tumor sites [1][2][3][4][5][6][7] . In recent years, cellbased delivery vehicles for nanomedicine has become a new research focus in the field of nanomedicine. ...
Objective:
To construct a novel nanoplatform GNS@CaCO3/Ce6-NK by loading the CaCO3-coated gold nanostars (GNSs) with Chlorin e6 molecules (Ce6) into human peripheral blood mononuclear cells (PBMCs)-derived NK cells for tumor targeted therapy.
Methods:
GNS@CaCO3/Ce6 nanoparticles were prepared and characterized by TEM and UV-vis. The cell surface markers and cytokines secretion of NK cells before and after loading the GNS@CaCO3/Ce6 nanoparticles were detected by Flow Cytometry (FCM) and ELISA. Effects of the GNS@CaCO3/Ce6-NK cells on A549 cancer cells was determined by FCM and CCK-8. Intracellular fluorescent signals of GNS@CaCO3/Ce6-NK cells were detected via Confocal laser scanning microscopic (CLSM) and FCM at different time points. Intracellular ROS generation of GNS@CaCO3/Ce6-NK cells under laser irradiation were examined by FCM. The distribution of GNS@CaCO3/Ce6-NK in A549 tumor-bearing mice were observed by fluorescence imaging and PA imaging. The combination therapy of GNS@CaCO3/Ce6-NK under laser irradiation were investigated on tumor-bearing mice.
Results:
The coated CaCO3 shell on the surface of GNSs exhibited prominent delivery and protection effect of Ce6 during the cellular uptake process. The as-prepared multifunctional GNS@CaCO3/Ce6-NK cells possessed bimodal functions of fluorescence imaging and photoacoustic imaging. The as-prepared multifunctional GNS@CaCO3/Ce6-NK cells could actively target tumor tissues with the enhanced photothermal/photodynamic therapy and immunotherapy.
Conclusions:
The GNS@CaCO3/Ce6-NK shows effective tumor-targeting ability and prominent therapeutic efficacy toward lung cancer A549 tumor-bearing mice. Through fully utilizing the features of GNSs and NK cells, this new nanoplatform provides a new synergistic strategy for enhanced photothermal/photodynamic therapy and immunotherapy in the field of anticancer development in the near future.
... So, it has broad application prospects in nano-electronics, nano-photonics, catalysis, sensors, biomarkers, and many other areas [6][7][8]. Because AuNPs have large surface area and spherical shape, they can be used as carrier for antineoplastic drugs [9][10][11][12]. Moreover, many AuNP complex have been mainly used for the new type of antitumor drugs in order to treat cancer [13,14]. ...
Abstract Functionalized gold nanoparticles (AuNPs) have widely applied in many fields, due to their good biocompatibility, a long drug half-life, and their bioactivity is related to their size and the modified ligands on their surface. Here, we synthesized the AuNPs capped with ligands that possess polyethylene glycol (PEG) and lithocholic acid (LCA) linked by carboxyl groups (AuNP@MPA-PEG-LCA). Our cytotoxicity results indicated that AuNP@MPA-PEG-LCA have better cell selectivity; in other words, it could inhibit the growth of multiple liver cancer cells more effectively than other cancer cells and normal cells. Apoptosis plays a role in AuNP@MPA-PEG-LCA inhibition cell proliferation, which was convincingly proved by some apoptotic index experiments, such as nuclear staining, annexin V-FITC, mitochondrial membrane potential (MMP) analysis, and AO/EB staining experiments. The most potent AuNP@MPA-PEG-LCA were confirmed to efficiently induce apoptosis through a reactive oxygen species (ROS) mediating mitochondrial dysfunction. And AuNP@MPA-PEG-LCA could be more effective in promoting programmed cell death of liver cancer cells.
... We found a significant (p < 0.001) decrease in coverage values, close to 25(2)% only for the maximum tested dose (500 µM ≈ 100 μg/mL). These values are in accordance with previous reports that show similar results for these AuNP concentrations [11,[24][25][26]76,77]. ...
Gold nanoparticles with NIR absorption are promising for photothermal therapy applications. Different syntheses have been proposed and, among them, that based on the reduction of Au(III) with thiosulfate is important because it yields gold nanotriangles (AuNTs) with strong absorption in the near-infrared region. It has been
previously reported by others that the nanoparticle surface is covered by relatively weak adsorbed S species (mostly sulfate), which would render the surface easy to functionalize in order to improve biocompatibility and therapeutic effects. In this work we have used XPS, XANES, UV–vis–NIR spectroscopy, HRTEM and AFM to
demonstrate that, in contrast to the previous reports, these AuNTs are covered by strongly adsorbed sulfur species (sulfide and polysulfide). A reaction pathway is proposed to explain the presence of reduced sulfur species and the absence of adsorbed sulfates and thiosulfates. Preliminary cytotoxicity assays show that the Scapped AuNTs do not show a deleterious effect for Au concentrations larger than those needed for in vivo photothermal treatments.
... The photo-thermal effects of silica-coated gold nanorods were effectively synergized with immunotherapy to treat gastric cancer [103]. The system was used as a Figure 4: Schematic representation of a dendrimeric system for chemoimmunotherapy. ...
Cancer continues to be ranked among the top causes of mortality in the world despite the advances made in science and technology. The sub-par performance of cancer therapeutic strategies is due to the transformation of the cancer from a proliferating mass of cells in to an impregnable fortress that manipulates and controls the microenvironment to prevent access to any potential cytotoxic factor as well as circumvent the innate immune-surveillance processes. Recruitment of the native immune cells to selectively recognize and kill cancer cells can serve to augment the cytotoxic effects of conventional cancer therapeutic approaches. In addition to annihilation of the cancer cells, the induction of memory in the immune cells prevents the possibility of cancer recurrence. However, despite the apparent benefits of cancer immunotherapy, there are several pitfalls that need to be addressed in order to extend these benefits to the clinic. In this context, engineered nanostructured carrier systems can be effectively employed for an activation and priming of the host immune system selectively against the target cancer cells. This has led to the emergence of ‘nanoimmunotherapy’ as an important therapeutic approach against cancer. The use of multifunctional nanomaterials in combination with immunotherapy offers possible solutions to overcome the current limitations in cancer therapy and represents the next generation of ‘smart therapeutics’, which forms the prime focus of discussion in this review.
... Since human tissues are almost transparent to radiation in the range of 700-1100 nm, gold nanorods are usually being tuned to these wavelengths [49]. Laser-irradiated gold nanorods were successfully employed in killing various types of cancer cells, such as prostate [50], breast [51] and gastric [52], or for treatments targeted to Staphylococcus aureus [53], and killing Pseudomonas aeruginosa bacteria in wounds [54]. Similarly, gold nanoshells gained popularity owing to their capacity to shift the resonant frequency based on the variation of the radii of silica core and gold shells [55]. ...
The optimal light dose, heat generation, consequent heat spread, and an accurate thermal damage model, are key components of effective laser therapies. Recent advances in nanotechnology offer numerous possibilities on how to increase the efficacy of hyperthermia for tumour treatments. Gold nanoparticles are a promising candidate towards the achievement of this goal owing to their properties for efficiently converting light to heat. In this review, we summarise the numerical tools that are available for theoretical studies of gold-nanoparticle-mediated photo-thermal therapy. The processes that occur in the treatments based on light propagation inside biological tissues and the subsequent temperature distributions are considered first, followed by evaluation of the thermal damage. The fundamental ideas underlying the presented methods are described in addition to their applications in photo-thermal therapy and its effects. The descriptions of extensively used tools for the characterisation of nanoparticles across multiple research fields are also presented for estimating the electromagnetic properties of gold nanoparticles (e.g., discrete dipole approximations, finite-difference time-domain simulations), the Monte Carlo model of light propagation in biological tissues, and the Pennes’ bio-heat equation. In addition, the Arrhenius damage evaluation and the cumulative effective minutes normalisation methods are described. Finally, recent in vivo and in vitro results from the rapidly growing field of nanomedicine are presented.
... Therefore, CHRDL1 methylation status may represent a novel biomarker to identify and predict the prognosis of gastric cancer patients CHRDL1. Targeted therapy attracted more and more interest [31]. Our study of CHRDL1 may offer a new target for future treatment. ...
CHRDL1 (Chordin-like 1) is a secreted protein that acts as an antagonist of bone morphogenetic protein (BMP). BMP plays a role as an activator of BMP receptor II (BMPR II), which mediates extracellular to intracellular signal transmission and is involved in carcinogenesis and metastasis. Herein, we report that CHRDL1 expression was significantly down-regulated in gastric cancer tissues and associated with poor survival. Clinic-pathological parameters demonstrated a close relationship between low CHRDL1 expression and metastasis. In vitro, CHRDL1 knockdown promoted tumor cell proliferation and migration through BMPR II by activating Akt, Erk and β-catenin. Furthermore, we observed the hypermethylation of the CHRDL1 promoter in gastric cancer, which induced low expression of CHRDL1 and decreased its secretion to the supernatant. Finally, in vivo experiments confirmed that CHRDL1 acted as a tumor suppressor gene in suppressing tumor growth and metastasis.
... Cytokines production by CIK cells is fast and efficient, leading to effective function of CIK cells. IFN-g and TNF-a are the main cytokines produced by CIK cells, 35,36 which are involved in regulating innate and adaptive immunities. The other positive regulatory cytokines that could be detected in tumor immunotherapy laboratories are IL-2 and IL-4. ...
Cell-based immunotherapy holds promise in the quest for the treatment of cancer, having potential synergy with surgery, chemotherapy and radiotherapy. As a novel approach for adoptive cell-based immunotherapy, cytokine-induced killer (CIK) cells have moved from the ‘bench to bedside’. CIK cells are a heterogeneous subset of ex-vitro expanded, polyclonal T-effector cells with both natural killer (NK) and T-cell properties, which present potent non-major histocompatibility complex-restricted cytotoxicity against a variety of tumor target cells. Initial clinical studies on CIK cell therapy have provided encouraging results and revealed synergistic antitumor effects when combined with standard therapeutic procedures. At the same time, issues such as inadequate quality control and quantity of CIK cells as well as exaggerated propaganda were continuously emerging. Thus, the Ministry of Health in China stopped CIK cell therapy in May 2016, which was a major setback for the innovation of CIK cell-based immunotherapy. Thus, it is very important to modify technical criteria in order to develop a standardized operation procedure (SOP) and standardized system for evaluating antitumor efficacy in a safe way.
... In vitro cell experiment shows that human CIK cells labeled with gold nanorods actively target gastric cancer MGC803 cells, inhibit growth of MGC803 cells by inducing cell apoptosis, and kill MGC803 cells under low power density near-infrared (NIR) laser treatment (808-nm continuous wave laser, 1.5 W/cm 2 , 3 min). In vivo experiment results showed that human CIK cells labeled with gold nanorods could target actively and image subcutaneous gastric cancer vessels via photoacoustic imaging at 4 hrs postinjection, could enhance immunotherapy efficacy by up-regulating cytokines such as IL-1, IL-12, IL-2, IL-4, IL-17, and IFN-gamma, and kill gastric cancer tissues by photothermal therapy via direct injection into tumor site under near-infrared (NIR) laser irradiation [45]. High-performance human CIK cells labeled with Au nanorods are a good novel theranostic platform to exhibit great potential in applications such as tumor-targeted photoacoustic imaging, enhanced immunotherapy, and photothermal therapy in the near future. ...
Over the past few years, gastric cancer prewarning and early theranostic system have achieved great advances. Gastric cancer theranostic strategies still focus on prediction and prewarning of early gastric cancer, early diagnosis and molecular imaging directed operation therapy, enhanced immunotherapy and killing gastric cancer stem cells to overcome multidrug resistance (MDR). Here we review the main advances in this field over the past few years, explore the clinical translational prospects, and discuss the concepts, issues, approaches, and challenges, with the aim of stimulating a broader interest in developing gastric cancer prewarning and early theranostic system and promoting clinical translation.
... Enhanced targeting of specific MPS subsets by nanomaterials may decrease off-target effects of drug therapy, improve targeted immunotherapy, and offer treatments for inflammation-driven pathologies like cardiovascular disease (CVD). [10][11][12][13] Atherosclerosis is an inflammatory condition within the walls of arterial vessels and a principal cause of CVD. Accumulation of inflammatory cells and their products induces maturation of atheromas, or plaques, ultimately resulting in plaque rupture, leading to ischemic stroke or myocardial infarction. ...
Atherosclerosis, a leading cause of heart disease, results from chronic vascular inflammation that is driven by diverse immune cell populations. Nanomaterials may function as powerful platforms for diagnostic imaging and controlled delivery of therapeutics to inflammatory cells in atherosclerosis, but efficacy is limited by non-specific uptake by cells of the mononuclear phagocytes system (MPS). MPS cells located in the liver, spleen, blood, lymph nodes and kidney remove from circulation the vast majority of intravenously administered nanomaterials regardless of surface functionalization or conjugation of targeting ligands. Here, we report that nanostructure morphology alone can be engineered for selective uptake by dendritic cells (DCs), which are critical mediators of atherosclerotic inflammation. Employing near infrared fluorescence imaging and flow cytometry as a multimodal approach, we compared organ and cellular level biodistributions of micelles, vesicles (i.e. polymersomes) and filomicelles, all assembled from poly(ethylene glycol)-bl-poly(propylene sulfide) (PEG-bl-PPS) block copolymers with identical surface chemistries. While micelles and filomicelles were respectively found to associate with liver macrophages and blood-resident phagocytes, polymersomes were exceptionally efficient at targeting splenic DCs (up to 85% of plasmacytoid DCs) and demonstrated significantly lower uptake by other cells of the MPS. In a mouse model of atherosclerosis, polymersomes demonstrated superior specificity for DCs (p<0.005) in atherosclerotic lesions. Furthermore, significant differences in polymersome cellular biodistributions were observed in atherosclerotic compared to naïve mice, including impaired targeting of phagocytes in lymph nodes. These results present new avenues for immunotherapies in cardiovascular disease and demonstrate that nanostructure morphology can be tailored to enhance targeting specificity.
... CD3 + CD56 + phenotype is the main effective cellular subtype for killing tumor cells. Therefore, CIK cells have an extraordinary cytolytic potential to recognize autologous malignant cells and possess higher lytic activity against target tumor cells [18,[22][23][24][25]. CIK-mediated cellular lysis is major histocompatibility antigen (MHC) unrestricted cytotoxicity. ...
Cellular immunotherapy has become a potential therapeutic method for different diseases. Herein, we reported clinical trial results of Cytokine-induced killer (CIK) cells used for patients with hepatitis B, cirrhosis and liver cancers from 2000 to 2015. Results showed CIK cell therapeutic effects were closely positively associated with CIK cell numbers, treated times and HBV genotypes. Different stages of HBV patients treated with > 10¹⁰ CIK cells per time for more than ten times exhibited remarkable decrease of HBV DNA numbers (P < 0.01), ALT and AST gradually recovered to normal scope, cytokine factors such as IFN-γ, IL-1b, IL-2, IL-4, IL-6, IL-10, IL-22 and IL-27 exhibited obvious increase, lifespan of patients with cirrhosis and hepatocellular carcinoma were extended, and that all the patients felt better in sleep, diet and pain during the period of CIK therapy. In conclusion, CIK cell therapy is a good alternative therapeutic method and can be effectively used for treatment of different stages of HBV patients. © 2016 Fangfang Xia, Ruihua Song, Jingjing Zhang, Yang Zhu, Yao Yang, Ling He, Yun Cao, Chenlu Li, Zheng Wang, Shangli Cheng, Jian Ni, Lijun Ma, Ding Li and Daxiang Cui.
... For example, human CIK cells labeled with gold nanorods were used for photothermal-immunological combined therapy of in vivo gastric cancer models, and maximal tumor growth inhibition was achieved. The fact highly suggests that available nanotechnology can be used for enhanced immunotherapeutic efficacy [4]. Cancer nanotechnology or cancer nanomedicine has provided a practical solution for overcoming the limitations of traditional immunotherapy. ...
Phototheranostic based on photothermal therapy (PTT) and photoacoustic imaging (PAI), as one of avant-garde medical techniques, have sparked growing attention because it allows noninvasive, deeply penetrative, and highly selective and effective therapy. Among a variety of phototheranostic nanoagents, single-component inorganic nanostructures are found to be novel and attractive PAI and PTT combined nanotheranostic agents and received tremendous attention, which not only exhibit structural controllability, high tunability in physiochemical properties, size-dependent optical properties, high reproducibility, simple composition, easy functionalization, and simple synthesis process, but also can be endowed with multiple therapeutic and imaging functions, realizing the superior therapy result along with bringing less foreign materials into body, reducing systemic side effects and improving the bioavailability. In this review, according to their synthetic components, conventional single-component inorganic nanostructures are divided into metallic nanostructures, metal dichalcogenides, metal oxides, carbon based nanostructures, upconversion nanoparticles (UCNPs), metal organic frameworks (MOFs), MXenes, graphdiyne and other nanostructures. On the basis of this category, their detailed applications in PAI guide PTT of tumor treatment are systematically reviewed, including synthesis strategies, corresponding performances, and cancer diagnosis and therapeutic efficacy. Before these, the factors to influence on photothermal effect and the principle of in vivo PAI are briefly presented. Finally, we also comprehensively and thoroughly discussed the limitation, potential barriers, future perspectives for research and clinical translation of this single-component inorganic nanoagent in biomedical therapeutics.
Gold nanorods (AuNRs) are successfully employed in drug delivery, biosensors, and biotechnologies. Their wide success is due to their unique chemical properties, biocompatibility, easy, cheap and versatile synthesis. In this framework, AuNRs were synthetized with the aim to obtain strongly hydrophilic nanomaterials, suitable as drug delivery system. AuNRs were synthetized by seed mediated methods in two steps. After careful purification AuNRs were investigated by means of UV-Vis-NIR showing typical surface plasmon resonance (SPR) bands at 550 nm and 970 nm. The Fourier Transform Infrared Spectroscopy (FT-IR) and High-resolution X-ray photoelectron Spectroscopy (HR-XPS) investigations verified the surface functionalization by ascorbic acid (AA) and cetyl trimethyl ammonium bromide (CTAB) and allowed to examine the chemical structure and the interaction between capping agent and metal surface. Moreover, transmission electron microscopy (TEM) observations showed AuNRs with regular shape and size in the range of 20-80 nm. These results point to AuNRs as promising systems for drug delivery applications.
In recent years, intensive research has been done to develop an efficient and low‐cost catalyst for sustainable and scalable solar‐driven energy conversion. Single‐atom catalyst (SAC) offers an ideal active site with 100% accessibility for the reaction that could simultaneously enhance both catalytic activity and selectivity for various photoelectrochemical (PEC) energy conversion reactions. This chapter summarizes SAC development literature for energy applications, typically PEC water splitting and CO 2 conversion into value‐added products. In SAC, different types of support are discussed, starting from single atom (SA) immobilized in carbon support, SA supported in metal oxide, and phosphide‐based semiconductors, in addition to the SA supported in 2D and 3D porous materials, including metal–organic frameworks (MOFs) and covalent organic frameworks (COFs). The catalytic performance of each system is discussed alongside its stability and relationship between active metal sites and its support.
This chapter provides an overview of the field of nanotechnology, its current applications and potential use in biology and medicine. We are witnessing the convergence of nanotechnology and biological sciences, which has the potential to revolutionize medical research and immunotherapy. The combination of nanotechnology and molecular biology has already generated a myriad of nanoscale-based devices and methods for probing the cell machinery, elucidating intimate life processes that were heretofore invisible to human inquiry, and detecting early signs of disease occurring at the molecular level. Furthermore, applied research in nanotechnology has now led to the development of nanoparticles (NPs) that can be engineered with multiple useful therapeutic features, involving various payloads with antigens and/or immunomodulatory agents such as cytokines, ligands for immunostimulatory receptors or antagonists for immunosuppressive receptors. In this chapter, we review multiple approaches to NP-based therapies designed to affect the tumor microenvironment and stimulate innate and adaptive immune systems to obtain effective anti-tumor immune responses for novel and improved immunotherapy.
Mesenchymal stem cell (MSC)-based cell therapy can provide opportunities for the treatment of various diseases. However, when used in vivo, these cells should be labelled and monitored by a non-invasive method during delivery to the desired locations within the body. This study describes a biomimicry method that effectively labels human Wharton's jelly-derived MSCs (hWJ-MSCs) with a photoacoustics (PA) contrast agent, gold nanorods (GNRs), without the need for transfection agents (TAs). In this method for cell labelling, the hWJ-MSCs were co-incubated with non-adherent cells isolated from fresh umbilical cord for 2 days immediately before incubation with GNRs. Next, hWJ-MSCs were labelled with the GNRs at a concentration of approximately 10¹⁰ nanorads/mL (NR/mL) followed by transmission electron microscopy (TEM) and inductively coupled plasma mass spectroscopy (ICP-MS) to verify their labelling effectiveness. The GNRs-labelled MSCs prepared by this method had an intracellular gold (Au) concentration of 3.4 ± 0.4 pg/cell, which is an acceptable amount for cell labelling.
Immunotherapy is an effective tumor treatment strategy that has several advantages over conventional methods such as surgery, radiotherapy and chemotherapy. Studies show that multifunctional nanoprobes can achieve multi-mode image-guided multiple tumor treatment modes. The tumor cells killed by chemotherapies or phototherapies release antigens that trigger an immune response and augment the effects of tumor immunotherapy. Thus, combining immunotherapy and multifunctional nanoprobes can achieve early cancer diagnosis and treatment. In this review, we have summarized the current research on the applications of multifunctional nanoprobes in image-guided immunotherapy. In addition, image-guided synergistic chemotherapy/photothermal therapy/photodynamic therapy and immunotherapy have also been discussed. Furthermore, the application potential and clinical prospects of multifunctional nanoprobes in combination with immunotherapy have been assessed.
Cancer is a life-threatening disease, and there is a significant need for novel technologies to treat cancer with an effective outcome and low toxicity. Photothermal therapy (PTT) is a noninvasive therapeutic tool that transports nanomaterials into tumors, absorbing light energy and converting it into heat, thus killing tumor cells. Gold nanorods (GNRs) have attracted widespread attention in recent years due to their unique optical and electronic properties and potential applications in biological imaging, molecular detection, and drug delivery, especially in the PTT of cancer and other diseases. This review summarizes the recent progress in the synthesis methods and surface functionalization of GNRs for PTT. The current major synthetic methods of GNRs and recently improved measures to reduce toxicity, increase yield, and control particle size and shape are first introduced, followed by various surface functionalization approaches to construct a controlled drug release system, increase cell uptake, and improve pharmacokinetics and tumor-targeting effect, thus enhancing the photothermal effect of killing the tumor. Finally, a brief outlook for the future development of GNRs modification and functionalization in PTT is proposed.
Novel strategies modulating the immune system yielded enhanced anticancer responses and improved cancer survival. Nevertheless, the success rate of immunotherapy in cancer treatment has been below expectation(s) due to unpredictable efficacy and off-target effects from systemic dosing of immunotherapeutic. As a result, there is an unmet clinical need for improving conventional immunotherapy. Nanotechnology offers several new strategies, multimodality, and multiplex biological targeting advantage to overcome many of these challenges. These efforts enable programming the pharmacodynamics, pharmacokinetics, delivery of immunomodulatory agents/co-delivery of compounds to prime at the tumor sites for improved therapeutic benefits. This review provides an overview of the design and clinical principles of biomaterials driven nanotechnology and their potential use in personalized nanomedicines, vaccines, localized tumor modulation, and delivery strategies for cancer immunotherapy. In this review, we also summarize the latest highlights and recent advances in combinatorial therapies avail in the treatment of cold and complicated tumors. It also presents key steps and parameters implemented for clinical success. Finally, we analyse, discuss, and provide clinical perspectives on the integrated opportunities of nanotechnology and immunology to achieve synergistic and durable responses in cancer treatment.
Cancer has been widely investigated yet limited in its manifestation. Cancer treatment holds innovative and futuristic strategies considering high disease heterogeneity. Chemotherapy, radiotherapy and surgery are the most explored pillars; however optimal therapeutic window and patient compliance recruit constraints. Recently evolved immunotherapy demonstrates a vital role of the host immune system to prevent metastasis recurrence, still undesirable clinical response and autoimmune adverse effects remain unresolved. Overcoming these challenges, tunable biomaterials could effectively control the co-delivery of anticancer drugs and immunomodulators. Current status demands a potentially new approach for minimally invasive, synergistic, and combinatorial nano-biomaterial assisted targeted immune-based treatment including therapeutics, diagnosis and imaging. This review discusses the latest findings of engineering biomaterial with immunomodulating properties and implementing novel developments in designing versatile nanosystems for cancer theranostics. We explore the functionalization of nanoparticle for delivering antitumor therapeutic and diagnostic agents promoting immune response. Through understanding the efficacy of delivery system, we have enlightened the applicability of nanomaterials as immunomodulatory nanomedicine further advancing to preclinical and clinical trials. Future and present ongoing improvements in engineering biomaterial could result in generating better insight to deal with cancer through easily accessible immunological interventions.
The use of gold nanoparticles as diagnostic tools is burgeoning, especially in the cancer community with a focus on theranostic applications to both cancer diagnosis and treatment. Gold nanoparticles have also demonstrated great potential for use in diagnostic and therapeutic approaches in ophthalmology. Although many ophthalmic imaging modalities are available, there is still a considerable unmet need, in particular for ophthalmic molecular imaging for the early detection of eye disease before morphological changes are more grossly visible. An understanding of how gold nanoparticles are leveraged in other fields could inform new ways they could be utilized in ophthalmology. In this paper, we review current ophthalmic imaging techniques and then identify optical coherence tomography (OCT) and photoacoustic imaging (PAI) as the most promising technologies amenable to the use of gold nanoparticles for molecular imaging. Within this context, the development of gold nanoparticles as OCT and PAI contrast agents are reviewed, with the most recent developments described in detail.
Nanoparticles with multifunctionality are being designed and formulated to overcome various limitations of drugs as well as conventional drug delivery systems. Engineered nanoparticles to specifically target cancer cells have the ability to reduce collateral damage on normal tissue due to pan-toxic effects of drugs. Pragmatic approaches are being in consideration to make advancement in cancer therapy as the new developed methods exhibited an improved targeted anticancer therapeutic delivery with better treatment outcomes. An effective cancer therapy requires both the passive and active targeting to successfully achieve targeted delivery. The nanoparticles can be conjugated with specific ligands, antibodies and carbohydrates for active targeting of cancer cells with great affinity and precision. This review presents some recent strategies such as immunotherapy, role of cell sex and protein corona in for targeted cancer therapy and also discusses some examples of engineered nanoparticles exploited for active cancer targeting and their limitations and associated toxicity.
Enhanced biocompatibility of nanosized contrast agent with high radiodensity and specific bio-distribution is an important parameter for localized tumor imaging and organ safety. Various nanoparticles, especially gold nanorods (GNRs) have been applied for tumor diagnosis. However, their toxicity, nonspecific bio-distribution and easy aggregation are critical issues in cancer medicine. To avoid these issues, the GNRs are encapsulated in the core of nanoscopic mesoporous silica (MS) under ambient conditions, yielding multifunctional nanomaterials for cancer nanomedicine, is a recent and active development. Interestingly, GNRs embedded MS nanohybrid (GNR-MS) though promising materials in nanomedicine is rarely examined for tumor diagnosis, in vivo toxicity, organs safety, contrast ability and excretion. Herein, we report a systematic in vivo examination of folic acid functionalized GNR-MS (GNR-MS-FA) for localized 4T1 breast tumor diagnosis, organ safety and excretion using a onetime dose administration. The nanomaterials show good aqueous dispersibility, biocompatibility, high radiodensity and tumor specific targeting ability (in vitro as well as in vivo). The in vivo tumor diagnosis and specific bio-distribution of injected nanomaterials clearly demonstrates their potential for the visualization of tumors deep in the body of mice. In addition, all organs including the healthy glomerulus of kidney are observed to be free of the tissue injuries thereby indicating the superior biocompatibility of the nanomaterials.
Nanomaterial-based photothermal therapy using near-infrared (NIR) light is a promising strategy in cancer treatment. However, delivery of nano-agents to specific tumor sites poses a great challenge, especially in the tumor hypoxia regions, where the hypoxia-associated drug delivery barriers prevent effective intratumoral distribution of the nanomaterials. In this respect, tumor-tropic cells including macrophages, monocytes, neural stem cells (NSCs), and mesenchymal stem cells (MSCs) have been proposed as “Trojan Horse” delivery vehicles to transport various nano-agents to overcome the drug delivery barriers, increase the tumor targeting ability of nano-agents, and enhance the efficiency of photothermal therapy. In this review, we summarize recent research activities and emerging trends in this field, describe the advantages of combining cellular therapies and nanotechnology to achieve more effective cancer treatment, and discuss the clinical prospects of photothermal therapy.
Two of the challenges for clinical implementation of nano-therapeutic strategies are optimization of tumor targeting and clearance of the nanoagents in vivo. Herein, a cell-mediated therapy by transporting 2D Bi2Se3 nanosheets within macrophage vehicles is described. The Bi2Se3 nanosheets with excellent near-infrared photothermal performance exhibit high macrophage uptake and negligible cytotoxicity thus facilitating the fabrication of Bi2Se3-laden-macrophages. Compared with bare Bi2Se3, the Bi2Se3-laden-macrophages after intravenous injection show prolonged blood circulation and can overcome the hypoxia-associated drug delivery barrier to target the tumor efficiently and dramatically enhance the efficiency of photothermal cancer therapy. The Bi2Se3-laden-macrophages possess good biocompatibility as demonstrated by the biochemical and histological analyses and furthermore, most of the materials are excreted from the body within 25 days. Our findings reveal a desirable system for highly efficient near-infrared photothermal cancer therapy.
How to improve effective accumulation and intratumoral distribution of plasmonic gold nanoparticles has become a great challenge for photothermal therapy of tumor. Herein, we reported a nanoplatform with photothermal therapeutic effects by fabricating Au nanorods@SiO2@CXCR4 nanoparticles and loading the prepared nanoparticles into the human induced pluripotent stem cells(AuNRs-iPS). In virtue of the prominent optical properties of Au nanorods@SiO2@CXCR4 and remarkable tumor target migration ability of iPS cells, the Au nanorods delivery mediated by iPS cells via the nanoplatform AuNRs-iPS was found to have a prolonged retention time and spatially even distribution in MGC803 tumor-bearing nude mice observed by photoacoustic tomography and two-photon luminescence. Based on these improvements, the nanoplatform displayed a robust migration capacity to target the tumor site and to improve photothermal therapeutic efficacy on inhibiting the growth of tumors in xenograft mice under a low laser power density. The combination of gold nanorods with human iPS cells as a theranostic platform paves an alternative road for cancer theranostics and holds great promise for clinical translation in the near future.
Gastric cancer is the second leading cause of cancer-related death worldwide. RNA nanotechnology has recently emerged as an important field due to recent finding of its high thermodynamic stability, favorable and distinctive in vivo attributes. Here we reported the use of the thermostable three-way junction (3WJ) of bacteriophage phi29 motor pRNA to escort folic acid, a fluorescent image marker and BRCAA1 siRNA for targeting, imaging, delivery, gene silencing and regression of gastric cancer in animal models. In vitro assay revealed that the RNA nanoparticles specifically bind to gastric cancer cells, and knock-down the BRCAA1 gene. Apoptosis of gastric cancer cells was observed. Animal trials confirmed that these RNA nanoparticles could be used to image gastric cancer in vivo, while showing little accumulation in crucial organs and tissues. The volume of gastric tumors noticeably decreased during the course of treatment. No damage to important organs by RNA nanoparticles was detectible. All the results indicated that this novel RNA nanotechnology can overcome conventional cancer therapeutic limitations and opens new opportunities for specific delivery of therapeutics to stomach cancer without damaging normal cells and tissues, reduce the toxicity and side effect, improve the therapeutic effect, and exhibit great potential in clinical tumor therapy.
Developing safe and effective nanoprobes for targeted imaging and selective therapy of gastric cancer stem cells (GCSCs) has become one of the most promising anticancer strategies. Herein, gold nanostars-based PEGylated multifunctional nanoprobes were prepared with conjugated CD44v6 monoclonal antibodies (CD44v6-GNS) as the targeting ligands. It was observed that the prepared nanoprobes had high affinity towards GCSC spheroid colonies and destroyed them completely with a low power density upon near-infrared (NIR) laser treatment (790 nm, 1.5 W/cm(2), 5 min) in vitro experiment. Orthotopic and subcutaneous xenografted nude mice models of human gastric cancer were established. Subsequently, biodistribution and photothermal therapeutic effects after being intravenously injected with the prepared nanoprobes were assessed. Photoacoustic imaging revealed that CD44v6-GNS nanoprobes could target the gastric cancer vascular system actively at 4 h post-injection, while the probes inhibited tumor growth remarkably upon NIR laser irradiation, and even extended survivability of the gastric cancer-bearing mice. The CD44v6-GNS nanoprobes exhibited great potential for applications of gastric cancer targeted imaging and photothermal therapy in the near future.
Gold nanobeacons can be used as a powerful tool for cancer theranostics. Here, we proposed a nanomaterial platform based on gold nanobeacons to detect, target and inhibit the expression of a mutant Kras gene in an in vivo murine gastric cancer model. The conjugation of fluorescently-labeled antisense DNA hairpin oligonucleotides to the surface of gold nanoparticles enables using their localized surface plasmon resonance properties to directly track the delivery to the primary gastric tumor and to lung metastatic sites. The fluorescently labeled nanobeacons reports on the interaction with the target as the fluorescent Cy3 signal is quenched by the gold nanoparticle and only emit light following conjugation to the Kras target owing to reorganization and opening of the nanobeacons, thus increasing the distance between the dye and the quencher. The systemic administration of the anti-Kras nanobeacons resulted in approximately 60% tumor size reduction and a 90% reduction in tumor vascularization. More important, the inhibition of the Kras gene expression in gastric tumors prevents the occurrence of metastasis to lung (80% reduction), increasing mice survival in more than 85%. Our developed platform can be easily adjusted to hybridize with any specific target and provide facile diagnosis and treatment for neoplastic diseases.
Introduction:
The National Central Cancer Registry (NCCR) of China collected population-based cancer registration data from all cancer registries in China. This study aimed to compile national cancer incidences and mortalities in 2011 and estimate cancer incident new cases and cancer deaths.
Methods:
In 2014, there were 234 cancer registries that submitted records of new cancer cases and cancer deaths that occurred in 2011 to the NCCR. All datasets were evaluated based on the criteria of data quality of the NCCR. The data of 177 registries was of sufficient quality and was compiled to evaluate cancer statistics in 2011. The pooled data were stratified by area, sex, age group, and cancer type. Cancer incident cases and deaths were estimated using age-standardized rates (ASR) and the Chinese population. All incidences and mortalities were age-standardized to the 2000 Chinese standard population and Segi's population.
Results:
The estimates of new cancer incident cases and cancer deaths were 3,372,175 and 2,113,048 in 2011, respectively. The crude incidence was 250.28/1,00,000 (277.77/1,00,000 for males and 221.37/1,00,000 for females). The ASRs of incidence by the Chinese standard population (ASRIC) and by the world standard population (ASRIW) were 186.34/1,00,000 and 182.76/1,00,000, respectively, with a cumulative incidence (0-74 years old) of 21.20%. Cancers of the lung, female breast, stomach, liver, colorectum, esophagus, cervix, uterus, prostate, and ovary were the most common cancers, accounting for approximately 75% of all new cancer cases. Lung, liver, gastric, esophageal, colorectal, female breast, pancreatic, brain, and cervical cancers and leukemia were the leading causes of cancer death, accounting for approximately 80% of all cancer deaths. Cancer incidence, mortality, and spectrum were all different between urban and rural areas and between males and females.
Conclusions:
The population covered by the cancer registries greatly increased from 2010 to 2011. The data quality and representativeness of cancer registries have gradually improved. Cancer registries have an irreplaceable role in research on cancer prevention and control. The disease burden of cancer is increasing, and the health department must implement effective measures to contain the increased cancer burden in China.
Photodynamic therapy (PDT) has emerged as an alternative and promising noninvasive treatment for cancer as well as non-cancer diseases, which involves the uptake of photosensitizers (PSs) by cancer cells followed by irradiation. The use of nanomaterials as carriers of PSs is a very promising approach to improve the development of PDT in clinical medicine. In this study, a novel folic acid-conjugated graphene oxide (GO) was strategically designed and prepared as targeting drug delivery system to achieve higher specificity. The second generation photosensitizer (PS) Chlorin e6 (Ce6) was effectively loaded into the system via hydrophobic interactions and π-π stacking. The nanocarriers can significantly increase the accumulation of Ce6 in tumor cells and lead to a remarkable photodynamic efficacy on MGC803 cells upon irradiation. These suggested that folic acid-conjugated GO loaded Ce6 had great potential as effective drug delivery system in targeting PDT.
Photoacoustic (PA) imaging is a biomedical imaging modality that provides functional information regarding the cellular and molecular signatures of tissue by using endogenous and exogenous contrast agents. There has been tremendous effort devoted to the development of PA imaging agents, and gold nanoparticles as exogenous contrast agents have great potential for PA imaging due to their inherent and geometrically induced optical properties. The gold-based nanoparticles that are most commonly employed for PA imaging include spheres, rods, shells, prisms, cages, stars and vesicles. This article provides an overview of the current state of research in utilizing these gold nanomaterials for PA imaging of cancer, atherosclerotic plaques, brain function and image-guided therapy.
Gold nanoclusters (GNCs) attract increasing attention due to their potential applications in sensing, catalysis, optoelectronics, and biomedicine. Herein, the formation of highly fluorescent glutathione (GSH)-capped GNCs is achieved through the delicate control of the reduction kinetics and thermodynamic selection of the Au(I)–SG complexes. Furthermore, the GNCs-based nanoprobes are developed by the covalent coupling folic acid (FA) and PEG (polyethylene glycol) on the surface of GNCs directly, followed by trapping photosensitizer (chlorin e6, Ce6) within PEG networks and attaching to the GNCs surface. The fabricated nanoprobes (Ce6@GNCs-PEG2K-FA) possess a uniform particle size (hydrodynamic diameter ≈6.1 ± 1.2 nm), without affecting the yield of singlet oxygen of the trapped Ce6. In vitro studies show the enhanced cellular uptake and satisfactory photodynamic therapy (PDT) effectiveness toward MGC-803 cells when compared with free Ce6. The biodistribution and excretion pathway studies of the nanoprobes in MGC-803 tumor-bearing nude mice reveal their superior penetration and retention behavior in tumors, while the preserved features of renal clearance and stealthy to reticulo-endothelial system are mainly attributed to the small hydrodynamic diameters and the FA-capped PEGylated ligands. The enhanced PDT efficacy and the nontoxicity to mice provide an exciting new nano-platform with promising clinical translational potential.
Activation in lectin-free interleukin 2 (IL-2) containing supernatants of peripheral blood mononuclear leukocytes (PBL) from cancer patients or normal individuals resulted in expression of cytotoxicity toward 20 of 21 natural killer (NK)-resistant fresh solid tumor cells tested. Fresh solid tumor cells were resistant to NK-mediated lysis in 10 autologous patients' PBL-tumor interactions, and from 17 normal individuals tested against 13 allogeneic fresh tumors. Culture of PBL in IL-2 for 2-3 d was required for the lymphokine activated killers (LAK) to be expressed, and lytic activity toward a variety of NK-resistant fresh and cultured tumor targets developed in parallel. Autologous IL-2 was functional in LAK activation, as well as interferon-depleted IL-2 preparations. Irradiation of responder PBL before culture in IL-2 prevented LAK development. Precursors of LAK were present in PBL depleted of adherent cells and in NK-void thoracic duct lymphocytes, suggesting that the precursor is neither a monocyte nor an NK cell. LAK effectors expressed the serologically defined T cell markers of OKT.3, Leu-1, and 4F2, but did not express the monocyte/NK marker OKM-1. Lysis of autologous fresh solid tumors by LAK from cancer patients' PBL was demonstrated in 85% of the patient-fresh tumor combinations. Our data present evidence that the LAK system is a phenomenon distinct from either NK or CTL systems that probably accounts for a large number of reported nonclassical cytotoxicities. The biological role of LAK cells is not yet known, although it is suggested that these cells may be functional in immune surveillance against human solid tumors.
Cytokine-induced killer (CIK) cells are a heterogeneous population of immune effector cells that feature a mixed T- and Natural killer (NK) cell-like phenotype in their terminally-differentiated CD3+CD56+ subset. The easy availability, high proliferation rate and widely major histocompatibility complex (MHC)-unrestricted antitumor activity of CIK cells contribute to their particularly advantageous profile, making them an attractive approach for adoptive immunotherapy. CIK cells have shown considerable cytotoxicity against both solid tumors and hematological malignancies in vitro and in animal studies. Recently, initial clinical experiences demonstrated the feasibility and efficacy of CIK cell immunotherapy in cancer patients, even at advanced disease stages. Likewise, the clinical application of CIK cells in combination with standard therapeutic procedures revealed synergistic antitumor effects. In this report, we will focus our consideration on CIK cells in the treatment of hematological malignancies. We will give insight into the latest advances and future perspectives and outline the most prominent results obtained in 17 clinical studies. Overall, CIK cells demonstrated a crucial impact on the treatment of patients with hematological malignancies, as evidenced by complete remissions, prolonged survival durations and improved quality of life. However, up to now, the optimal application schedule eventually favoring their integration into clinical practice has still to be developed.
Herein, we reported for the first time that RGD-conjugated silica-coated gold nanorods on the surface of multiwalled carbon nanotubes were successfully used for targeted photoacoustic imaging of in vivo gastric cancer cells. A simple strategy was used to attach covalently silica-coated gold nanorods (sGNRs) onto the surface of multiwalled carbon nanotubes (MWNTs) to fabricate a hybrid nanostructure. The cross-linked reaction occurred through the combination of carboxyl groups on the MWNTs and the amino group on the surface of sGNRs modified with a silane coupling agent. RGD peptides were conjugated with the sGNR/MWNT nanostructure; resultant RGD-conjugated sGNR/MWNT probes were investigated for their influences on viability of MGC803 and GES-1 cells. The nude mice models loaded with gastric cancer cells were prepared, the RGD-conjugated sGNR/MWNT probes were injected into gastric cancer-bearing nude mice models via the tail vein, and the nude mice were observed by an optoacoustic imaging system. Results showed that RGD-conjugated sGNR/MWNT probes showed good water solubility and low cellular toxicity, could target in vivo gastric cancer cells, and obtained strong photoacoustic imaging in the nude model. RGD-conjugated sGNR/MWNT probes will own great potential in applications such as targeted photoacoustic imaging and photothermal therapy in the near future.
Aim:
The synergistic effects of gold nanorod (GNR)-mediated mild hyperthermia (MHT; 42-43°C) and cisplatin (CP) activity was evaluated against chemoresistant SKOV3 cells in vitro and with a tumor xenograft model.
Materials & methods:
In vitro studies were performed using CP at cytostatic concentrations (5 µM) and polyethylene glycol-stabilized GNRs, using near-infrared laser excitation for MHT.
Results:
The amount of polyethylene glycol-GNRs used for environmental MHT was 1 µg/ml, several times lower than the loadings used in tumor tissue ablation. GNR-mediated MHT increased CP-mediated cytotoxicity by 80%, relative to the projected additive effect, and flow cytometry analysis suggested MHT also enhanced CP-induced apoptosis. In a pilot in vivo study, systemically administered polyethylene glycol-GNRs generated sufficient levels of MHT to enhance CP-induced reductions in tumor volume, despite their heterogeneous distribution in tumor tissue.
Conclusion:
These studies imply that effective chemotherapies can be developed in combination with low loadings of nanoparticles for localized MHT. Original submitted 6 July 2013; Revised submitted 20 October 2013.
Gastric cancer is the second leading cause of death from malignant disease worldwide and most frequently discovered in advanced stages. Because curative surgery is regarded as the only option for cure, early detection of resectable gastric cancer is extremely important for good patient outcomes. Therefore, noninvasive diagnostic modalities such as evolutionary endoscopy and positron emission tomography are utilized as screening tools for gastric cancer. To date, early gastric cancer is being treated using minimally invasive methods such as endoscopic treatment and laparoscopic surgery, while in advanced cancer it is necessary to consider multimodality treatment including chemotherapy, radiotherapy, and surgery. Because of the results of large clinical trials, surgery with extended lymphadenectomy could not be recommended as a standard therapy for advanced gastric cancer. Recent clinical trials had shown survival benefits of adjuvant chemotherapy after curative resection compared with surgery alone. In addition, recent advances of molecular targeted agents would play an important role as one of the modalities for advanced gastric cancer. In this review, we summarize the current status of diagnostic technology and treatment for gastric cancer.
Embryonic stem (ES) cells have great potential in applications such as disease modeling, pharmacological screening and stem cell therapies. Up to date, there is no related report on the use of ES cells as tracking and contrast reagents of cancer cells in vivo. Herein we report that DiR-labeled murine ES cells can recognize and target gastric cancer cells in vivo. DiR-labeled murine ES (mES) cells (5×10(6)) were intravenously injected into gastric tumor-bearing mice. The biodistribution of DiR-labeled mES cells was monitored by IVIS imaging within 24 h. Major organs were harvested and analyzed by immunofluorescence staining and Western blotting. Chemotaxis assay was employed to investigate the chemotaxis of ES cells tracking cancer cells. Fluorescent imaging results showed that DiR-labeled mES cells targeted gastric cancer tissue in vivo as early as 10 min post-injection, reaching a peak at 2h post-injection. Immunofluorescence staining and Western blotting results showed gastric cancer tissues specifically expressed SSEA-1. In vitro migration tests confirmed that mES cells actively moved to test sites with different concentration of CXCL12 in a dose-dependent manner. In conclusion, DiR-labeled mES cells may be used for gastric cancer targeted imaging in vivo, and have great potential in applications such as identifying and imaging of early gastric cancer in near future.
CD3(+)CD56(+) cytokine-induced killer (CIK) cells display a potent cytolytic activity. The adhesion molecule lymphocyte function-associated antigen-1 plays a crucial role in binding as well as in cytolytic activity of CIK cells against tumor target cells expressing the corresponding ligands. CIK cells express activating natural killer (NK) receptors, including NKG2D, DNAX accessory molecule-1 (DNAM-1), and low levels of NKp30. Cell signaling not only through TCR/CD3 but also through NKG2D, DNAM-1, and NKp30 leads to CIK cell activation resulting in granule exocytosis, cytokine secretion, and cytotoxicity. Antibody blocking experiments showed that DNAM-1, NKG2D, and NKp30 are involved in the TCR-independent tumor cell recognition and killing. Anti-CMV-specific CIK cells could be expanded in standard CIK cultures and mediate both specific, MHC-restricted recognition and TCR-independent NK-like cytolytic activity against leukemic cell lines or fresh leukemic blasts. Antibody blocking of lymphocyte function-associated antigen-1 and DNAM-1 led to significant reduction of both CTL and NK-cell functions, whereas blocking of NKG2D and NKp30 only inhibited NK-like cytotoxicity. Their dual-effector function suggests that CIK cells, when used in a clinical setting, may control both neoplastic relapses and viral infections, 2 frequently associated complications in patients who received a transplant.
Activation in lectin-free interleukin 2 (IL-2) containing supernatants of peripheral blood mononuclear leukocytes (PBL) from cancer patients or normal individuals resulted in expression of cytotoxicity toward 20 of 21 natural killer (NK)-resistant fresh solid tumor cells tested. Fresh solid tumor cells were resistant to NK-mediated lysis in 10 autologous patients' PBL-tumor interactions, and from 17 normal individuals tested against 13 allogeneic fresh tumors. Culture of PBL in IL-2 for 2-3 d was required for the lymphokine activated killers (LAK) to be expressed, and lytic activity toward a variety of NK-resistant fresh and cultured tumor targets developed in parallel. Autologous IL-2 was functional in LAK activation, as well as interferon-depleted IL-2 preparations. Irradiation of responder PBL before culture in IL-2 prevented LAK development. Precursors of LAK were present in PBL depleted of adherent cells and in NK-void thoracic duct lymphocytes, suggesting that the precursor is neither a monocyte nor an NK cell. LAK effectors expressed the serologically defined T cell markers of OKT.3, Leu-1, and 4F2, but did not express the monocyte/NK marker OKM-1. Lysis of autologous fresh solid tumors by LAK from cancer patients' PBL was demonstrated in 85% of the patient-fresh tumor combinations. Our data present evidence that the LAK system is a phenomenon distinct from either NK or CTL systems that probably accounts for a large number of reported nonclassical cytotoxicities. The biological role of LAK cells is not yet known, although it is suggested that these cells may be functional in immune surveillance against human solid tumors.
Photodynamic therapy (PDT) has emerged as an alternative and promising noninvasive treatment for cancer as well as non-cancer diseases, which involves the uptake of photosensitizers (PSs) by cancer cells followed by irradiation. The use of nanomaterials as carriers of PSs is a very promising approach to improve the development of PDT in clinical medicine. In this study, a novel folic acid-conjugated graphene oxide (GO) was strategically designed and prepared as targeting drug delivery system to achieve higher specificity. The second generation photosensitizer (PS) Chlorin e6 (Ce6) was effectively loaded into the system via hydrophobic interactions and π-π stacking. The nanocarriers can significantly increase the accumulation of Ce6 in tumor cells and lead to a remarkable photodynamic efficacy on MGC803 cells upon irradiation. These suggested that folic acid-conjugated GO loaded Ce6 had great potential as effective drug delivery system in targeting PDT.
Unlabelled:
Recent interest in using gold nanoparticles (Au NPs) for therapy in radiation medicine has motivated development of a liposome-based system to enhance their delivery to cells. In this study, liposomes were demonstrated to perform like a "Trojan Horse" to deliver small (1.4 nm) Au NPs into tumor cells by overcoming the energetically unfavorable endocytosis process for small NPs. The results reveal that the liposomal approach provides a thousand-fold enhancement in the cellular uptake of the small Au NPs. Real-time intracellular tracking of the Au NP-liposomes revealed an average speed of 12.48 +/- 3.12 microm/hr for their intracellular transport. Analysis of the time-dependent intracellular spatial distribution of the Au NP-liposomes demonstrated that they reside in lysosomes (final degrading organelles) within 40 minutes of incubation. Knowledge gained in these studies opens the door to pursuing liposomes as a viable strategy for delivery of Au NPs in radiation therapy applications.
From the clinical editor:
Gold nanoparticles (Au NPs) as part of an optimized liposome-based delivery system have been proposed for therapy in radiation medicine. The approach resulted in a thousand-fold enhancement in the cellular uptake of Au NPs compared to conventional delivery methods, with the nanoparticles residing in lysosomes within 40 minutes of incubation.
Plasmonic nanomaterials have the opportunity to considerably improve the specificity of cancer ablation by i.v. homing to tumors and acting as antennas for accepting externally applied energy. Here, we describe an integrated approach to improved plasmonic therapy composed of multimodal nanomaterial optimization and computational irradiation protocol development. We synthesized polyethylene glycol (PEG)-protected gold nanorods (NR) that exhibit superior spectral bandwidth, photothermal heat generation per gram of gold, and circulation half-life in vivo (t(1/2), approximately 17 hours) compared with the prototypical tunable plasmonic particles, gold nanoshells, as well as approximately 2-fold higher X-ray absorption than a clinical iodine contrast agent. After intratumoral or i.v. administration, we fuse PEG-NR biodistribution data derived via noninvasive X-ray computed tomography or ex vivo spectrometry, respectively, with four-dimensional computational heat transport modeling to predict photothermal heating during irradiation. In computationally driven pilot therapeutic studies, we show that a single i.v. injection of PEG-NRs enabled destruction of all irradiated human xenograft tumors in mice. These studies highlight the potential of integrating computational therapy design with nanotherapeutic development for ultraselective tumor ablation.
C.B-17 severe combined immune deficient (SCID) mice, which lack functional B and T lymphocytes, allow xenografts and, therefore, can be used to study the biology of human malignancies. Two different human B cell lymphoma cell lines, SU-DHL-4 and OCI-Ly8, which both harbor the t(14;18) chromosomal translocation, were injected into C.B-17 SCID mice. Mice injected intravenously or intraperitoneally developed tumors and died in a dose-dependent manner. The presence of tumor cells in various murine tissues could be demonstrated by a clonogenic tumor assay, staining of frozen sections with a monoclonal antibody (mAb) against a human B cell antigen (CD19), and with the polymerase chain reaction technique. A protocol using cytotoxic effector cells was developed and used to selectively deplete the tumor cells from bone marrow. These cells were developed by growing peripheral blood mononuclear cells in the presence of interferon gamma (IFN-gamma), anti-CD3 mAb, and interleukin 2 (IL-2). The timing of IFN-gamma treatment was critical and optimal if IFN-gamma was added before IL-2 treatment. The cells that were stimulated by IFN-gamma, followed by IL-2, could be expanded by treatment with a mAb directed against CD3. These cells could be further activated by IL-1, but not by tumor necrosis factor alpha. With this protocol, a tumor cell kill of 3 logs was obtained as measured by a clonogenic assay. Interestingly, despite their high cytotoxic activity against lymphoma cells, these cells had little toxicity against a subset of normal human hematopoietic precursor cells (granulocyte/macrophage colony-forming units). These cells were further tested by treating murine bone marrow contaminated with the human lymphoma cell line SU-DHL-4, and injecting these cells into SCID mice to assay for tumor growth in vivo. The animals injected with bone marrow contaminated with SU-DHL-4 cells had enhanced survival if the bone marrow was treated with the cytokine-induced killer cells before infusion. The SCID mouse provides a useful in vivo model for evaluation of new therapeutic approaches for lymphoma treatment. The cytokine-induced killer cells generated as described here could have an important impact on bone marrow purging for autologous bone marrow transplantation as well as for adoptive immunotherapy.
To develop a microarray-based prewarning system consisting of gastric cancer chip, prewarning data and analysis software for early detection of gastric cancer and pre-cancerous lesions.
Two high-density chips with 8,464 human cDNA sites were used to primarily identify potential genes specific for normal gastric mucosa, pre-cancerous lesion and gastric cancer. The low-density chips, composed of selected genes associated with normal gastric mucosa, precancerous lesion and gastric cancer, were fabricated and used to screen 150 specimens including 60 specimens of gastric cancer, 60 of pre-cancerous tissues and 30 of normal gastric mucosa. CAD software was used to screen out the relevant genes and their critical threshold values of expression levels distinguishing normal mucosa from pre-cancerous lesion and cancer. All data were stored in a computer database to establish a prewarning data library for gastric cancer. Two potential markers brcaa1 and ndr1 were identified by Western blot and immunohistochemistry.
A total of 412 genes associated with three stages of gastric cancer development were identified. There were 216 genes displaying higher expression in gastric cancer, 85 genes displaying higher expression in pre-cancerous lesion and 88 genes displaying higher expression in normal gastric mucosa. Also 15 genes associated with metastasis of gastric cancer and 8 genes associated with risk factors were screened out for target genes of diagnosis chip of early gastric cancer. The threshold values of 412 selected genes to distinguish gastric cancer, pre-cancerous lesion from normal gastric mucosa were defined as 6.01+/-2.40, 4.86+/-1.94 and 5.42+/-2.17, respectively. These selected 412 genes and critical threshold values were compiled into an analysis software, which can automatically provide reports by analyzing the results of 412 genes obtained by examining gastric tissues. All data were compiled into a prewarning database for gastric cancer by CGO software. Northern blot and immunohistochemistry analysis confirmed that gene and protein of brcaa1 displayed lower expression in normal gastric mucosa and higher expression in gastric cancer tissues, conversely, ndr1 displayed lower expression in gastric cancer and higher expression in normal gastric mucosa.
The microarray-based prewarning system for gastric cancer was developed. This system consisted of gastric cancer-associated gene chip, prewarning data and analysis software, which has a high potential for applications in the early detection of gastric cancer. The two potential markers brcaa1 and ndr1 identified may be used to distinguish cancer status fand non-cancer status.
Gold nanorods excited at 830 nm on a far-field laser-scanning microscope produced strong two-photon luminescence (TPL) intensities, with a cos⁴ dependence on the incident polarization. The TPL excitation spectrum can be superimposed onto the longitudinal plasmon band, indicating a plasmon-enhanced two-photon absorption cross section. The TPL signal from a single nanorod is 58 times that of the two-photon fluorescence signal from a single rhodamine molecule. The application of gold nanorods as TPL imaging agents is demonstrated by in vivo imaging of single nanorods flowing in mouse ear blood vessels.
• in vivo imaging
• plasmon resonance
• multiphoton
• nonlinear optics
Lung cancer is associated with very poor prognosis and considered one of the leading causes of death worldwide. Here, highly potent and selective biohybrid RNA interference (RNAi)-peptide nanoparticles (NPs) are presented that can induce specific and long-lasting gene therapy in inflammatory tumor associated macrophages (TAMs), via an immune modulation of the tumor milieu combined with tumor suppressor effects. The data here prove that passive gene silencing can be achieved in cancer cells using regular RNAi NPs. When combined with M2 peptide–based targeted immunotherapy that immuno-modulates TAMs cell population, a synergistic effect and long-lived tumor eradication can be observed along with increased mice survival. Treatment with low doses of siRNA (ED50 0.0025–0.01 mg kg−1) in a multi and long-term dosing system substantially reduces the recruitment of inflammatory TAMs in lung tumor tissue, reduces tumor size (≈95%), and increases animal survival (≈75%) in mice. The results here suggest that it is likely that the combination of silencing important genes in tumor cells and in their supporting immune cells in the tumor microenvironment, such as TAMs, will greatly improve cancer clinical outcomes.
C.B-17 severe combined immune deficient (SCID) mice, which lack functional B and T lymphocytes, allow xenografts and, therefore, can be used to study the biology of human malignancies. Two different human B cell lymphoma cell lines, SU-DHL-4 and OCI-Ly8, which both harbor the t(14;18) chromosomal translocation, were injected into C.B-17 SCID mice. Mice injected intravenously or intraperitoneally developed tumors and died in a dose-dependent manner. The presence of tumor cells in various murine tissues could be demonstrated by a clonogenic tumor assay, staining of frozen sections with a monoclonal antibody (mAb) against a human B cell antigen (CD19), and with the polymerase chain reaction technique. A protocol using cytotoxic effector cells was developed and used to selectively deplete the tumor cells from bone marrow. These cells were developed by growing peripheral blood mononuclear cells in the presence of interferon gamma (IFN-gamma), anti-CD3 mAb, and interleukin 2 (IL-2). The timing of IFN-gamma treatment was critical and optimal if IFN-gamma was added before IL-2 treatment. The cells that were stimulated by IFN-gamma, followed by IL-2, could be expanded by treatment with a mAb directed against CD3. These cells could be further activated by IL-1, but not by tumor necrosis factor alpha. With this protocol, a tumor cell kill of 3 logs was obtained as measured by a clonogenic assay. Interestingly, despite their high cytotoxic activity against lymphoma cells, these cells had little toxicity against a subset of normal human hematopoietic precursor cells (granulocyte/macrophage colony-forming units). These cells were further tested by treating murine bone marrow contaminated with the human lymphoma cell line SU-DHL-4, and injecting these cells into SCID mice to assay for tumor growth in vivo. The animals injected with bone marrow contaminated with SU-DHL-4 cells had enhanced survival if the bone marrow was treated with the cytokine-induced killer cells before infusion. The SCID mouse provides a useful in vivo model for evaluation of new therapeutic approaches for lymphoma treatment. The cytokine-induced killer cells generated as described here could have an important impact on bone marrow purging for autologous bone marrow transplantation as well as for adoptive immunotherapy.
Dendritic cells (DCs) have displayed the promising potential in cancer immunity. How to enhance DCs immunotherapeutic effect in cancer targeted immunotherapy and prevention is still a great challenge. Herein, we report for the first time the allogenic DCs and tumor cell fused vaccine combined with cytokine induced killing cells (CIKs) for targeted imaging and enhanced immunotherapeutic efficacy of gastric cancer (GC). The fused vaccine was prepared by PEG mediated fusion between mature DCs and inactive gastric cancer MGC803 cells. The immunotherapeutic and prophylactic potential of the fused cells (FCs) were evaluated in tumor-bearing, post-surgery and tumor free mice models. The migration and homing process of near infrared region quantum dots (NIR-QDs) labeled FCs were investigated by real-time animal imaging system. Results showed that the FCs and FC + CIKs could trigger the tumor-specific CTLs against GC cells, target the tumor tissue initiatively and enhance the prophylactic effects, suppress the tumor growth remarkably in vivo. The potential mechanism is also investigated. In conclusion, allogenic DCs and tumor cell fused vaccine can be used for targeted imaging and enhanced immunotherapeutic efficacy of GC, and the FC + CIKs strategy own great potential in clinical applications such as early therapy and prevention of tumor-metastasis and relapse in near future.
Copyright © 2015 Elsevier Ltd. All rights reserved.
In this paper, we report that gold nanorods with different aspect ratios are controllably synthesised by a facile modified seed-mediated growth procedure. The growth rate of gold nanorods is lowered by adding H2SO4, and the yield of gold nanorods is improved. Increasing the concentration of AgNO3 yields gold nanorods with different aspect ratios that differed from 1.83 to 5.04. To prevent aggregation of cetyltrimethylammonium bromide (CTAB)-capped gold nanorods and investigate the sensitivity to the solution refractive index, surface modification is carried out. After assembling poly (sodium-p-styrensulfonate) onto the surface of gold nanorods, the samples can disperse well in water and dimethyl sulfoxide. The localised surface plasmon resonance (LSPR) wavelength of the as-prepared gold nanorods redshifts with increasing the refractive index of the solvent and a good linear relationship between LSPR peaks and refractive index is achieved.
Nanoenabled technology holds great potential for health issues and biological research. Among the numerous inorganic nanoparticles that are available today, gold nanoparticles are fully developed as therapeutic and diagnostic agents both in vitro and in vivo due to their physicochemical properties. Owing to this, substantial work has been conducted in terms of developing biosensors for noninvasive and targeted tumor diagnosis and treatment. Some studies have even expanded into clinical trials. This article focuses on the fundamentals and synthesis of gold nanoparticles, as well as the latest, most promising applications in cancer research, such as molecular diagnostics, immunosensors, surface-enhanced Raman spectroscopy and bioimaging. Challenges to their further translational development are also discussed.
Gold nanorods (GNRs) have attracted significant interest in the field of medicine as theranostic agents for both imaging and photothermal ablation of cancerous cells/tissues. Targeting theranostic GNRs specifically to cancer cells is necessary to enhance treatment efficacy and minimize undesired side effects. In this study, targeting functionalized GNR to EphA2 receptors that are overexpressed on prostate cancer cells was investigated as a strategy to achieve enhanced GNR uptake by cancer cells. In addition, the influence of targeting peptide orientation on functionalized GNR uptake by PC-3 cells was explored. GNRs of aspect ratio 4 were functionalized with an EphA2 homing peptide, YSA, using a layer-by-layer polypeptide wrapping approach. In parallel, an analogous population of YSA-modified GNRs, which display a reversed YSA peptide, with the N- and C- termini reversed, was also prepared. GC-MS analysis of the YSA-GNRs indicated that functionalized GNRs displayed approximately 3000 peptides/GNR. The functionalized GNRs remained well-dispersed in biological media for short times (<24 h). An increase in GNRs uptake of the YSA-GNRs by PC-3 cells, compared to the reversed YSA-GNRs, was observed under identical incubation conditions. Lastly, the effect of the YSA-GNRs binding to EphA2 receptors on prostate cancer cell proliferation was also studied. The YSA-functionalized GNRs inhibit PC-3 proliferation at a significantly lower effective dose than free YSA. Overall, the polypeptide LBL deposition technique provides a facile route to target nanoparticles to overexpressed cellular receptors, with the caveat that the specific orientation and display of the targeting moiety plays a critical role in the interaction between the nanoparticle and the cell.
External stimuli, such as ultrasound, magnetic field and light, can be applied to activate in vivo tumor targeting. Herein, we fabricated polymer encapsulated gold nanorods to couple the photothermal properties of gold nanorods and the thermo- and pH-responsive properties of polymers in a single nanocomposite. The activation mechamism was thus transformed from heat to near infrared (NIR) laser which can be more easily controlled. Doxorubicin, a clinical anti-cancer drug, can be loaded into the nanocomposite through electrostatic interactions with high loading content up to 24%. The nanocomposite's accumulation in tumor post systematic administration can be significantly enhanced by NIR laser irradiation, providing a prerequisite for their therapeutic application which almost completely inhibited tumor growth and lung metastasis. Since laser can be manipulated very precisely and flexibly, the nanocomposite provides an ideally versatile platform to simultaneously deliver heat and anticancer drugs in a laser-activation mechanism with facile control of the area, time, and dosage. The NIR laser-induced targeted cancer thermo-chemotherapy without using targeting ligands represents a novel targeted anti-cancer strategy with facile control and practical efficacy.
Inspired by the ability of SERS nanoantennas to provide an integrated platform to enhance disease targeting in vivo, we developed a highly sensitive probe for in vivo tumoral recognition with the capacity to target specific cancer biomarkers such as
epidermal growth factor receptors (EGFR) on human cancer cells and xenograft tumour
models. Here, we used ~90 nm gold nanoparticles capped by a Raman reporter,
encapsulated and entrapped by larger polymers and a FDA antibody-drug conjugate – Cetuximab (Erbitux®) – that specifically targets EGFR and turns off a main signalling
cascade for cancer cells to proliferate and survive. These drug/SERS gold nanoantennas
present a high Raman signal both in cancer cells and in mice bearing xenograft tumours.
Moreover, the Raman detection signal is accomplished simultaneously by extensive
tumour growth inhibition in mice, making these gold nanoantennas ideal for cancer
nanotheranostics, i.e. tumour detection and tumoral cell inhibition at the same time.
Each year, the American Cancer Society estimates the numbers of new cancer cases and deaths expected in the United States in the current year and compiles the most recent data on cancer incidence, mortality, and survival based on incidence data from the National Cancer Institute, the Centers for Disease Control and Prevention, and the North American Association of Central Cancer Registries and mortality data from the National Center for Health Statistics. A total of 1,660,290 new cancer cases and 580,350 cancer deaths are projected to occur in the United States in 2013. During the most recent 5 years for which there are data (2005-2009), delay-adjusted cancer incidence rates declined slightly in men (by 0.6% per year) and were stable in women, while cancer death rates decreased by 1.8% per year in men and by 1.5% per year in women. Overall, cancer death rates have declined 20% from their peak in 1991 (215.1 per 100,000 population) to 2009 (173.1 per 100,000 population). Death rates continue to decline for all 4 major cancer sites (lung, colorectum, breast, and prostate). Over the past 10 years of data (2000-2009), the largest annual declines in death rates were for chronic myeloid leukemia (8.4%), cancers of the stomach (3.1%) and colorectum (3.0%), and non-Hodgkin lymphoma (3.0%). The reduction in overall cancer death rates since 1990 in men and 1991 in women translates to the avoidance of approximately 1.18 million deaths from cancer, with 152,900 of these deaths averted in 2009 alone. Further progress can be accelerated by applying existing cancer control knowledge across all segments of the population, with an emphasis on those groups in the lowest socioeconomic bracket and other underserved populations. CA Cancer J Clin 2013;. © 2013 American Cancer Society.
The use of heat producing GNRs to augment the dosing of chemotherapeutic agents in cultured mammalian cells was investigated. Hexadecyltrimethylammonium bromide was purchased from Fluka. GNRs were synthesized using standard protocols detailed in a previous publication, with reference to the Murphy and Liz-Marzán groups. GNRs were synthesized by combining CTAB, gold chloride, silver nitrate, ascorbic acid, and gold seed. GNRs were coated in Poly(diallyldimethylammonium chloride) (PDADMAC) by washing as-synthesized material twice in distilled water resuspending in 1 mM NaCl, and coated with a layer of negatively charged PSS followed by a layer of positively charged PDADMAC. It was observed that nanoparticles offer localized heating with a non-invasive probe, and provide heat generation inside cancerous cells.
Ganoderma lucidum polysaccharides (Gl-PS) have shown a variety of immune modulating effects. Culture of immunologic effector cells termed cytokine induced killer (CIK) cells is dependent on exogenous cytokines. It is not known about effects of Gl-PS on cytokine production, perforin and granzyme B expression in CIK cells. We made use of CIK cells as a means to investigate interaction between Gl-PS and cytokines, and explore mechanism of Gl-PS acting on proliferation and anti-tumor activity of CIK cells. The results suggested that Gl-PS (400 or 100 μg/ml) promoting CIK cells proliferation and cytotoxicity were relevant to enhancing IL-2, TNF production, protein and mRNA expression of granzyme B and perforin in CIK cells through synergizing cytokines in decreasing doses of IL-2 and anti-CD3 by 75 and 50%, and maybe were irrelevant to nitric oxide (NO). These results confirmed that Gl-PS was a promising biological response modifier (BRM) and immune potentiator.
Photoacoustic signal generation by metal nanoparticles relies on the efficient conversion of light to heat, its transfer to the environment, and the production of pressure transients. In this study we demonstrate that a dielectric shell has a strong influence on the amplitude of the generated photoacoustic signal and that silica-coated gold nanorods of the same optical density are capable of producing about 3-fold higher photoacoustic signals than nanorods without silica coating. Spectrophotometry measurements and finite difference time domain (FDTD) analysis of gold nanorods before and after silica coating showed only an insignificant change of the extinction and absorption cross sections, hence indicating that the enhancement is not attributable to changes in absorption cross section resulting from the silica coating. Several factors including the silica thickness, the gold/silica interface, and the surrounding solvent were varied to investigate their effect on the photoacoustic signal produced from silica-coated gold nanorods. The results suggest that the enhancement is caused by the reduction of the gold interfacial thermal resistance with the solvent due to the silica coating. The strong contrast enhancement in photoacoustic imaging, demonstrated using phantoms with silica-coated nanorods, shows that these hybrid particles acting as "photoacoustic nanoamplifiers" are high efficiency contrast agents for photoacoustic imaging or photoacoustic image-guided therapy.
Plasmonic nanoparticles have shown promise in hyperthermic cancer therapy, both in vitro and in vivo. Previous reports have described hyperthermic ablation using targeted and nontargeted nanoparticles internalized by cancer cells, but most reports do not describe a theoretical analysis for determining optimal parameters. The focus of the current research was first to evaluate the spatiotemporal temperature distribution and cell death induced by extracellular hyperthermia in which gold nanorods (GNRs) were maintained in the dispersion outside human prostate cancer cells. The nanorod dispersion was irradiated with near-infrared (NIR) laser, and the spatiotemporal distribution of temperature was determined experimentally. This information was employed to develop and validate theoretical models of spatiotemporal temperature profiles for gold nanorod dispersions undergoing laser irradiation and the impact of the resulting heat generation on the viability of human prostate cancer cells. A cell injury/death model was then coupled to the heat transfer model to predict spatial and temporal variations in cell death and injury. The model predictions agreed well with experimental measurements of both temperature and cell death profiles. Finally, the model was extended to examine the impact of selective binding of gold nanorods to cancer cells compared to nonmalignant cells, coupled with a small change in cell injury activation energy. The impact of these relatively minor changes results in a dramatic change in the overall cell death rate. Taken together, extracellular hyperthermia using gold nanorods is a promising strategy, and tailoring the cellular binding efficacy of nanorods can result in varying therapeutic efficacies using this approach.
Successful development of safe and effective nanoprobes for tumor targeting and selective therapy is a challenging task. Although gold nanorods(GNRs) have the potential to perform such a role, the toxicity of surfactant cetyltrimethylammonium bromides (CTAB) on their surfaces limits their applications. Here, polyamidoamine dendrimer was applied to replace CTAB molecules on the surface of gold nanorods. When the resultant dendrimer-modified gold nanorods conjugated with arginine-glycine-aspartic acid (RGD) peptides, they showed highly selective targeting and destructive effects on the cancer cells and solid tumors under near-infrared laser irradiation. Also, we successfully observed the disappearance of tumors implanted in four sample mice from test group of ten. High-performance RGD-conjugated dendrimer-modified GNR nanoprobes exhibit great potential in applications such as tumor targeting, imaging, and selective photothermal therapy.
Gold nanorods of different aspect ratios are prepared using the growth-directing surfactant, cetyltrimethylammonium bromide (CTAB), which forms a bilayer on the gold nanorod surface. Toxicological assays of CTAB-capped nanorod solutions with human colon carcinoma cells (HT-29) reveal that the apparent cytotoxicity is caused by free CTAB in solution. Overcoating the nanorods with polymers substantially reduces cytotoxicity. The number of nanorods taken up per cell, for the different surface coatings, is quantitated by inductively coupled plasma mass spectrometry on washed cells; the number of nanorods per cell varies from 50 to 2300, depending on the surface chemistry. Serum proteins from the biological media, most likely bovine serum albumin, adsorb to gold nanorods, leading to all nanorod samples bearing the same effective charge, regardless of the initial nanorod surface charge. The results suggest that physiochemical surface properties of nanomaterials change substantially after coming into contact with biological media. Such changes should be taken into consideration when examining the biological properties or environmental impact of nanoparticles.
The adoptive transfer of tumor-infiltrating lymphocytes (TIL) expanded in interleukin-2 (IL-2) to mice bearing micrometastases
from various types of tumors showed that TIL are 50 to 100 times more effective in their therapeutic potency than are lymphokine-activated
killer (LAK) cells. Therefore the use of TIL was explored for the treatment of mice with large pulmonary and hepatic metastatic
tumors that do not respond to LAK cell therapy. Although treatment of animals with TIL alone or cyclophosphamide alone had
little impact, these two modalities together mediated the elimination of large metastatic cancer deposits in the liver and
lung. The combination of TIL and cyclophosphamide was further potentiated by the simultaneous administration of IL-2. With
the combination of cyclophosphamide, TIL, and IL-2, 100% of mice (n = 12) bearing the MC-38 colon adenocarcinoma were cured
of advanced hepatic metastases, and up to 50% of mice were cured of advanced pulmonary metastases. Techniques have been developed
to isolate TIL from human tumors. These experiments provide a rationale for the use of TIL in the treatment of humans with
advanced cancer.
Recently, we have reported a novel protocol for the generation of highly efficient cytotoxic effector cells by culturing PBLs in the presence of IFN-gamma, IL-2, mAb against CD3, and IL-1 alpha. We have termed these cultures cytokine-induced killer (CIK) cells because the phenotype of the cells with the greatest cytotoxicity expresses both the T cell marker CD3 and the NK cell marker CD56. Cells with this phenotype are rare (approximately 1 to approximately 5%) in uncultured PBLs. CD3+CD56+ cells expand nearly 1000-fold under these culture conditions. The majority of the CD3+CD56+ cytotoxic cells in CIK cultures were derived from CD3+CD56- T cells, and not CD3-CD56+ NK cells. Expression of CD56, but not CD8, on CD3+ cells correlated with the greatest cytotoxicity against various cellular targets. We have used mice with severe combined immunodeficiency (SCID) injected with human lymphoma cells to evaluate the in vivo antitumor effects of CIK vs lymphokine-activated killer (LAK) cells. Groups of animals inoculated with 1 x 10(6) SU-DHL4 cells (a human B lymphoma cell line with a t(14;18) chromosomal translocation), injected 1 day later with CIK cells either i.v. or i.p., had significantly prolonged survival compared with control animals injected with tumor cells alone (median survival 90 days vs 58 days, p < 0.001) or animals treated with LAK cells (median survival 90 days vs 68 days, p < 0.002). Approximately 30% of the SCID mice challenged with SU-DHL4 cells and treated with CIK cells became long-term survivors compared with none of the animals treated with LAK cells. No molecular evidence of occult lymphoma was found in the CIK cell-treated long-term survivors when their bone marrow, spleen, liver, and lung were analyzed by t(14;18) PCR at the end of 6 mo. By using these culture conditions, a novel population of cytotoxic cells can be generated readily from T cells that have superior in vivo antitumor activity in SCID mice, as compared with LAK cells.
Cytokine-induced killer (CIK) cells are non-major histocompatibility complex-restricted cytotoxic cells generated by incubation of peripheral blood lymphocytes with anti-CD3 monoclonal antibody (MoAb), interleukin-2 (IL-2), IL-1, and interferon-gamma. Cells with the greatest effector function in CIK cultures coexpress CD3 and CD56 surface molecules. CIK cell cytotoxicity can be blocked by MoAbs directed against the cell surface protein leukocyte function associated antigen-1 but not by anti-CD3 MoAbs. CIK cells undergo release of cytoplasmic cytotoxic granule contents to the extracellular space upon stimulation with anti-CD3 MoAbs or susceptible target cells. Maximal granule release was observed from the CD3+ CD56+ subset of effector cells. The cytoplasmic granule contents are lytic to target cells. Treatment of the effector cells with a cell-permeable analog of cyclic adenosine monophosphate (cAMP) inhibited anti-CD3 MoAb and target cell-induced degranulation and cytotoxicity of CIK cells. The immunosuppressive drugs cyclosporin (CsA) and FK506 inhibited anti-CD3-mediated degranulation, but did not affect cytotoxicity of CIK cells against tumor target cells. In addition, degranulation induced by target cells was unaffected by CsA and FK506. Our results indicate that two mechanisms of cytoplasmic granule release are operative in the CD3+ CD56+ killer cells; however, cytotoxicity proceeds through a cAMP-sensitive, CsA- and FK506-insensitive pathway triggered by yet-to-be-identified target cell surface molecules.
Cytokine-induced killer (CIK) cells are highly efficient cytotoxic effector cells capable of lysing tumor cell targets. Cultures of human CIK cells have been shown to have enhanced cytotoxicity and to proliferate more rapidly than lymphokine activated killer (LAK) cells by both in vitro and in vivo studies. In this report, we have further characterized the phenotype of CIK cells and explored the molecular structures involved in CIK-mediated cell lysis of tumor target cells. The dominant cell phenotype in CIK cell cultures expresses the alpha, beta T cell receptor (TCR-alpha/beta). In addition, CD56 is expressed on the main effector cell on a per-cell basis. Interestingly, the total number of CD56+ cells increases more than 1000-fold during the generation of CIK cells, mainly due to expansion of CD56+ cells coexpressing CD3. The higher lytic activity of CIK cells as compared to LAK cells is mainly due to the higher proliferation of CD3+CD56+ cells and to the cytotoxic activity of TCR-alpha/beta+ cells in CIK cell cultures. CIK-mediated cellular lysis is non-major histocompatibility antigen (MHC) restricted. The cytotoxic effect of CIK cells against tumor targets is blocked by antibodies directed against lymphocyte function-associated antigen (LFA-1) and its counter receptor, intercellular adhesion molecule-1 (ICAM-1).
Over the past two decades, attempts have been made to develop immunotherapy for patients with cancer. A significant obstacle to the development of successful adoptive immunotherapy has been the availability of appropriate cytotoxic cells. Immunologic effector cells such as lymphokine-activated killer (LAK) cells, activated T cells such as tumor-infiltrating lymphocytes (TILs), and cytokine-induced killer (CIK) cells may be suitable to remove residual tumor cells.
Immunologic effector cells termed cytokine-induced killer (CIK) cells are generated in vitro from peripheral blood lymphocytes by addition of interferon-gamma, interleukin (IL)-2, IL-1 and an antibody against CD3. CIK cells have been shown to eradicate established tumors in a SCID mouse/human lymphoma model. CIK cells are dependent on exogenous cytokines such as IL-2, IL-7, or IL-12. We studied the effect of these cytokines in detail. Cellular proliferation was analyzed using an MTT proliferation assay, surface antigen expression via flow cytometry, cytotoxic activity using an LDH release assay, and apoptosis via flow cytometric analysis. IL-2, IL-7 and IL-12 led to significant growth of lymphocytes. Cells grown in IL-2 and IL-7 showed higher proliferation rates than cells grown in IL-12 according to the MTT assay. Concerning surface antigen expression, exogenous IL-7 led to a decrease in IL-7 receptor expression (4.8% from 60.4%) and exogenous IL-2 to a decrease in IL-2 receptor expression (61.2% from 73.2%). CD28 expression was higher in cells grown in IL-7 (77.3%) than in cells grown in IL-2 (62.5%). IL-12 led to a decrease in ICAM-1 adhesion molecule expression (57.7% from 76.7%) and an increase in CD56 expression compared with exogenous IL-7. IL-7 led to higher number of CD4-positive cells than IL-2 (53.0% vs 49.5%). No significant difference was found between IL-2, IL-7 and IL-12 in cytotoxic activity measured in an LDH release assay. Small amounts of apoptotic cells were found with all cytokines. However, the percentage of necrotic cells was higher with exogenous IL-12 than with IL-2 or IL-7. In summary, CIK cells can be generated using exogenous IL-2, IL-7 or IL-12. No difference in cytotoxic activity was found. However, significant differences were found in cell proliferation rates, antigen expression and percentage of necrotic cells.
This review explores recent work directed towards more targeted treatment of cancer, whether through more specific anti-cancer agents or through methods of delivery. These areas include delivery by avoiding the reticuloendothelial system, utilizing the enhanced permeability and retention effect and tumor-specific targeting. Treatment opportunities using antibody-targeted therapies are summarized. The ability to treat cancer by targeting delivery through angiogenesis is also discussed and antiangiogenic drugs in clinical trials are presented. Delivery methods that specifically use nanoparticles are also highlighted, including both degradable and nondegradable polymers.
Photoacoustic tomography (PAT) in a circular scanning configuration was developed to image deeply embedded optical heterogeneity in biological tissues. While the optical penetration was maximized with near-infrared laser pulses of 800-nm wavelength, the optical contrast was enhanced by Indocyanine Green (ICG) dye whose absorption peak matched the laser wavelength. This optimized PAT was able to image objects embedded at depths of as much as 5.2 cm, 6.2 times the 1/e optical penetration depth, in chicken breast muscle at a resolution of <780 microm and a sensitivity of <7 pmol of ICG in blood. The resolution was found to deteriorate slowly with increasing imaging depth. The effects of detection bandwidth on the quality of images acquired simultaneously by four different ultrasonic transducers are described.
The induction of apoptosis and antiproliferation effect of cytokine-induced killer cells (CIK cells) on MGC- 803 cells and its mechanisms were studied by using a tetrazolium dye-based (MTT) assay. Morphological changes were observed by using inverted microscope, haematoxylin/eosin (HE) staining, scanning electron microscope, and transmission electron microscope. The TdT-mediated dUTP nick and labeling (TUNEL) method was used to detect the apoptosis-induced by CIK cells. The expression rate of p53, p16, C-myc, Bcl-2, and Bax proteins were studied by using immunohistochemical staining. There were significant differences according to varied effector-target ratios at the same working time (p < 0.01) and the same effector-target ratios at different working times (p < 0.01). Inverted microscope and HE staining observation showed that CIK cells were closer to the target cells and formed a typical "rose" shape. The scanning electron microscope showed that most target cells had undergone apoptosis and many "apoptotic bodies," and that transmission electron microscopy showed condensed chromatin, disintegration of the nucleolus, vacuoles in the cytoplasm, and apoptotic bodies appearing in most target cells. TUNEL analysis showed that apoptotic cells contract and turn navy blue in nuclei or perinuclei in the experimental group. The apoptotic rate was upmodulated between 5 and 14 hours and downregulated between 14 and 24 hours in the "CIK" experimental group. The expression of p53, p16, C-myc, and Bcl-2 were significantly downregulated (p < 0.01), and the expression of Bax was upregulated over the time of coculture in the "CIK" experimental group, compared to the control group. Our studies suggested that CIK cells induce apoptosis and have an antiproliferative effect on human MGC-803 gastric cancer cells. The CIK cells kill MGC-803 gastric cancer cells by inducing apoptosis in the early stage and by inducing necrosis in the late stage through the downregulating expression of p53, C-myc, and Bcl-2 and the upregulating expression of Bax.
Gold nanorods prepared in hexadecyltrimethylammonium bromide (CTAB) solution are expected to provide novel materials for photothermal therapy and photo-controlled drug delivery systems. Since gold nanorods stabilized with CTAB show strong cytotoxicity, we developed a technique to modify these with polyethyleneglycol (PEG) for medical applications. PEG-modification was achieved by adding mPEG-SH in the CTAB solution, then, excess CTAB was removed by dialysis. PEG-modified gold nanoparticles showed a nearly neutral surface, and had little cytotoxicity in vitro. Following intravenous injection into mice, 54% of injected PEG-modified gold nanoparticles were found in blood at 0.5 h after intravenous injection, whereas most of gold was detected in the liver in the case of original gold nanorods stabilized with CTAB.
Human oral cancer cells are found to assemble and align gold nanorods conjugated to anti-epidermal growth factor receptor (anti-EGFR) antibodies. Immnoconjugated gold nanorods and nanospheres were shown previously to exhibit strong Rayleigh (Mie) scattering useful for imaging. In the present letter, molecules near the nanorods on the cancer cells are found to give a Raman spectrum that is greatly enhanced (due to the high surface plasmon field of the nanorod assembly in which their extended surface plasmon fields overlap), sharp (due to a homogeneous environment), and polarized (due to anisotropic alignments). These observed properties can be used as diagnostic signatures for cancer cells.
Phenotypic characterization and identification of effector cells involved in tumor cell recognition of cytokine-induced killer cells
- I Schmidt-Wolf
- P Lefterova
- B Mehta
- L Fernandez
- D Huhn
- K Blume
- IL Weissman
- RS Neqrin
Schmidt-Wolf I, Lefterova P, Mehta B, Fernandez L, Huhn D, Blume K,
Weissman IL, Neqrin RS (1993) Phenotypic characterization and
identification of effector cells involved in tumor cell recognition of cytokineinduced killer cells. Exp Hematol 21:1673-1679