Nanoparticles containing magnetic materials, such as magnetite (Fe3O4), are particularly useful for imaging and separation techniques. As these nanoparticles are generally considered to be biologically and chemically inert, they are typically coated with metal catalysts, antibodies or enzymes to increase their functionality as separation agents. Here, we report that magnetite nanoparticles in fact possess an intrinsic enzyme mimetic activity similar to that found in natural peroxidases, which are widely used to oxidize organic substrates in the treatment of wastewater or as detection tools. Based on this finding, we have developed a novel immunoassay in which antibody-modified magnetite nanoparticles provide three functions: capture, separation and detection. The stability, ease of production and versatility of these nanoparticles makes them a powerful tool for a wide range of potential applications in medicine, biotechnology and environmental chemistry.

Intrinsic peroxidase-like activity of ferromagnetic nanoparticles

The rapid recognition of intravenously injected colloidal carriers, such as liposomes and polymeric nanospheres from the blood by Kupffer cells, has initiated a surge of development for "Kupffer cell-evading" or long-circulating particles. Such carriers have applications in vascular drug delivery and release, site-specific targeting (passive as well as active targeting), as well as transfusion medicine. In this article we have critically reviewed and assessed the rational approaches in the design as well as the biological performance of such constructs. For engineering and design of long-circulating carriers, we have taken a lead from nature. Here, we have explored the surface mechanisms, which affords red blood cells long-circulatory lives and the ability of specific microorganisms to evade macrophage recognition. Our analysis is then centered where such strategies have been translated and fabricated to design a wide range of particulate carriers (e.g., nanospheres, liposomes, micelles, oil-in-water emulsions) with prolonged circulation and/or target specificity. With regard to the targeting issues, attention is particularly focused on the importance of physiological barriers and disease states.

Long-Circulating and Target-Specific Nanoparticles: Theory to Practice

The integrin family of cell adhesion receptors regulates a diverse array of cellular functions crucial to the initiation, progression and metastasis of solid tumours. The importance of integrins in several cell types that affect tumour progression has made them an appealing target for cancer therapy. Integrin antagonists, including the alphavbeta3 and alphavbeta5 inhibitor cilengitide, have shown encouraging activity in Phase II clinical trials and cilengitide is currently being tested in a Phase III trial in patients with glioblastoma. These exciting clinical developments emphasize the need to identify how integrin antagonists influence the tumour and its microenvironment.

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Integrins in cancer: biological implications and therapeutic opportunities

Poly(ethylene glycol) (PEG) is the most used polymer and also the gold standard for stealth polymers in the emerging field of polymer-based drug delivery. The properties that account for the overwhelming use of PEG in biomedical applications are outlined in this Review. The first approved PEGylated products have already been on the market for 20 years. A vast amount of clinical experience has since been gained with this polymer--not only benefits, but possible side effects and complications have also been found. The areas that might need consideration and more intensive and careful examination can be divided into the following categories: hypersensitivity, unexpected changes in pharmacokinetic behavior, toxic side products, and an antagonism arising from the easy degradation of the polymer under mechanical stress as a result of its ether structure and its non-biodegradability, as well as the resulting possible accumulation in the body. These possible side effects will be discussed in this Review and alternative polymers will be evaluated.

Poly(ethylene glycol) in Drug Delivery: Pros and Cons as Well as Potential Alternatives

Bevacizumab plus Irinotecan,Fluorouracil,and Leucovorin for Metastatic Colorectal Cancer

467 Objectives There is an urgent need for a method that would noninvasively determine beta cell mass (BCM) loss after transplantation in vivo in patients. We have developed a noninvasive imaging technique that specifically visualizes BCM in vivo. This method is based on the targeting of the glucagon-like peptide 1 receptor (GLP-1R) which is expressed at high levels on pancreatic beta cells. Our tracer specifically binds to the GLP-1R: In-111-Exendin-3. We examined whether intramuscularly transplanted islets in rats could be visualized by SPECT after i.v. injection with radiolabeled Exendin-3. Methods Islets (250,500,750,1000) were isolated from Wag/Rij rats and transplanted in the thigh muscle and vehicle was injected into the contralateral muscle as a control. Two,7,14,21,28,42 and 77 days after transplantation In-111-Exendin-3 was injected i.v. and SPECT images were acquired 1h post injection using a U-SPECT II microSPECT scanner. At the last day the rats were euthanized and biodistribution, microautoradiography (MAR) and immunohistochemistry (IHC) was performed. Results The transplanted islets were clearly visualized with SPECT at all time points (Fig.1). Tracer uptake was linearly correlated with number of islets transplanted (Fig.3). After graft was established, uptake in the islets was stable over time (Fig.2). Ex vivo MAR showed high uptake of In-111-Exendin-3 in the islets. IHC confirmed that islets were viable and produced insulin. Tracer uptake in the muscle with islets was higher than uptake in the control muscle (0.27±0.06%ID vs 0.07±0.02%ID). Conclusions Transplanted islets were clearly delineated with SPECT after injection of In-111-Exendin-3. SPECT images can be analyzed quantitatively, enabling longitudinal monitoring of BCM over time with a linear correlation of SPECT quantification with the number of islets transplanted. In-111-Exendin-3 could potentially be used for noninvasive BCM determination. Research Support Supported by NIH grant 1R01AG030328-01 and the European Community9s 7th FP (FP7/2007-2013) under grant agreement n° 222980

In vivo visualization of transplanted islets in rats by SPECT with In-111-Exendin-3

Purpose: There is increasing evidence that the chimeric monoclonal antibody G250 (cG250) can be internalized by G250 antigen-expressing renal cell carcinoma (RCC) cells. Thus, accumulation in tumors of cG250 labeled with residualizing radionuclides might be higher than that of nonresidualizing 131I-cG250. Here, we present a study comparing intrapatiently the accumulation of 131I-cG250 and 111In-cG250 in RCC metastases.

Experimental Design: Five patients were i.v. injected with 222 MBq 111In-ITC-DTPA-cG250 and 222 MBq 131I-cG250 on days 0 and 4, respectively. Directly and 4 days after the injection of both antibody preparations, whole body gamma camera images were acquired. The scintigraphic images were analyzed visually and quantitatively. The radioactivity in tissues was calculated and expressed as percentage injected dose in organs or percentage injected dose/g in metastases. For the latter, tumor:blood ratios were also calculated. Twenty-five metastases were analyzed completely.

Results: At 4 days postinjection, the 111In-ITC-DTPA-cG250 images revealed more metastatic lesions ( n = 47) than 131I-cG250 ( n = 30). Quantitative analysis of the images showed higher activities of 111In-ITC-DTPA-cG250 than 131I-cG250 in 20 of 25 lesions. The mean overall half-life of both antibody preparations in plasma was similar.

Conclusions: 111In-ITC-DTPA-cG250 outperformed 131I-cG250 for visualization of metastatic RCC lesions, not just because of the superior gamma camera characteristics of 111In, but more importantly, also because higher tumor:blood ratios were obtained. The higher activities of 111In-ITC-DTPA-cG250 in metastatic lesions might be caused by internalization and subsequent intracellular retention of the radiolabel, implying that in future radioimmunotherapy trials with cG250 in RCC patients, the use of a residualizing radionuclide should be considered.

Targeting of Metastatic Renal Cell Carcinoma with the Chimeric Monoclonal Antibody G250 Labeled with 131I or 111In

With interest we read the paper by Lee et al., entitled \"Immunoscintigraphy in the detection of tuberculosis with radiolabeled antibody fragment against Mycobacterium boris bacillus Calmette-Gu6rin: a preliminary study in a rabbit model\", dealing with specific targeting of tuberculous lesions [1]. Although their objective demonstration of specific antibody uptake in tuberculous infectionis attractive, we have encountered several problems with the presentation and especially the interpretation of the results: 1. It is not possible to induce a tuberculous infection with heat-killed Mycobacteriurn tuberculosis (BCG): what one induces is dead-BCG granulomas. 2. It is not surprising that the antibody performs less well in the acute syphilis model (injection of antibody 10 days after inoculation) than in the subacute deadBCG model (injection of antibody 6 weeks after inoculation). As we have shown previously, iodinated proteins do not show prolonged retention in acute infection due to the high turnover rate in these lesions [2, 3]. In the acute syphilis model, one observes a relatively higher increase in vascular permeability, resulting in a high influx rate (initially high target to background ratios), but also a high efflux rate (relatively poor target to background ratios at later time points). The data reported by Lee et al. further emphasize the role of the radiolabel in imaging experimental infectious disease. Fundamental differences between indium-111 labelled and iodinated proteins both specific and non-specific antibodies can be observed in the efflux rate out of the lesion due to the properties of the radiolabel after release from the protein [4-6]. For these reasons, conclusions on the performance of a specific antibody for subacute infection cannot be derived from comparison to an acute model. 3. The authors confirmed the presence of antigen in the cytoplasm of histiocytes in the tuberculous lesions by immunohistochemical and acid-fast bacilli stains. However, their conclusion that antigen-antibody reaction is therefore an important factor in accumulation of the antibody is invalid since antibody-antigen interaction is not demonstrated. This can only be done with autoradiographic methods showing association of the radiolabel with the antigen. Even then, it remains to be proven that the intact radiolabel-antibody complex is actually bound to the antigen. Moreover, how do the authors explain specific targeting of intracytoplasmic antigen with large radiolabelled proteins? 4. The non-specific control antibody shows even higher uptake in the BCG foci than the BCG-specific antibody. While the so-called specific antibody is washed out of the focus after 24 h, the control antibody shows persistently high uptake, even at 48 h. This is perhaps the strongest argument against specific targeting of the dead-BCG bacilli with the specific antibody. The results of Lee et al. are very similar to those reported by Rubin et al. [7]. In conclusion, the data presented by Lee et al. fortunately confirm previous studies with regard to the relevance of non-specific uptake of radiolabelled proteins in infectious foci and the pitfalls encountered when interpreting the results of animal data [8]. Unfortunately, the authors' conclusions are not in concordance with their results.

Specific antibody uptake in tuberculosis

Objectives: It has been postulated that radiopharmaceuticals can be used to predict the therapeutic response to (chemo)therapy, which could lead to individualized treatment regimens. In this study, 18F-deoxyglucose, 99mTc-tetrofosmin, 125I-deoxyuridineribose, and 125I-methyltyrosine were tested for this purpose. Methods: The uterine sarcoma cell line MES-SA (MDR–) and its multidrug resistant variant, MES-SA/Dx5 (MDR+), were used. The MDR+ cells express high levels of P-glycoprotein, which makes them relatively resistant to various chemotherapeutic agents. Cells were cultured in the presence of escalating concentrations of doxorubicin, and the cellular uptake of the radiopharmaceuticals was determined. Results: Decreasing 18F-deoxyglucose uptake at escalating doxorubicin concentrations reflected the chemosensitivity of the cells: 18F-deoxyglucose uptake in the MDR– cells was reduced to 40% of the baseline level in the presence of 1 mM of doxorubicin, compared to 74% in the MDR+ cells. The 125Ideoxyuridiner...

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Otto C. Boerman

Papers

In vivo visualization of transplanted islets in rats by SPECT with In-111-Exendin-3

Targeting of Metastatic Renal Cell Carcinoma with the Chimeric Monoclonal Antibody G250 Labeled with 131I or 111In

Specific antibody uptake in tuberculosis

Tracers to monitor the response to chemotherapy: in vitro screening of four radiopharmaceuticals.

336 Sorafenib decreases Indium-111-girentuximab tumor uptake in clear cell renal cell carcinoma patients