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      Surveillance nanotechnology for multi-organ cancer metastases

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          Abstract

          The identification and molecular profiling of early metastases remains a major challenge in cancer diagnostics and therapy. Most in vivo imaging methods fail to detect small cancerous lesions, a problem that is compounded by the distinct physical and biological barriers associated with different metastatic niches. Here, we show that intravenously injected rare-earth-doped albumin-encapsulated nanoparticles emitting short-wave infrared light (SWIR) can detect targeted metastatic lesions in vivo, allowing for the longitudinal tracking of multi-organ metastases. In a murine model of basal human breast cancer, the nanoprobes enabled whole-body SWIR detection of adrenal gland microlesions and bone lesions that were undetectable via contrast-enhanced magnetic resonance imaging (CE-MRI) as early as, respectively, three weeks and five weeks post-inoculation. Whole-body SWIR imaging of nanoprobes functionalized to differentially target distinct metastatic sites and administered to a biomimetic murine model of human breast cancer resolved multi-organ metastases that showed varied molecular profiles at the lungs, adrenal glands and bones. Real-time surveillance of lesions in multiple organs should facilitate pre-therapy and post-therapy monitoring in preclinical settings.

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          Most cited references31

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          Albumin as a drug carrier: design of prodrugs, drug conjugates and nanoparticles.

          Albumin is playing an increasing role as a drug carrier in the clinical setting. Principally, three drug delivery technologies can be distinguished: coupling of low-molecular weight drugs to exogenous or endogenous albumin, conjugation with bioactive proteins and encapsulation of drugs into albumin nanoparticles. The accumulation of albumin in solid tumors forms the rationale for developing albumin-based drug delivery systems for tumor targeting. Clinically, a methotrexate-albumin conjugate, an albumin-binding prodrug of doxorubicin, i.e. the (6-maleimido)caproylhydrazone derivative of doxorubicin (DOXO-EMCH), and an albumin paclitaxel nanoparticle (Abraxane) have been evaluated clinically. Abraxane has been approved for treating metastatic breast cancer. An alternative strategy is to bind a therapeutic peptide or protein covalently or physically to albumin to enhance its stability and half-life. This approach has been applied to peptides with antinociceptive, antidiabetes, antitumor or antiviral activity: Levemir, a myristic acid derivative of insulin that binds to the fatty acid binding sites of circulating albumin, has been approved for the treatment of diabetes. Furthermore, Albuferon, a fusion protein of albumin and interferon, is currently being assessed in phase III clinical trials for the treatment of hepatitis C and could become an alternative to pegylated interferon. This review gives an account of the different drug delivery systems which make use of albumin as a drug carrier with a focus on those systems that have reached an advanced stage of preclinical evaluation or that have entered clinical trials.
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            Exogenous Expression of N-Cadherin in Breast Cancer Cells Induces Cell Migration, Invasion, and Metastasis

            E- and N-cadherin are calcium-dependent cell adhesion molecules that mediate cell–cell adhesion and also modulate cell migration and tumor invasiveness. The loss of E-cadherin–mediated adhesion has been shown to play an important role in the transition of epithelial tumors from a benign to an invasive state. However, recent evidence indicates that another member of the cadherin family, N-cadherin, is expressed in highly invasive tumor cell lines that lacked E-cadherin expression. These findings have raised the possibility that N-cadherin contributes to the invasive phenotype. To determine whether N-cadherin promotes invasion and metastasis, we transfected a weakly metastatic and E-cadherin–expressing breast cancer cell line, MCF-7, with N-cadherin and analyzed the effects on cell migration, invasion, and metastasis. Transfected cells expressed both E- and N-cadherin and exhibited homotypic cell adhesion from both molecules. In vitro, N-cadherin–expressing cells migrated more efficiently, showed an increased invasion of Matrigel, and adhered more efficiently to monolayers of endothelial cells. All cells produced low levels of the matrix metalloproteinase MMP-9, which was dramatically upregulated by treatment with FGF-2 only in N-cadherin–expressing cells. Migration and invasion of Matrigel were also greatly enhanced by this treatment. When injected into the mammary fat pad of nude mice, N-cadherin–expressing cells, but not control MCF-7 cells, metastasized widely to the liver, pancreas, salivary gland, omentum, lung, lymph nodes, and lumbar spinal muscle. The expression of both E- and N-cadherin was maintained both in the primary tumors and metastatic lesions. These results demonstrate that N-cadherin promotes motility, invasion, and metastasis even in the presence of the normally suppressive E-cadherin. The increase in MMP-9 production by N-cadherin–expressing cells in response to a growth factor may endow them with a greater ability to penetrate matrix protein barriers, while the increase in their adherence to endothelium may improve their ability to enter and exit the vasculature, two properties that may be responsible for metastasis of N-cadherin–expressing cells.
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              Differential uptake of functionalized polystyrene nanoparticles by human macrophages and a monocytic cell line.

              Tumor cell lines are often used as models for the study of nanoparticle-cell interactions. Here we demonstrate that carboxy (PS-COOH) and amino functionalized (PS-NH2) polystyrene nanoparticles of ∼100 nm in diameter are internalized by human macrophages, by undifferentiated and by PMA-differentiated monocytic THP-1 cells via diverse mechanisms. The uptake mechanisms also differed for all cell types and particles when analyzed either in buffer or in medium containing human serum. Macrophages internalized ∼4 times more PS-COOH than THP-1 cells, when analyzed in serum-containing medium. By contrast, in either medium, THP-1 cells internalized PS-NH2 more rapidly than macrophages. Using pharmacological and antisense in vitro knockdown approaches, we showed that, in the presence of serum, the specific interaction between the CD64 receptor and the particles determines the macrophage uptake of particles by phagocytosis, whereas particle internalization in THP-1 cells occurred via dynamin II-dependent endocytosis. PMA-differentiated THP-1 cells differed in their uptake mechanism from macrophages and undifferentiated THP-1 cells by internalizing the particles via macropinocytosis. In line with our in vitro data, more intravenously applied PS-COOH particles accumulated in the liver, where macrophages of the reticuloendothelial system reside. By contrast, PS-NH2 particles were preferentially targeted to tumor xenografts grown on the chorioallantoic membrane of fertilized chicken eggs. Our data show that the amount of internalized nanoparticles, the uptake kinetics, and its mechanism may differ considerably between primary cells and a related tumor cell line, whether differentiated or not, and that particle uptake by these cells is critically dependent on particle opsonization by serum proteins.
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                Author and article information

                Journal
                101696896
                45929
                Nat Biomed Eng
                Nat Biomed Eng
                Nature biomedical engineering
                2157-846X
                13 November 2017
                12 December 2017
                2017
                12 June 2018
                : 1
                : 993-1003
                Affiliations
                [1 ]Department of Biomedical Engineering, Rutgers University, 599 Taylor Road, Piscataway, NJ 08854
                [2 ]Engineering Product Development, Singapore University of Technology and Design, 8 Somapah Rd, Singapore 487372, Singapore
                [3 ]Rutgers Cancer Institute of New Jersey, 195 Little Albany Street, New Brunswick, NJ 08903
                [4 ]Department of Materials Science and Engineering, Rutgers University, 607 Taylor Road, Piscataway, NJ 08855
                [5 ]Department of Chemical & Biochemical Engineering, Rutgers University, Piscataway, NJ 08854, USA
                [6 ]Department of Computer Science, Rutgers University, Piscataway, NJ 08854, USA
                Author notes
                [* ] Corresponding Authors: Prabhas V. Moghe, PhD., Vidya Ganapathy, PhD., & Mark C. Pierce, PhD
                [#]

                H. Kantamneni and M. Zevon are equal first co-authors

                [#]

                Contact Author: Prabhas Moghe, PhD, Distinguished Professor of Biomedical Engineering, moghe@ 123456rutgers.edu ; Phone: 908-230-0147

                Article
                NIHMS918098
                10.1038/s41551-017-0167-9
                5844578
                29531851
                0a88c92e-8d11-4aac-bd85-8f268601a6a6

                Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms

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                Article

                cancer metastasis,nanotechnology,shortwave infrared imaging,rare earths

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