Tumor Angiogenesis Phenotyping by Nanoparticle-facilitated Magnetic Resonance and Near-infrared Fluorescence Molecular Imaging

AbstractOne of the challenges of tailored antiangiogenic therapy is the ability to adequately monitor the angiogenic activity of a malignancy in response to treatment. The αvβ3 integrin, highly overexpressed on newly formed tumor vessels, has been successfully used as a target for Arg-Gly-Asp (RGD)-functionalized nanoparticle contrast agents. In the present study, an RGD-functionalized nanocarrier was used to image ongoing angiogenesis in two different xenograft tumor models with varying intensities of angiogenesis (LS174T > EW7). To that end, iron oxide nanocrystals were included in the core of the nanoparticles to provide contrast for T2*-weighted magnetic resonance imaging (MRI), whereas the fluorophore Cy7 was attached to the surface to enable near-infrared fluorescence (NIRF) imaging. The mouse tumor models were used to test the potential of the nanoparticle probe in combination with dual modality imaging for in vivo detection of tumor angiogenesis. Pre-contrast and post-contrast images (4 hours) were acquired at a 9.4-T MRI system and revealed significant differences in the nanoparticle accumulation patterns between the two tumor models. In the case of the highly vascularized LS174T tumors, the accumulation was more confined to the periphery of the tumors, where angiogenesis is predominantly occurring. NIRF imaging revealed significant differences in accumulation kinetics between the models. In conclusion, this technology can serve as an in vivo biomarker for antiangiogenesis treatment and angiogenesis phenotyping

Synthesis and in vitro evaluation of a multifunctional and surface-switchable nanoemulsion platform

We present a multifunctional nanoparticle platform that has targeting moieties shielded by a matrix metalloproteinase-2 (MMP2) cleavable PEG coating. Upon incubation with MMP2 this surface-switchable coating is removed and the targeting ligands become available for binding. The concept was evaluated in vitro using biotin and αvβ3-integrin-specific RGD-peptide functionalized nanoparticles.National Heart, Lung, and Blood InstituteNational Institutes of Health (U.S.) (Program of Excellence in Nanotechnology (PEN) Award Contract HHSN268201000045C

Data integration for large-scale models of species distributions

With the expansion in the quantity and types of biodiversity data being collected, there is a need to find ways to combine these different sources to provide cohesive summaries of species’ potential and realized distributions in space and time. Recently, model-based data integration has emerged as a means to achieve this by combining datasets in ways that retain the strengths of each. We describe a flexible approach to data integration using point process models, which provide a convenient way to translate across ecological currencies. We highlight recent examples of large-scale ecological models based on data integration and outline the conceptual and technical challenges and opportunities that arise

Synthesis and in vitro evaluation of a multifunctional and surface-switchable nanoemulsion platform

We present a multifunctional nanoparticle platform that has targeting moieties shielded by a matrix metalloproteinase-2 (MMP2) cleavable PEG coating. Upon incubation with MMP2 this surface-switchable coating is removed and the targeting ligands become available for binding. The concept was evaluated in vitro using the biotin and αvβ3-integrin-specific RGD-peptide functionalized nanoparticles

The elusive Heisenberg limit in quantum enhanced metrology

We provide efficient and intuitive tools for deriving bounds on achievable precision in quantum enhanced metrology based on the geometry of quantum channels and semi-definite programming. We show that when decoherence is taken into account, the maximal possible quantum enhancement amounts generically to a constant factor rather than quadratic improvement. We apply these tools to derive bounds for models of decoherence relevant for metrological applications including: dephasing,depolarization, spontaneous emission and photon loss.Comment: 10 pages, 4 figures, presentation imporved, implementation of the semi-definite program finding the precision bounds adde

Modified natural nanoparticles as contrast agents for medical imaging

The development of novel and effective contrast agents is one of the drivers of the ongoing improvement in medical imaging. Many of the new agents reported are nanoparticle-based. There are a variety of natural nanoparticles known, e.g. lipoproteins, viruses or ferritin. Natural nanoparticles have advantages as delivery platforms such as biodegradability. In addition, our understanding of natural nanoparticles is quite advanced, allowing their adaptation as contrast agents. They can be labeled with small molecules or ions such as Gd(3+) to act as contrast agents for magnetic resonance imaging, (18)F to act as positron emission tomography contrast agents or fluorophores to act as contrast agents for fluorescence techniques. Additionally, inorganic nanoparticles such as iron oxide, gold nanoparticles or quantum dots can be incorporated to add further contrast functionality. Furthermore, these natural nanoparticle contrast agents can be re-routed from their natural targets via the attachment of targeting molecules. In this review, we discuss the various modified natural nanoparticles that have been exploited as contrast agent

Heparin blocks transfer of extracellular vesicles between donor and recipient cells

Extracellular vesicles (EVs) have been implicated in tumorigenesis. Biomolecules which can block EV binding and uptake into recipient cells may be of therapeutic value as well as enhance understanding of EV biology. Here, we show that heparin interacts with uptake of tumor-derived as well as non-tumor-derived EVs into recipient cells. Incubation of glioma cell-derived EVs with heparin resulted in micron-sized structures observed by transmission electron microscopy, with EVs clearly visible within these structures. Inclusion of heparin greatly diminished transfer of labeled EVs from donor to recipient tumor cells. We also show a direct interaction between heparin and EVs using confocal microscopy. We found that the block in EV uptake was at the level of cell binding and not internalization. Finally, incubation of glioma-derived EVs containing EGFRvIII mRNA with heparin reduced transfer of this message to recipient cells. The effect of heparin on EVs uptake may provide a unique tool to study EV function. It may also foster research of heparin or its derivatives as a therapeutic for disease in which EVs play a rol

Multifunctional imaging nanoprobes

Multifunctional imaging nanoprobes have proven to be of great value in the research of pathological processes, as well as the assessment of the delivery, fate, and therapeutic potential of encapsulated drugs. Moreover, such probes may potentially support therapy schemes by the exploitation of their own physical properties, e.g., through thermal ablation. This review will present four classes of nanoparticulate imaging probes used in this area: multifunctional probes (1) that can be tracked with at least three different and complementary imaging techniques, (2) that carry a drug and have bimodal imaging properties, (3) that are employed for nucleic acid delivery and imaging, and (4) imaging probes with capabilities that can be used for thermal ablation. We will highlight several examples where the suitable combination of different (bio)materials like polymers, inorganic nanocrystals, fluorophores, proteins/peptides, and lipids can be tailored to manufacture multifunctional probes to accomplish nanomaterials of each of the aforementioned classes. Moreover, it will be demonstrated how multimodality imaging approaches improve our understanding of in vivo nanoparticle behavior and efficacy at different levels, ranging from the subcellular level to the whole bod

The biological properties of iron oxide core high-density lipoprotein in experimental atherosclerosis

Lipoproteins are a family of plasma nanoparticles responsible for the transportation of lipids throughout the body. High-density lipoprotein (HDL), the smallest of the lipoprotein family, measures 7-13 nm in diameter and consists of a cholesteryl ester and triglyceride core that is covered with a monolayer of phospholipids and apolipoproteins. We have developed an iron oxide core HDL nanoparticle (FeO-HDL), which has a lipid based fluorophore incorporated in the phospholipid layer. This nanoparticle provides contrast for optical imaging, magnetic resonance imaging (MRI) and transmission electron microscopy (TEM). Consequently, FeO-HDL can be visualized on the anatomical, cellular and sub-cellular level. In the current study we show that the biophysical features of FeO-HDL closely resemble those of native HDL and that FeO-HDL possess the ability to mimic HDL characteristics both in vitro as well as in vivo. We demonstrate that FeO-HDL can be applied to image HDL interactions and to investigate disease settings where HDL plays a key function. More generally, we have demonstrated a multimodal approach to study the behavior of biomaterials in vitro as well as in vivo. The approach allowed us to study nanoparticle dynamics in circulation, as well as nanoparticle targeting and uptake by tissues and cells of interest. Moreover, we were able to qualitatively assess nanoparticle excretion, critical for translating nanotechnologies to the clini

The effect of nanoparticle polyethylene glycol surface density on ligand-directed tumor targeting studied in vivo by dual modality imaging

The development and application of nanoparticles as in vivo delivery vehicles for therapeutic and/or diagnostic agents has seen a drastic growth over the last decades. Novel imaging techniques allow real-time in vivo study of nanoparticle accumulation kinetics at the level of the cell and targeted tissue. Successful intravenous application of such nanocarriers requires a hydrophilic particle surface coating, of which polyethylene glycol (PEG) has become the most widely studied and applied. In the current study, the effect of nanoparticle PEG surface density on the targeting efficiency of ligand-functionalized nanoemulsions was investigated. We synthesized 100 nm nanoemulsions with a PEG surface density varying from 5 to 50 mol %. Fluorescent and paramagnetic lipids were included to allow their multimodal detection, while RGD peptides were conjugated to the PEG coating to obtain specificity for the α(v)β(3)-integrin. The development of a unique experimental imaging setup allowed us to study, in real time, nanoparticle accumulation kinetics at (sub)-cellular resolution in tumors that were grown in a window chamber model with confocal microscopy imaging, and at the macroscopic tumor level in subcutaneously grown xenografts with magnetic resonance imaging. Accumulation in the tumor occurred more rapidly for the targeted nanoemulsions than for the nontargeted versions, and the PEG surface density had a strong effect on nanoparticle targeting efficiency. Counterintuitively, yet consistent with the PEG density conformation models, the highest specificity and targeting efficiency was observed at a low PEG surface densit