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1.
Targeted drug delivery using functionalized nanocarriers (NCs) is a strategy in therapeutic and diagnostic applications. In this paper we review the recent development of models at multiple length and time scales and their applications to targeting of antibody functionalized nanocarriers to antigens (receptors) on the endothelial cell (EC) surface. Our mesoscale (100 nm-1 μm) model is based on phenomenological interaction potentials for receptor-ligand interactions, receptor-flexure and resistance offered by glycocalyx. All free parameters are either directly determined from independent biophysical and cell biology experiments or estimated using molecular dynamics simulations. We employ a Metropolis Monte Carlo (MC) strategy in conjunction with the weighted histogram analysis method (WHAM) to compute the free energy landscape (potential of mean force or PMF) associated with the multivalent antigen-antibody interactions mediating the NC binding to EC. The binding affinities (association constants) are then derived from the PMF by computing absolute binding free energy of binding of NC to EC, taking into account the relevant translational and rotational entropy losses of NC and the receptors. We validate our model predictions by comparing the computed binding affinities and PMF to a wide range of experimental measurements, including in vitro cell culture, in vivo endothelial targeting, atomic force microscopy (AFM), and flow chamber experiments. The model predictions agree closely and quantitatively with all types experimental measurements. On this basis, we conclude that our computational protocol represents a quantitative and predictive approach for model driven design and optimization of functionalized NCs in targeted vascular drug delivery.  相似文献   

2.
Site directed therapy promises to minimize treatment-limiting systemic effects associated with cytotoxic agents that have no specificity for pathologic tissues. One general strategy is to target cell surface receptors uniquely presented on particular tissues. Highly specific in vivo targeting of an emerging neoplasm through a single molecular recognition mechanism has not generally been successful. Nonspecific binding and specific binding to non-target cells compromise the therapeutic index of small molecule, ubiquitous cancer targeting ligands. In this work, we have designed and fabricated a nanoparticle (NP) construct that could potentially overcome the current limitations of targeted in vivo delivery. Quantum dots (QDs) were functionalized with a poly(ethylene glycol) (PEG) modified to enable specific cleavage by matrix metalloprotease-7 (MMP-7). The QDs were further functionalized with folic acid, a ligand for a cell surface receptor that is overexpressed in many tumors, but also expressed in some normal tissues. The nanomolecular construct is designed so that the PEG initially conceals the folate ligand and construct binding to cells is inhibited. MMP-7 activated peptide cleavage and subsequent unmasking of the folate ligand occurs only near tumor tissue, resulting in a proximity activated (PA) targeting system. QDs functionalized with both the MMP-7 cleavable substrate and folic acid were successfully synthesized and characterized. The proteolytic capability of the dual ligand QD construct was quantitatively assessed by fluorometric analysis and compared to a QD construct functionalized with only the PA ligand. The dual ligand PA nanoparticles studied here exhibit significant susceptibility to cleavage by MMP-7 at physiologically relevant conditions. The capacity to autonomously convert a biopassivated nanostructure to a tissue-specific targeted delivery agent in vivo represents a paradigm change for site-directed therapies.  相似文献   

3.
Nanostructures, which have sizes comparable to biological functional units involved in cellular communication, offer the potential for enhanced sensitivity and spatial resolution compared to planar metal and semiconductor structures. Silicon nanowire (SiNW) field-effect transistors (FETs) have been used as a platform for biomolecular sensors, which maintain excellent signal-to-noise ratios while operating on lengths scales that enable efficient extra- and intracellular integration with living cells. Although the NWs are tens of nanometers in diameter, the active region of the NW FET devices typically spans micrometers, limiting both the length and time scales of detection achievable with these nanodevices. Here, we report a new synthetic method that combines gold-nanocluster-catalyzed vapor-liquid-solid (VLS) and vapor-solid-solid (VSS) NW growth modes to produce synthetically encoded NW devices with ultrasharp (<5 nm) n-type highly doped (n(++)) to lightly doped (n) transitions along the NW growth direction, where n(++) regions serve as source/drain (S/D) electrodes and the n-region functions as an active FET channel. Using this method, we synthesized short-channel n(++)/n/n(++) SiNW FET devices with independently controllable diameters and channel lengths. SiNW devices with channel lengths of 50, 80, and 150 nm interfaced with spontaneously beating cardiomyocytes exhibited well-defined extracellular field potential signals with signal-to-noise values of ca. 4 independent of device size. Significantly, these "pointlike" devices yield peak widths of ~500 μs, which is comparable to the reported time constant for individual sodium ion channels. Multiple FET devices with device separations smaller than 2 μm were also encoded on single SiNWs, thus enabling multiplexed recording from single cells and cell networks with device-to-device time resolution on the order of a few microseconds. These short-channel SiNW FET devices provide a new opportunity to create nanoscale biomolecular sensors that operate on the length and time scales previously inaccessible by other techniques but necessary to investigate fundamental, subcellular biological processes.  相似文献   

4.
A transferrin-conjugated PEG-Fe(3) O(4) nanostructured matrix is developed to explore cellular responses in terms of enhanced cell adhesion, specific interactions between ligands in the matrix and molecular receptors on the cell membrane, comparison of cell shapes on 2D and 3D surfaces, and effect of polymer architecture on cell adhesion. Integration of such advanced synthetic nanomaterials into a functionalized 3D matrix to control cell behavior on surfaces will have implications in nanomedicine.  相似文献   

5.
Park WI  Zheng G  Jiang X  Tian B  Lieber CM 《Nano letters》2008,8(9):3004-3009
We report the nanocluster-catalyzed growth of ultralong and highly uniform single-crystalline silicon nanowires (SiNWs) with millimeter-scale lengths and aspect ratios up to approximately 100 000. The average SiNW growth rate using disilane (Si 2H 6) at 400 degrees C was 31 mum/min, while the growth rate determined for silane (SiH 4) reactant under similar growth conditions was 130 times lower. Transmission electron microscopy studies of millimeter-long SiNWs with diameters of 20-80 nm show that the nanowires grow preferentially along the 110 direction independent of diameter. In addition, ultralong SiNWs were used as building blocks to fabricate one-dimensional arrays of field-effect transistors (FETs) consisting of approximately 100 independent devices per nanowire. Significantly, electrical transport measurements demonstrated that the millimeter-long SiNWs had uniform electrical properties along the entire length of wires, and each device can behave as a reliable FET with an on-state current, threshold voltage, and transconductance values (average +/-1 standard deviation) of 1.8 +/- 0.3 muA, 6.0 +/- 1.1 V, 210 +/- 60 nS, respectively. Electronically uniform millimeter-long SiNWs were also functionalized with monoclonal antibody receptors and used to demonstrate multiplexed detection of cancer marker proteins with a single nanowire. The synthesis of structurally and electronically uniform ultralong SiNWs may open up new opportunities for integrated nanoelectronics and could serve as unique building blocks linking integrated structures from the nanometer through millimeter length scales.  相似文献   

6.
Vertically oriented well-aligned Indium doped ZnO nanowires (NWs) have been successfully synthesized on Au-coated Zn substrate by controlled thermal evaporation. The effect of indium dopant on the optical and field-emission properties of these well-aligned ZnO NWs is investigated. The doped NWs are found to be single crystals grown along the c-axis. The composition of the doped NWs is confirmed by X-ray diffraction (XRD), energy-dispersive spectroscopy (EDS), and X-ray photospectroscopy (XPS). The photoluminescence (PL) spectra of doped NWs having a blue-shift in the UV region show a prominent tuning in the optical band gap, without any significant peak relating to intrinsic defects. The turn-on field of the field emission is found to be ~2.4 V μm(-1) and an emission current density of 1.13 mA cm(-2) under the field of 5.9 V μm(-1). The field enhancement factor β is estimated to be 9490 ± 2, which is much higher than that of any previous report. Furthermore, the doped NWs exhibit good emission current stability with a variation of less than 5% during a 200 s under a field of 5.9 V μm(-1). The superior field emission properties are attributed to the good alignment, high aspect ratio, and better crystallinity of In-doped NWs.  相似文献   

7.
A new process has been developed to grow silicon (Si) nanowires (NWs), and their growth mechanisms were explored and discussed. In this process, SiNWs were synthesized by simply oxidizing and then reducing Si wafers in a high temperature furnace. The process involves H2, in an inert atmosphere, reacts with thermally grown SiO2 on Si at 1100 °C enhancing the growth of SiNWs directly on Si wafers. High-resolution transmission electron microscopy studies show that the NWs consists of a crystalline core of ~25 nm in diameter and an amorphous oxide shell of ~2 nm in thickness, which was also supported by selected area electron diffraction patterns. The NWs synthesized exhibit a high aspect ratio of ~167 and room temperature phonon confinement effect. This simple and economical process to synthesize crystalline SiNWs opens up a new way for large scale applications.  相似文献   

8.
Hong H  Shi J  Yang Y  Zhang Y  Engle JW  Nickles RJ  Wang X  Cai W 《Nano letters》2011,11(9):3744-3750
Herein we demonstrate that intrinsically fluorescent zinc oxide (ZnO) nanowires (NWs) can be adopted for molecularly targeted imaging of cancer cells, after they are functionalized to render water solubility, biocompatibility, and low cellular toxicity. Optical imaging of integrin α(v)β(3) on U87MG human glioblastoma cells was achieved with RGD peptide-conjugated green fluorescent ZnO NWs, which opened up new avenues of research for investigating ZnO NW-based agents in tumor vasculature-targeted molecular imaging and drug delivery.  相似文献   

9.
H Wang  L Wang  L Yuan  W Yang  JL Brash  H Chen 《Nanotechnology》2012,23(36):365101
The effect of nanomaterials on biological reactions has received much attention. We report herein that silicon nanowires (SiNWs) inhibit the polymerase chain reaction (PCR). The inhibitory effect was found to be concentration-dependent, with a minimum inhibitory concentration of about 0.4?mg?ml(-1). DNA polymerase, restriction endonucleases, lysozyme and horseradish peroxidase maintained their bioactivities after exposure to SiNWs. Also the interaction of SiNWs with primers and dNTP did not lead to decreased PCR yield. Compared to primers and dNTP, template DNA showed 4.7-10.5-fold greater adsorption on SiNWs. Template bound to SiNWs was ineffective in the PCR, whereas addition of free template to the PCR system increased the yield. The results of this work suggest that the inhibitory effect of SiNWs on the PCR was due to the selective adsorption of double-stranded DNA on SiNWs, thereby decreasing the availability of template for the reaction.  相似文献   

10.
Nanowire-based detection strategies provide promising new routes to bioanalysis and indeed are attractive to conventional systems because of their small size, high surface-to-volume ratios, electronic, and optical properties. A sequence-specific detection of single-stranded oligonucleotides using silicon nanowires (SiNWs) is demonstrated. The surface of the SiNWs is functionalized with densely packed organic monolayer via hydrosilylation for covalent attachment. Subsequently, deoxyribonucleic acid (DNA) is immobilized to recognize the complementary target DNA. The biomolecular recognition properties of the nanowires are tested via hybridization with γP32 tagged complementary and non-complementary DNA oligonucleotides, showing good selectivity and reversibility. No significant non-specific binding to the incorrect sequences is observed. X-ray photoelectron spectroscopy, fluorescence imaging, and nanodrop techniques are used to characterize the modified SiNWs and covalent attachment with DNA. The results show that SiNWs are excellent substrates for the absorption, stabilization and detection of DNA sequences and could be used for DNA microarrays and micro fabricated SiNWs DNA sensors.  相似文献   

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