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The early diagnosis of cancer is the critical element in successful treatment and long-term favorable patient prognoses. The high rate of mortality is mainly attributed to the tendency for late diagnoses as symptoms may not occur until the disease has metastasized, as well as the lack of effective systemic therapies. Late diagnosis is often associated with the lack of timely sensitive imaging modalities. The promise of nanotechnology is presently limited by the inability to simultaneously seek, treat, and image cancerous lesions. This study describes the design and synthesis of fluorescent calcium phosphosilicate nanocomposite particles (CPNPs) that can be systemically targeted to breast and pancreatic cancer lesions. The CPNPs are a approximately 20 nm diameter composite composed of an amorphous calcium phosphate matrix doped with silicate in which a near-infrared imaging agent, indocyanine green (ICG), is embedded. In the present studies, we describe and validate CPNP bioconjugation of human holotransferrin, anti-CD71 antibody, and short gastrin peptides via an avidin-biotin or a novel PEG-maleimide coupling strategy. The conjugation of biotinylated human holotransferrin (diferric transferrin) and biotinylated anti-CD71 antibody (anti-transferrin receptor antibody) to avidin-conjugated CPNPs (Avidin-CPNPs) permits targeting of transferrin receptors, which are highly expressed on breast cancer cells. Similarly, the conjugation of biotinylated pentagastrin to Avidin-CPNPs and decagastrin (gastrin-10) to PEG-CPNPs via PEG-maleimide coupling permits targeting of gastrin receptors, which are overexpressed in pancreatic cancer lesions. These bioconjugated CPNPs have the potential to perform as a theranostic modality, simultaneously enhancing drug delivery, targeting, and imaging of breast and pancreatic cancer tumors.
ACS Nano 2010 Mar 23
PMID:Bioconjugation of calcium phosphosilicate composite nanoparticles for selective targeting of human breast and pancreatic cancers in vivo. 2018 May 85

Multifunctional superparamagnetic nanoparticles have been developed for a wide range of applications in nanomedicine, such as serving as tumor-targeted drug carriers and molecular imaging agents. To function in vivo, the development of these novel materials must overcome several challenging requirements including biocompatibility, stability in physiological solutions, nontoxicity, and the ability to traverse biological barriers. Here we report a PEG-mediated synthesis process to produce well-dispersed, ultrafine, and highly stable iron oxide nanoparticles for in vivo applications. Utilizing a biocompatible PEG coating bearing amine functional groups, the produced nanoparticles serve as an effective platform with the ability to incorporate a variety of targeting, therapeutic, or imaging ligands. In this study, we demonstrated tumor-specific accumulation of these nanoparticles through both magnetic resonance and optical imaging after conjugation with chlorotoxin, a peptide with high affinity toward tumors of the neuroectodermal origin, and Cy5.5, a near-infrared fluorescent dye. Furthermore, we performed preliminary biodistribution and toxicity assessments of these nanoparticles in wild-type mice through histological analysis of clearance organs and hematology assay, and the results demonstrated the relative biocompatibility of these nanoparticles.
ACS Nano 2010 Apr 27
PMID:PEG-mediated synthesis of highly dispersive multifunctional superparamagnetic nanoparticles: their physicochemical properties and function in vivo. 2023 26

Given the emergence of nanotherapeutics and nanodiagnostics as key tools in today's medicine, it has become of critical importance to define precisely the interactions of nanomaterials with biological systems and to characterize the resulting cellular response. We report here the interactions of microglia and neurons with gold nanoparticles (GNPs) of three morphologies, spheres, rods, and urchins, coated with poly(ethylene glycol) (PEG) or cetyl trimethylammonium bromide (CTAB). Microglia are the resident immune cells of the brain, primarily involved in surveillance, macrophagy, and production of cytokines and trophic factors. Analysis by dark-field microscopy and by two-photon-induced luminescence (TPL) indicates that the exposure of neural cells to GNPs resulted in (i) GNP internalization by both microglial cells and primary hippocampal neurons, as revealed by dark-field microscopy and by two-photon-induced luminescence (TPL), (ii) transient toll-like receptor 2 (TLR-2) up-regulation in the olfactory bulb, after intranasal administration in transgenic mice, in vivo, in real time, and (iii) differential up-regulation in vitro of TLR-2 together with interleukin 1 alpha (IL-1alpha), granulocyte macrophage colony-stimulating factor (GM-CSF) and nitric oxide (NO) in microglia. The study demonstrates that GNP morphology and surface chemistry strongly influence the microglial activation status and suggests that interactions between GNPs and microglia can be differentially regulated by tuning GNP nanogeometry.
ACS Nano 2010 May 25
PMID:Microglial response to gold nanoparticles. 2049 53

We have characterized the adsorption and lubricating properties of the polycation-PEG graft copolymer poly(l-lysine)-graft-poly(ethylene glycol) (PLL-g-PEG) on human-hair surfaces by means of X-ray photoelectron spectroscopy (XPS), fluorescence microscopy, and atomic force microscopy (AFM). XPS measurements indicated that PLL-g-PEG copolymers spontaneously adsorbed onto the surface of bleached-hair samples (a good model of a weathered, damaged hair surface for cosmetic care applications) from an aqueous solution. Further treatment with cationic surfactants present in common shampoo formulations removed the adsorbed PLL-g-PEG from the hair samples. Fluorescence microscopy showed that the adsorption of PLL-g-PEG onto the hair samples from an aqueous polymer solution occurred inhomogeneously. Nanotribological studies with AFM (friction vs load plots) revealed that the relationship between load and friction was approximately linear for all hair samples, while the slopes of the plots varied considerably along the hair sample surface. Under ambient, "dry" conditions, the frictional properties of the bleached, bleached + PLL-g-PEG-treated, and bleached + PLL-g-PEG-treated and subsequently surfactant-treated hair samples did not reveal a clear difference. In distilled water, however, the bleached + PLL-g-PEG-treated hair samples showed statistically lower frictional properties than simply bleached or bleached + PLL-g-PEG-treated and subsequently surfactant-treated hair samples. Overall, the three instrumental techniques have consistently shown that the adsorption of PLL-g-PEG onto the hair sample surface occurs unevenly, which can be ascribed to the intrinsically heterogeneous properties of the human-hair surface. A control experiment, involving an injection of concentrated PLL-g-PEG solution into a liquid cell where an AFM tip was already scanning over a specific area (line scan mode), revealed an immediate and apparent reduction in the frictional force. Despite the inhomogeneity of the hair surface, the adsorption of the polymer seems to be extremely effective in promoting lubrication of the fiber. This suggests that the adsorbed graft copolymers act as a boundary lubricant on the hair surface. The presence of a more organized, brushlike layer of polymers contrasts with the usual random adsorption of chains that is believed to be present in the case of linear polyelectrolytes that are nowadays applied for shampoos and conditioners in the cosmetic or textile industries.
ACS Appl Mater Interfaces 2009 Sep
PMID:Adsorption and lubricating properties of poly(l-lysine)-graft-poly(ethylene glycol) on human-hair surfaces. 2035 18

The tribological properties of poly(L-lysine)-graft-poly(ethylene glycol) (PLL-g-PEG)-coated oxide interfaces have been investigated with atomic force microscopy (AFM) as a function of the molecular structure. Polymer-bearing surfaces were obtained via spontaneous adsorption of the polymer onto the oxide substrate from a buffered solution of physiological pH. Interfacial friction of these PLL-g-PEG-coated surfaces was found to be highly dependent on the duration of deposition and the architecture of PLL-g-PEG. In terms of the architecture, the PEG chain length and the grafting ratio (i.e., the molar ratio of L-lysine monomer to PEG side chain) of adsorbed PLL-g-PEG significantly influence the interfacial friction; specifically, friction is reduced as the PEG chain length increases and as the molar ratio of L-lysine monomer to PEG side chain decreases. The characteristics of the polymer deposition time and the influence of the lysine/PEG grafting ratio are rationalized in terms of spatial packing density considerations.
ACS Appl Mater Interfaces 2009 Jun
PMID:Tribological properties of poly(L-lysine)-graft-poly(ethylene glycol) films: influence of polymer architecture and adsorbed conformation. 2035 17

The penetration behavior of Kevlar fabric intercalated with dry particles and shear thickening fluids (STF), highly concentrated fluid-particle suspensions, is presented. In particular, the role of particle hardness is explored by comparing fabric treatments containing SiO(2) particles, which are significantly harder than Kevlar, to treatments containing softer poly(methyl methacrylate) (PMMA) particles. The fabric testing includes yarn pull-out, quasi-static spike puncture, and ballistic penetration resistance, performed on single fabric layers. It was found that both dry particle and STF treatments resulted in improvements in fabric properties relative to neat or poly(ethylene glycol) (PEG) treated fabrics. On comparison of treatments with different particle hardness, the SiO(2) materials performed better in all tests than comparable PMMA materials, although the SiO(2) treatments caused yarn failure in pull-out testing, reducing the total pull-out energy. In addition, resistance to yarn pull-out was found to be substantially higher for STF-treated fabrics than for dry particle treated fabrics. However, both dry particle addition and STF treatments exhibited comparable enhancements in puncture and ballistic resistance. These observations suggest that viscous stress transfer, friction, and physical entrainment of hard particles into filaments contribute to the demonstrated improvements in the properties of protective fabrics treated with shear thickening fluids.
ACS Appl Mater Interfaces 2009 Nov
PMID:Effect of particle hardness on the penetration behavior of fabrics intercalated with dry particles and concentrated particle-fluid suspensions. 2035 33

This paper describes a novel surface engineering approach that combines oxygen plasma treatment and electrochemical activation to create micropatterned cocultures on indium tin oxide (ITO) substrates. In this approach, photoresist was patterned onto an ITO substrate modified with poly(ethylene) glycol (PEG) silane. The photoresist served as a stencil during exposure of the surface to oxygen plasma. Upon incubation with collagen (I) solution and removal of the photoresist, the ITO substrate contained collagen regions surrounded by nonfouling PEG silane. Chemical analysis carried out with time-of-flight secondary ion mass spectrometry (ToF-SIMS) at different stages in micropatterned construction verified removal of PEG-silane during oxygen plasma and presence of collagen and PEG molecules on the same surface. Imaging ellipsometry and atomic force microscopy (AFM) were employed to further investigate micropatterned ITO surfaces. Biological application of this micropatterning strategy was demonstrated through selective attachment of mammalian cells on the ITO substrate. Importantly, after seeding the first cell type, the ITO surfaces could be activated by applying negative voltage (-1.4 V vs Ag/AgCl). This resulted in removal of nonfouling PEG layer and allowed to attach another cell type onto the same surface and to create micropatterned cocultures. Micropatterned cocultures of primary hepatocytes and fibroblasts created by this strategy remained functional after 9 days as verified by analysis of hepatic albumin. The novel surface engineering strategy described here may be used to pattern multiple cell types on an optically transparent and conductive substrate and is envisioned to have applications in tissue engineering and biosensing.
ACS Appl Mater Interfaces 2009 Nov
PMID:Micropatterning of proteins and mammalian cells on indium tin oxide. 2035 32

This paper describes a biomaterial microfabrication approach for interfacing functional biomolecules (enzymes) with electrode arrays. Poly (ethylene glycol) (PEG) hydrogel photopatterning was employed to integrate gold electrode arrays with the enzymes glucose oxidase (GOX) and lactate oxidase (LOX). In this process, PEG diacrylate (DA)-based prepolymer containing enzyme molecules as well as redox species (vinylferrocene) was spin-coated, registered, and UV cross-linked on top of an array of gold electrodes. As a result, enzyme-carrying circular hydrogel structures (600 microm diameter) were fabricated on top of 300 microm diameter gold electrodes. Importantly, when used with multiple masks, hydrogel photolithography allowed us to immobilize GOX and LOX molecules on adjacent electrodes within the same electrode array. Cyclic voltammetry and amperometry were used to characterize biosensor electrode arrays. The response of the biosensor array was linear for up to 20 mM glucose with sensitivity of 0.9 microA cm(-2) mM(-1) and 10 mM lactate with sensitivity of 1.1 microA cm(-2) mM(-1). Importantly, simultaneous detection of glucose and lactate from the same electrode array was demonstrated. A novel strategy for integrating biological and electrical components of a biosensor described in this paper provides the flexibility to spatially resolve and register different biorecognition elements with individual members of a miniature electrode array. Of particular interest to us are future applications of these miniature electrodes for real-time monitoring of metabolite fluxes in the vicinity of living cells.
ACS Appl Mater Interfaces 2010 Mar
PMID:Immobilizing enzymes onto electrode arrays by hydrogel photolithography to fabricate multi-analyte electrochemical biosensors. 2035 76

Three imidazolium-based ionic liquids containing sterically hindered phenol groups were synthesized. The cation was 1-(3,5-ditert-butyl-4-hydroxybenzyl)-3-methyl-imidazolium, and the anions were tetrafluoroborates, hexafluorophosphates, and bis(trifluoromethylsulfonyl)imide. The physical properties of the synthetic products and of poly(ethylene glycol) (PEG) with the additive were evaluated. The oxidative stability of 0.5 wt % 1-(3,5-di-tert-butyl-4-hydroxybenzyl)-3-methyl-imidazolium hexafluorophosphates in PEG were assessed via rotating bomb oxidation test (RBOT), thermal analysis, and copper strip test. The tribological behaviors of the additives for PEG application in steel/steel contacts were evaluated on an Optimol SRV-IV oscillating reciprocating friction and wear tester as well as on MRS-1J four-ball testers. The worn steel surface was analyzed by a JSM-5600LV scanning electron microscope and a PHI-5702 multifunctional X-ray photoelectron spectrometer. RBOT test, thermal analysis, and copper strip test results revealed that synthesized ionic liquids possessed excellent antioxidant properties. Tribological application results revealed that these could effectively reduce friction and wear of sliding pairs compared with the PEG films used without the additives. Specifically, (BHT-1)MIMPF(6) exhibited better antiwear properties at an optimum concentration of 1 wt %. At this level, its antiwear property significantly improved by 100 times with respect to using just the PEG base oil. Boundary lubrication films composed of metal fluorides, organic fluorines, organic phosphines, and nitride compounds were formed on the worn surface, which resulted in excellent friction reduction and antiwear performance.
ACS Appl Mater Interfaces 2010 Mar
PMID:Imidazolium ionic liquids as antiwear and antioxidant additive in poly(ethylene glycol) for steel/steel contacts. 2035 93

Photocured thiol-ene hydrogel coatings based on poly(ethylene glycol) (PEG) were investigated for marine antifouling purposes. By varying the PEG length, vinylic end-group, and thiol cross-linker, a library of hydrogel coatings with different structural composition was efficiently accomplished, with or without ester linkages. The thiol-methacrylate and thiol-allyl systems were evaluated with respect to curing, degradation, as well as antifouling properties. Methacrylate-based systems exhibited homopolymerization, whereas allyl-based systems reacted more selectively through thiol-ene couplings reaction. The ester-free hydrogels elucidated higher hydrolytic stability whereas longer PEG chains accelerated the degradation process. The antifouling properties were evaluated by protein adsorption with Bovine serum albumin (BSA) and bioassays with the marine bacteria, Cobetia marina, and the marine diatom, Amphora coffeaeformis; in all tests, longer PEG lengths improved the antifouling properties.
ACS Appl Mater Interfaces 2010 Mar
PMID:Poly(ethylene glycol)-based thiol-ene hydrogel coatings-curing chemistry, aqueous stability, and potential marine antifouling applications. 2035 97


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