One-pot synthesis of nitrogen doped mesoporous graphitic carbon spheres with dispersed metal oxide nanoparticles using a single temperature treatment step serves as one of the big challenges in materials research.

Glioblastomas are highly lethal cancers defined by resistance to conventional therapies and rapid recurrence. While new brain tumor cell-specific drugs are continuously becoming available, efficient drug delivery to brain tumors remains a limiting factor. We developed a multicomponent nanoparticle, consisting of an iron oxide core and a mesoporous silica shell that can effectively deliver drugs across the blood-brain barrier into glioma cells. When exposed to alternating low-power radiofrequency (RF) fields, the nanoparticle's mechanical tumbling releases the entrapped drug molecules from the pores of the silica shell. After directing the nanoparticle to target the near-perivascular regions and altered endothelium of the brain tumor via fibronectin-targeting ligands, rapid drug release from the nanoparticles is triggered by RF facilitating wide distribution of drug delivery across the blood-brain tumor interface.

Glioblastoma multiforme (GBM) remains highly lethal. This partially stems from the presence of brain tumor initiating cells (BTICs), a highly plastic cellular subpopulation that is resistant to current therapies. In addition to resistance, the blood–brain barrier limits the penetration of most drugs into GBMs. To effectively deliver a BTIC‐specific inhibitor to brain tumors, a multicomponent nanoparticle, termed Fe@MSN, which contains a mesoporous silica shell and an iron oxide core, is developed. Fibronectin‐targeting ligands direct the nanoparticle to the near‐perivascular areas of GBM. After Fe@MSN particles are deposited in the tumor, an external low‐power radiofrequency (RF) field triggers rapid drug release due to mechanical tumbling of the particle resulting in penetration of high amounts of drug across the blood–brain tumor interface and widespread drug delivery into the GBM. The nanoparticle is loaded with the drug 1400W, which is a potent inhibitor of the inducible nitric oxide synthase (iNOS). It is shown that iNOS is preferentially expressed in BTICs and is required for their maintenance. Using the 1400W‐loaded Fe@MSN and RF‐triggered release, in vivo studies indicate that the treatment disrupts the BTIC population in hypoxic niches, suppresses tumor growth and significantly increases survival in BTIC‐derived GBM xenografts.

Nanoparticles often only exploit the upregulation of a receptor on cancer cells to enhance intratumoral deposition of therapeutic and imaging agents. However, a single targeting moiety assumes that a tumor is homogenous and static. Tumoral microenvironments are both heterogenous and dynamic, often displaying variable spatial and temporal expression of targetable receptors throughout disease progression. Here, we evaluated the in vivo performance of an iron oxide nanoparticle in terms of targeting and imaging of orthotropic mouse models of aggressive breast tumors. The nanoparticle, a multi-component nanochain, was comprised of 3-5 iron oxide nanoparticles chemically linked in a linear chain. The nanoparticle's surface was decorated with two types of ligands each targeting two different upregulated biomarkers on the tumor endothelium, P-selectin and fibronectin. The nanochain exhibited improved tumor deposition not only through vascular targeting but also through its elongated structure. A single-ligand nanochain exhibited a ~2.5-fold higher intratumoral deposition than a spherical nanoparticle variant. Furthermore, the dual-ligand nanochain exhibited higher consistency in generating detectable MR signals compared to a single-ligand nanochain. Using a 7T MRI, the dual-ligand nanochains exhibited highly detectable MR signal within 3h after injection in two different animal models of breast cancer.

To synthesize multi-component nanochains, we developed a simple 'one-pot' synthesis, which exhibited high yield and consistency. The nanochains particles consist of parent nanospheres chemically linked into a higher-order, chain-like assembly. The one-pot synthesis is based on the addition of two types of parent nanospheres in terms of their surface chemical functionality (e.g., decorated with PEG-NH2 or PEG-COOH). By reacting the two types of parent nanospheres at a specific ratio (∼2 : 1) for a short period of time (∼30 min) under rigorous stirring, nanochains were formed. For example, we show the synthesis of iron oxide nanochains with lengths of about 125 nm consisting of 3-5 constituting nanospheres. The chain-like shaped nanoparticle possessed a unique ability to target and rapidly deposit on the endothelium of glioma sites via vascular targeting. To target and image invasive brain tumors, we used iron oxide nanochains with the targeting ligand being the fibronectin-targeting peptide CREKA. Overexpression of fibronectin is strongly associated with the perivascular regions of glioblastoma multiforme and plays a critical role in migrating and invasive glioma cells. In mice with invasive glioma tumors, 3.7% of the injected CREKA-targeted nanochains was found in gliomas within 1 h. Notably, the intratumoral deposition of the nanochain was ∼2.6-fold higher than its spherical variant. Using MR imaging, the precise targeting of nanochains to gliomas provided images with the exact topology of the disease including their margin of infiltrating edges and distant invasive sites.

Biocompatible nanoparticles of gadolinium-incorporated Prussian blue with the empirical formula K0.94Gd0.02Fe[Fe(CN)(6)] exhibit extremely high stability against the release of Gd3+ and CN- ions under the acidic conditions similar to stomach juice. The high r(1) relaxivity, low cytotoxicity and the ability of such nanoparticles to penetrate the cell membrane suggest that this coordination-polymer structural platform offers a unique opportunity for developing the next generation of T-1-weighted oral cellular MRI probes for the early detection of tumors in the gastrointestinal tract.

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A simple one-step method for preparing biocompatible nanoparticles of gadolinium ferrocyanide coordination polymer KGd(H2O)2[Fe(CN)6]·H2O is reported. The crystal structure of this coordination polymer is determined by X-ray powder diffraction using the bulk materials. The stability, cytotoxicity, cellular uptake, and MR phantom and cellular imaging studies suggest that this coordination-polymer structural platform offers a unique opportunity for developing the next generation of T1-weighted contrast agents with high relaxivity as cellular MR probes for biological receptors or markers. Such high-relaxivity MR probes may hold potential in the study of molecular events and may be used for in vivo MR imaging in biomedical research and clinical applications.

Biocompatible ZnMoS4 NPs can selectively remove intracellular copper ions via ion-exchange rather than chelation. This strategy represents a paradigm shift in designing new-generation intracellular metal detoxifying drugs.

A simple one-step method for preparing biocompatible nanoparticles of gadolinium ferrocyanide coordination polymer KGd(H2O)2[Fe(CN)6]·H2O is reported. The crystal structure of this coordination polymer is determined by X-ray powder diffraction using the bulk materials. The stability, cytotoxicity, cellular uptake, and MR phantom and cellular imaging studies suggest that this coordination-polymer structural platform offers a unique opportunity for developing the next generation of T1-weighted contrast agents with high relaxivity as cellular MR probes for biological receptors or markers. Such high-relaxivity MR probes may hold potential in the study of molecular events and may be used for in vivo MR imaging in biomedical research and clinical applications.

A series of cysteine-stabilized phenolic resin-based polymer and carbon spheres were prepared by the modified Stöber method. Cysteine plays a very important role in the proposed one-pot synthesis of the aforementioned spheres; namely, it acts as a particle stabilizer and a source of heteroatoms (nitrogen and sulfur) that can be introduced into these spheres. The diameter of these spheres can be tuned in the range of 70-610 nm by adjusting the cysteine amount and reaction temperature. Since polymer spheres obtained in the presence of cysteine contain sulfur and nitrogen heteroatoms, they were tested for adsorption of copper ions. It is shown that adsorption isotherms recorded for copper ions can be well fitted by Langmuir equation, giving unprecedented adsorption capacities up to ~65 mg/g.

A series of highly graphitized mesoporous carbons was synthesized by self-assembly of polymeric carbon precursors and block copolymer template in the presence of poly(vinylpyrrolidone) (PVP)-coated Prussian blue (PB) nanoparticles used as a graphitization catalyst. Resorcinol and formaldehyde were used as carbon precursors, poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide) triblock copolymer (Pluronic F127) was employed as a soft template. The carbon precursors were polymerized in hydrophilic domains of block copolymer along with PVP-coated PB nanoparticles, followed by carbonization. This recipe gave carbons with cylindrical mesopores created by thermal decomposition of the soft template, and with PB-derived iron oxide nanoparticles. In addition, the presence of iron species catalyzed graphitization at relatively low temperature. The XRD and TEM measurements revealed that the resulting carbons obtained with smaller amounts of PB exhibited ordered mesostructures with relatively high degree of graphitization; however, exceedingly graphitic carbons with disordered mesopores were obtained with higher amounts of PB. Furthermore, wide-angle XRD measurements and TGA analysis provided evidence that graphitization took place at 600 degrees C, which is considered to be a very low temperature for the graphitization process. N-2 adsorption and TGA analysis showed that the aforementioned carbons exhibited high surface area (reaching 621 m(2)/g) and an extremely high percentage of graphitic domains (approaching 87%). Interestingly, the carbon prepared with larger amount of PB showed magnetic properties. Electrochemical measurements performed on these carbons for double layer capacitors showed somewhat rectangular shape of cyclic voltammetry (CV) curves with a large capacitance of 211 F/g in 1 M H2SO4 electrolyte.

A layer-by-layer self-assembly method leads to the formation of Au@ZnMoS4 core-shell nanoparticles (NPs). The PEGylated Au@ZnMoS4 NPs are highly water-dispersible, exhibit no cytotoxicity and can penetrate the cell membrane to selectively remove copper(I) ions from HepG2 cells in the presence of other endogenous and biologically essential metal ions including Mg(II), Ca(II), Mn(II) and Fe(II), demonstrating their potential as a novel intracellular copper detoxifying agent.

Tumor angiogenesis, new blood vessel formation induced by cancer cells, is a rate-limiting step in cancer growth and metastasis, and is therefore an excellent target for therapy. Currently, the anticancer drugs based on anti-angiogenic strategies have limited efficacy, and often engender inherent or acquired resistance. Indeed, there is growing evidence to suggest that anti-angiogenic treatment of cancer using current inhibitors may trigger more invasive and metastatic tumors due to the fact that when one angiogenic signaling pathway is blocked, new signaling pathways are triggered. We have tackled the problem from a different angle by targeting the copper ion rather than the many angiogenesis inducing biomolecules. Copper is a co-factor for more than a dozen key angiogenic promoters essential for cancer angiogenesis. As such, depletion of copper should inactivate multiple angiogenic signaling pathways. Specifically, we have developed a nanoparticle-based drug to selectively sequester copper ions in order to disrupt tumor angiogenesis, resulting in inhibition of tumor growth and metastasis. Cellular uptake of nanoparticles (NPS) was documented by confocal microscopy of HuVEC and cancer cell lines treated with carboxyfluorescein tagged NPS. Copper levels were measured by atomic absorption spectrophotometry of lysates of CuCl2 treated cells, after 8-hr treatment with NPS or control diluent. Following treatment of HepG2 cells with copper depleting NPS, we observed that copper levels dropped from 402 fg/cell to undetectable levels. Although NPS significantly reduced copper levels of CuCl2 treated HepG2 cells, cell viability measured by trypan blue exclusion and MTT assays was > 89% (for 50 uM NPS). Similar viability was seen for the three cell lines tested. Using an in vitro model system for angiogenesis, we have examined induction of tube formation by human Vascular Endothelial cells (HuVEC) cultured on basement membrane extracts. Following induction by fibroblast growth factor 2 (FGF2) and vascular endothelial growth factor (VEGF) treatment, outgrowth and branching of HuVEC cells was measured in the presence or absence of NPS. We observed that the copper depleting NPS suppressed FGF2 induction of tube formation and branching by HuVEC cells. Overall our results have demonstrated that these novel zinc NPS: (i) are highly effective copper depleting agents able to accumulate in endothelial cells; (ii) are non-toxic to vascular endothelial and cancer cells, and (iii) inhibit endothelial cell tube formation in vitro. We expect these novel copper-depleting agents will significantly impact tumor angiogenesis in vivo and dramatically enhance cancer therapy in the future. Citation Format: Vindya S. Perera, Haiwa Wu, Liu D. Yang, Songping D. Huang, Gail C. Fraizer. Inhibition of vascular endothelial cell tube formation by zinc nanoparticles. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1615. doi:10.1158/1538-7445.AM2013-1615

AbstractNanoparticles of the title compound are prepared by slow mixing of an aqueous K4[Fe(CN)6] solution containing polyvinylpyrrolidone with an aqueous Bi(NO3)3 solution containing sodium citrate (room temperature, 30 min).

An aqueous synthetic procedure for preparing nanoparticles of the novel potassium bismuth ferrocyanide coordination polymer KBi(H(2)O)(2)[Fe(CN)(6)]·H(2)O is reported. The crystal structure of this coordination polymer is determined through X-ray powder diffraction using the bulk materials. The stability, cytotoxicity, and potential use of such nanoparticles coated with PVP as a CT contrast agent are investigated.