25 research outputs found
Deconvoluting hepatic processing of carbon nanotubes
Single-wall carbon nanotubes present unique opportunities for drug delivery, but have not advanced into the clinic. Differential nanotube accretion and clearance from critical organs have been observed, but the mechanism not fully elucidated. The liver has a complex cellular composition that regulates a range of metabolic functions and coincidently accumulates most particulate drugs. Here we provide the unexpected details of hepatic processing of covalently functionalized nanotubes including receptor-mediated endocytosis, cellular trafficking and biliary elimination. Ammonium-functionalized fibrillar nanocarbon is found to preferentially localize in the fenestrated sinusoidal endothelium of the liver but not resident macrophages. Stabilin receptors mediate the endocytic clearance of nanotubes. Biocompatibility is evidenced by the absence of cell death and no immune cell infiltration. Towards clinical application of this platform, nanotubes were evaluated for the first time in non-human primates. The pharmacologic profile in cynomolgus monkeys is equivalent to what was reported in mice and suggests that nanotubes should behave similarly in humans
Synthesis, pharmacokinetics, and biological use of lysine-modified single-walled carbon nanotubes [Erratum]
Scorpionate complexes with the main group elements Ca, Ba, Sr
The poly(pirazolyl)borate ligands together with various
substituted forms have developed into one of the most versatile
ancillary ligand in metal coordination chemistry. Particular attention is
sometimes devoted to special azolyl rings, such as triazolyl, methylor
trifluoromethyl-pyrazolyl rings. These ligands can exert quite
different electronic and structural effects when compared with the
analogues. Very little has been done on poly(pyrazolyl)borate systems
bearing electron withdrawing substituents. The electron withdrawing
groups in polyfluorinated ligands commonly improve the volatility,
oxidation resistance, thermal stability, and solubility of metal
complexes. To our knowledge, no poly(azolyl)borates containing
a -NO2 function have been prepared, presumably due to difficulties in
the synthesis of ligands having both a hydride and a nitro group.
However, a poly(azolyl)borate containing a -NO2 substituent could be
of interest due to its high coordinative flexibility from 4- to μ4-N2O2
coordination ability.
We report here on the syntheses and structural investigations of
main-group metal elements Ca, Ba and Sr with the hydrotris(3-
methylpyrazolyl)borate, the hydrotris(1,2,4-triazolyl)borate and the
new hydrotris(3-nitro-1,2,4-triazolyl)borate, an emerging category of
electron withdrawing substituted scorpionate ligands
Synthesis and spectroscopic characterization of new triorganotin(IV) complexes with the bis(1-methyl-1H-imidazol-2-ylthio)acetate ligand: effects on trout erythrocyte components
Triorganotin(IV) derivatives containing the anionic ligand bis(1-methyl-1H-imidazol-2-ylthio)acetate [(S-tim)(2)CHCO2](-) were synthesized from the reaction between R3SnCl acceptors (R = Me and Ph) and the sodium salt of the ligand. Mono-nuclear complexes of the type [(S-tim)(2)CHCO2]SnR3 were obtained, which were fully characterized by elemental analyses and FT-IR in the solid state, and by NMR (H-1, C-13 and Sn-119) spectroscopy and electrospray ionization mass in solution. The toxic effects shown by these compounds on trout erythrocyte components showed that the toxicity of the organotin(IV) complexes depends on the nature and on the lipophilicity of the substituents on the metal centre
Fibrillar pharmacology of functionalized nanocellulose
Abstract Cellulose nanocrystals (CNC) are linear organic nanomaterials derived from an abundant naturally occurring biopolymer resource. Strategic modification of the primary and secondary hydroxyl groups on the CNC introduces amine and iodine group substitution, respectively. The amine groups (0.285 mmol of amine per gram of functionalized CNC (fCNC)) are further reacted with radiometal loaded-chelates or fluorescent dyes as tracers to evaluate the pharmacokinetic profile of the fCNC in vivo. In this way, these nanoscale macromolecules can be covalently functionalized and yield water-soluble and biocompatible fibrillar nanoplatforms for gene, drug and radionuclide delivery in vivo. Transmission electron microscopy of fCNC reveals a length of 162.4 ± 16.3 nm, diameter of 11.2 ± 1.52 nm and aspect ratio of 16.4 ± 1.94 per particle (mean ± SEM) and is confirmed using atomic force microscopy. Size exclusion chromatography of macromolecular fCNC describes a fibrillar molecular behavior as evidenced by retention times typical of late eluting small molecules and functionalized carbon nanotubes. In vivo, greater than 50% of intravenously injected radiolabeled fCNC is excreted in the urine within 1 h post administration and is consistent with the pharmacological profile observed for other rigid, high aspect ratio macromolecules. Tissue distribution of fCNC shows accumulation in kidneys, liver, and spleen (14.6 ± 6.0; 6.1 ± 2.6; and 7.7 ± 1.4% of the injected activity per gram of tissue, respectively) at 72 h post-administration. Confocal fluorescence microscopy reveals cell-specific accumulation in these target tissue sinks. In summary, our findings suggest that functionalized nanocellulose can be used as a potential drug delivery platform for the kidneys
Deploying RNA and DNA with Functionalized Carbon Nanotubes
Carbon nanotubes internalize into
cells and are potential molecular
platforms for siRNA and DNA delivery. A comprehensive understanding
of the identity and stability of ammonium-functionalized carbon nanotube
(f-CNT)-based nucleic acid constructs is critical to deploying them
in vivo as gene delivery vehicles. This work explored the capability
of f-CNT to bind single- and double-strand oligonucleotides by determining
the thermodynamics and kinetics of assembly and the stoichiometric
composition in aqueous solution. Surprisingly, the binding affinity
of f-CNT and short oligonucleotide sequences was in the nanomolar
range, kinetics of complexation were extremely rapid, and from one
to five sequences were loaded per nanotube platform. Mechanistic evidence
for an assembly process that involved electrostatic, hydrogen bonding,
and π-stacking bonding interactions was obtained by varying
nanotube functionalities, oligonucleotides, and reaction conditions. <sup>31</sup>P NMR and spectrophotometric fluorescence emission data described
the conditions required to assemble and stably bind a DNA or RNA cargo
for delivery in vivo and the amount of oligonucleotide that could
be transported. The soluble oligonucleic acid–f-CNT supramolecular
assemblies were suitable for use in vivo. Importantly, key evidence
in support of an elegant mechanism by which the bound nucleic acid
material can be “off-loaded” from the f-CNT was discovered
Carbon nanotubes exhibit fibrillar pharmacology in primates
<div><p>Nanomedicine rests at the nexus of medicine, bioengineering, and biology with great potential for improving health through innovation and development of new drugs and devices. Carbon nanotubes are an example of a fibrillar nanomaterial poised to translate into medical practice. The leading candidate material in this class is ammonium-functionalized carbon nanotubes (fCNT) that exhibits unexpected pharmacological behavior in vivo with important biotechnology applications. Here, we provide a multi-organ evaluation of the distribution, uptake and processing of fCNT in nonhuman primates using quantitative whole body positron emission tomography (PET), compartmental modeling of pharmacokinetic data, serum biomarkers and ex vivo pathology investigation. Kidney and liver are the two major organ systems that accumulate and excrete [<sup>86</sup>Y]fCNT in nonhuman primates and accumulation is cell specific as described by compartmental modeling analyses of the quantitative PET data. A serial two-compartment model explains renal processing of tracer-labeled fCNT; hepatic data fits a parallel two-compartment model. These modeling data also reveal significant elimination of the injected activity (>99.8%) from the primate within 3 days (t<sub>1/2</sub> = 11.9 hours). These favorable results in nonhuman primates provide important insight to the fate of fCNT in vivo and pave the way to further engineering design considerations for sophisticated nanomedicines to aid late stage development and clinical use in man.</p></div