RESUMEN
Ultrasmall nanoparticulate materials with core sizes in the 1-3nm range bridge the gap between single molecules and classical, larger-sized nanomaterials, not only in terms of spatial dimension, but also as regards physicochemical and pharmacokinetic properties. Due to these unique properties, ultrasmall nanoparticles appear to be promising materials for nanomedicinal applications. This review overviews the different synthetic methods of inorganic ultrasmall nanoparticles as well as their properties, characterization, surface modification and toxicity. We moreover summarize the current state of knowledge regarding pharmacokinetics, biodistribution and targeting of nanoscale materials. Aside from addressing the issue of biomolecular corona formation and elaborating on the interactions of ultrasmall nanoparticles with individual cells, we discuss the potential diagnostic, therapeutic and theranostic applications of ultrasmall nanoparticles in the emerging field of nanomedicine in the final part of this review.
Asunto(s)
Nanomedicina/tendencias , Nanopartículas/uso terapéutico , Humanos , Nanoestructuras , Nanotecnología , Distribución TisularRESUMEN
A new Boc-protected 1,4,7-triazacyclononane (TACN)-based pro-chelator compound featuring a "clickable" azidomethylpyridine pendant has been developed as a building block for the construction of multimodal imaging agents. Conjugation to a model alkyne (propargyl alcohol), followed by deprotection, generates a pentadentate ligand, as confirmed by X-ray crystallographic analysis of the corresponding distorted square-pyramidal Cu(II) complex. The ligand exhibits rapid (64)Cu(II)-binding kinetics (>95% radiochemical yield in <5 min) and a high resistance to demetalation. It may thus prove suitable for use in (64)Cu(II)-based in vivo positron emission tomography (PET). The new chelating building block has been applied to the construction of a bimodal (PET/fluorescence) peptide-based imaging probe targeting the epidermal growth factor (EGF) receptor, which is highly overexpressed on the surface of several types of cancer cells. The probe consists of a hexapeptide sequence, Leu-Ala-Arg-Leu-Leu-Thr (designated "D4"), followed by a Cys-ß-Ala-ß-Ala spacer, then a ß-homopropargylglycine residue with the TACN-based chelator "clicked" to its side chain. A sulfonated near-infrared (NIR) fluorescent cyanine dye (sulfo-Cy5) was introduced at the N-terminus to study the EGF receptor-binding ability of the probe by laser-fluorescence spectroscopy. Binding was also confirmed by coimmunoprecipitation methods, and an apparent dissociation constant (Kd) of ca. 10 nM was determined from radioactivity-based measurements of probe binding to two EGF receptor-expressing cell lines (FaDu and A431). The probe is shown to be a biased or partial allosteric agonist of the EGF receptor, inducing phosphorylation of Thr669 and Tyr992, but not the Tyr845, Tyr998, Tyr1045, Tyr1068, or Tyr1148 residues of the receptor, in the absence of the orthosteric EGF ligand. Additionally, the probe was found to suppress the EGF-stimulated autophosphorylation of these latter residues, indicating that it is also a noncompetitive antagonist.