ABSTRACT
Novel nanoscale drug delivery biomaterials are of great importance for the diagnosis and treatment of different cancers. We have developed a new pegylated squalene (SQ-PEG) derivative with self-assembly properties. Supramolecular assembly with a lipophilic photosensitizer pyropheophorbide-a (Ppa) by nanoprecipitation gave nanoconstructs SQ-PEG:Ppa with an average size of 200 nm in diameter and a drug loading of 18% (w/w). The composite material demonstrates nanoscale optical properties by tight packing of Ppa within Sq-PEG:Ppa resulting in 99.99% fluorescence self-quenching. The biocompatibility of the nanomaterial and cell phototoxicity under light irradiation were investigated on PC3 prostate tumor cells in vitro. SQ-PEG:Ppa showed excellent phototoxic effect at low light dose of 5.0 J/cm2 as a consequence of efficient cell internalization of Ppa by the nanodelivery system. The diagnostic potential of SQ-PEG:Ppa nanoconstructs to deliver Ppa to tumors in vivo was demonstrated in chick embryo model implanted with U87MG glioblastoma micro tumors.
Subject(s)
Chlorophyll/analogs & derivatives , Glioblastoma/drug therapy , Nanoparticles/administration & dosage , Photosensitizing Agents/administration & dosage , Prostatic Neoplasms/drug therapy , Squalene/administration & dosage , Theranostic Nanomedicine , Animals , Apoptosis , Cell Proliferation , Chick Embryo , Chlorophyll/chemistry , Chorioallantoic Membrane/drug effects , Drug Delivery Systems , Female , Glioblastoma/metabolism , Glioblastoma/pathology , Humans , Light , Male , Mice , Nanoparticles/chemistry , Photochemotherapy , Photosensitizing Agents/chemistry , Polyethylene Glycols/chemistry , Prostatic Neoplasms/metabolism , Prostatic Neoplasms/pathology , Squalene/chemistry , Tumor Cells, Cultured , Xenograft Model Antitumor AssaysABSTRACT
Gadolinium-loaded nanomicelles show promise as future magnetic resonance imaging (MRI) contrast agents (CAs). Their increased size and high gadolinium (Gd) loading gives them an edge in proton relaxivity over smaller molecular Gd-complexes. Their size and stealth properties are fundamental for their long blood residence time, opening the possibility for use as blood-pool contrast agents. Using l-tyrosine as a three-functional scaffold we synthesized a nanostructure building block 8. The double C18 aliphatic chain on one side, Gd-1,4,7,10-tetraazacyclododecane-1-4-7-triacetic acid (Gd-DO3A) with access to bulk water in the center and 2â kDa PEG on the hydrophilic side gave the amphiphilic properties required for the core-shell nanomicellar architecture. The self-assembly into Gd-loaded monodispersed 10-20â nm nanomicelles occurred spontaneously in water. These nanomicelles (Tyr-MRI) display very high relaxivity at 29â mm-1 s-1 at low field strength and low cytotoxicity. Good contrast enhancement of the blood vessels and the heart together with prolonged circulation time in vivo, makes Tyr-MRI an excellent candidate for a new supramolecular blood-pool MRI CA.
Subject(s)
Contrast Media/chemistry , Coordination Complexes/chemistry , Gadolinium/chemistry , Magnetic Resonance Imaging/methods , Nanoparticles/chemistry , Animals , Blood Vessels/diagnostic imaging , Cell Line, Tumor , Cell Survival , Contrast Media/toxicity , Coordination Complexes/toxicity , Humans , Hydrophobic and Hydrophilic Interactions , Male , Mice, Inbred C57BL , Micelles , Nanoparticles/toxicity , Particle Size , Phantoms, Imaging , Surface Properties , Tissue Distribution , Tyrosine/chemistryABSTRACT
Molecular medical imaging is intended to increase the accuracy of diagnosis, particularly in cardiovascular and cancer-related diseases, where early detection could significantly increase the treatment success rate. In this study, we present mixed micelles formed from four building blocks as a magnetic resonance imaging targeted contrast agent for the detection of atheroma and cancer cells. The building blocks are a gadolinium-loaded DOTA ring responsible for contrast enhancement, a fibrin-specific CREKA pentapeptide responsible for targeting, a fluorescent dye and DSPE-PEG2000. The micelles were fully characterized in terms of their size, zeta potential, stability, relaxivity and toxicity. Target binding assays performed on fibrin clots were quantified by fluorescence and image signal intensities and proved the binding power. An additional internalization assay showed that the micelles were also designed to specifically enter into cancer cells. Overall, these multimodal mixed micelles represent a potential formulation for MRI molecular imaging of atheroma and cancer cells.
Subject(s)
Contrast Media/administration & dosage , Magnetic Resonance Imaging/methods , Molecular Imaging/methods , Neoplasms/diagnosis , Plaque, Atherosclerotic/diagnosis , Cell Line , Contrast Media/pharmacokinetics , Fibrin/metabolism , Fluorescent Dyes/administration & dosage , Fluorescent Dyes/pharmacokinetics , Heterocyclic Compounds/administration & dosage , Heterocyclic Compounds/pharmacokinetics , Human Umbilical Vein Endothelial Cells , Humans , Intravital Microscopy , MCF-7 Cells , Micelles , Organometallic Compounds/administration & dosage , Organometallic Compounds/pharmacokinetics , Phosphatidylethanolamines/administration & dosage , Phosphatidylethanolamines/pharmacokinetics , Polyethylene Glycols/administration & dosage , Polyethylene Glycols/pharmacokineticsABSTRACT
A synthetic nano building block endowed with amphiphilic properties and chelated gadolinium is presented. Spontaneous self-assembly into small 12 nm corona-core stealth Gd-micelles with inherently high gadolinium loading occurs in water. Gd-Micelles are a new blood pool contrast agent with high relaxivity for magnetic resonance imaging.