Engineering Tumor-Targeted Gadolinium Hexanedione Nanoparticles for Potential Application in Neutron Capture Therapy

Abstract

Microemulsions (oil-in-water) have been employed as templates to engineer nanoparticles containing high concentrations of gadolinium for potential application in neutron capture therapy of tumors. Gadolinium hexanedione (GdH), synthesized by complexation of Gd(3+) with 2,4-hexanedione, was used as the nanoparticle matrix alone or in combination with either emulsifying wax or PEG-400 monostearate. Solid nanoparticles (<125 nm size) were obtained by simple cooling of the microemulsions prepared at 60 degrees C to room temperature in one vessel. The feasibility of tumor targeting via folate receptors was studied. A folate ligand was synthesized by chemically linking folic acid to distearoylphosphatidylethanolamine (DSPE) via a poly(ethylene glycol) (PEG; MW 3350) spacer. To obtain folate-coated nanoparticles, the folate ligand (0.75% w/w to 15% w/w) was added to either the microemulsion templates at 60 degrees C or nanoparticle suspensions at 25 degrees C. Efficiencies of folate ligand attachment/adsorption to nanoparticle formulations were monitored by gel permeation chromatography. Cell uptake studies were carried out in KB cells (human nasopharyngeal epidermal carcinoma cell line), known to overexpress folate receptors. The uptake of folate-coated nanoparticles was about 10-fold higher than uncoated nanoparticles after 30 min at 37 degrees C. The uptake of folate-coated nanoparticles at 4 degrees C was 20-fold lower than the uptake at 37 degrees C and comparable to the uptake of uncoated nanoparticles at 37 degrees C. Folate-mediated endocytosis was further verified by the inhibition of folate-coated nanoparticles uptake by free folic acid. It was observed that folate-coated nanoparticles uptake decreased to approximately 2% of its initial value with the coincubation of 0.001 mM of free folic acid. The results suggested that these tumor-targeted nanoparticles containing high concentrations of Gd may have potential for neutron capture therapy.

Nanoparticles for Cancer Drug Delivery

“…Cell death occurred through gadolinium neutron capture therapy [122] in KB cells but not in the receptor-negative MCF-7 cells. Cell death was observed only after gadolinium-folate nanoparticles had accumulated in the KB cells [122].…”

“…Cell death occurred through gadolinium neutron capture therapy [122] in KB cells but not in the receptor-negative MCF-7 cells. Cell death was observed only after gadolinium-folate nanoparticles had accumulated in the KB cells [122]. Similar results were obtained when folate-receptor-positive breast cancer cells and macrophages were incubated with folate-decorated superparamagnetic nanoparticles.…”

Albumin-bound formulation of paclitaxel (Abraxane&reg; ABI-007) in the treatment of breast cancer

“…Most well studied are liposomes, 36 dendrimers, 37,38 super paramagnetic nanoparticulates, 39,40 polymer-based platforms, 41,42 gold nanoshells, 43,44 silicon-and silica-based nanoparticles, [45][46][47] carbon-60 fullerenes, 48 and nanocrystals. 49 They can be divided into three generations of compound, according to whether or not they were developed to target a specifi c target which is expressed on the tumor cells or the endothelium.…”

Gd@C82metallofullerenes for neutron capture therapy—fullerene solubilization by poly(ethylene glycol)-block-poly(2-(N,N-diethylamino)ethyl methacrylate) and resultant efficacyin vitro

“…Owing to this property, gadolinium has traditionally been used in radiocontrast agents in biomedical phases [6]. Since gadolinium ions are very toxic, chelation with specific ligands such as diethylenetriaminepentaacetic acid (DTPA), 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) and hexane-2,4-dione has been used to reduce the toxicity [16][17][18][19]. Other radiocontrast agents based on Gd chelates have been proposed to improve the proton relaxivity [20][21][22] because the relaxation properties of the gadolinium ion depend on its environment [23].…”

“…For GdNCT, however, the administered dose must be much higher than that of the MRI contrast agent and the resultant toxicity would be unacceptable. To improve blood circulation and tumor site accumulation, several kinds of matrices such as lipids [17,25], chitosan [26,27], polymers and ligands have been proposed for GdNCT [28,29]. Gadolinium-functionalized nanoparticles with improved accumulation properties were developed for high-contrast MRI [30,31].…”