Chitosan-gadopentetic acid complex nanoparticles for gadolinium neutron-capture therapy of cancer: preparation by novel emulsion-droplet coalescence technique and characterization.
OBJECTIVE
The gadopentetic acid (Gd-DTPA)-loaded chitosan nanoparticles (Gd-nanoCPs) were prepared for gadolinium neutron-capture therapy (Gd-NCT) and characterized and evaluated as a device for intratumoral (i.t.) injection.


METHODS
Gd-nanoCPs were prepared by a novel emulsion-droplet coalescence technique. The effects of the deacetylation degree of chitosan and Gd-DTPA concentration in chitosan medium on the particle size and the gadolinium content in Gd-nanoCPs were examined. In vitro Gd-DTPA release from Gd-nanoCPs was evaluated using an isotonic phosphate-buffered saline solution (PBS, pH 7.4) and human plasma. In vivo Gd-DTPA retention in the tumor after i.t. injection of Gd-nanoCPs was estimated on mice bearing s.c. B16F10 melanoma.


RESULTS
Gd-nanoCPs with the highest Gd content, which were obtained using 100% deacetylated chitosan in 15% Gd-DTPA aqueous solution, were 452 nm in diameter and 45% in Gd-DTPA content. A lower deacetylation degree of chitosan led to an increase in particle size and a decrease in Gd-DTPA content in Gd-nanoCPs. As Gd-DTPA concentration in the chitosan solution increased, Gd-DTPA content in Gd-nanoCPs increased but the particle size did not vary. Gd-DTPA loaded to Gd-nanoCPs was hardly released over 7 days in PBS (1.8%) despite the high water solubility of Gd-DTPA. In contrast, 91% of Gd-DTPA was released in plasma over 24 hours. When Gd-nanoCPs were i.t. injected, 92% of Gd-DTPA injected effectually without outflow was held in the tumor tissue for 24 hours, which was different from the case of gadopentetate solution injection (only 1.2%).


CONCLUSIONS
Gd-nanoCPs highly incorporating Gd-DTPA were successfully prepared by the emulsion-droplet coalescence technique. Their releasing properties and their ability for long-term retention of Gd-DTPA in the tumor indicated that Gd-nanoCPs might be useful as an i.t. injectable device for Gd-NCT.
Tokumitsu
H
H
Faculty of Pharmaceutical Sciences, Kobe Gakuin University, Japan. tokumitu@pharm.kobegakuin.ac.jp
Ichikawa
H
H
Fukumori
Y
Y
D000818:Animals; D002626:Chemistry, Pharmaceutical; D002686:Chitin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics; D048271:Chitosan; D003287:Contrast Media / Q000008:administration & dosage / Q000737:chemistry* / Q000493:pharmacokinetics; D004655:Emulsions; D019786:Gadolinium DTPA / Q000008:administration & dosage / Q000737:chemistry* / Q000493:pharmacokinetics; D007267:Injections; D008297:Male; D008546:Melanoma, Experimental / Q000532:radiotherapy; D051379:Mice; D008810:Mice, Inbred C57BL; D008863:Microspheres; D009369:Neoplasms / Q000532:radiotherapy*; D017247:Neutron Capture Therapy; D010316:Particle Size; D012996:Solutions
D003287:Contrast Media; D004655:Emulsions; D012996:Solutions; D002686:Chitin; D048271:Chitosan; D019786:Gadolinium DTPA