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Chitosan-Gadopentetic Acid Complex Nanoparticles for Gadolinium Neutron-Capture Therapy of Cancer: Preparation by Novel Emulsion-Droplet Coalescence Technique and Characterization

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Abstract

Purpose. 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.

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Correspondence to Hiroyuki Tokumitsu.

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Tokumitsu, H., Ichikawa, H. & Fukumori, Y. Chitosan-Gadopentetic Acid Complex Nanoparticles for Gadolinium Neutron-Capture Therapy of Cancer: Preparation by Novel Emulsion-Droplet Coalescence Technique and Characterization. Pharm Res 16, 1830–1835 (1999). https://doi.org/10.1023/A:1018995124527

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