Design and preparation of gadolinium-loaded chitosan particles for cancer neutron capture therapy

Gadolinium-loaded chitosan particulate devices for the gadolinium neutron-c apture therapy of cancer are described in this paper. Firstly, cross-linked chitosan microspheres (Gd-DTPA-CMSs) were prepared by a conventional metho d using glutaraldehyde. The increase in glutaraldehyde applied contributed to a size reduction and to the formation of a reservoir structure via prefe rential surface-hardening with glutaraldehyde, but competitively led to a d ecrease in the gadolinium content of Gd-DTPA-CMSs. The smallest mass median diameter of Gd-DTPA-CMSs was 1.9 mu m and the Gd content 61%, equivalent t o a Gd-DTPA content of 21.2%. Next, a novel emulsion droplet-coalescence te chnique was developed in order to prepare an injectable gadolinium-loaded c hitosan particulate system without cross-linking agents. This method is bas ed on neutralization of w/o emulsion droplets containing chitosan and Gd-DT PA and subsequent precipitation of the chitosan-Gd-DTPA complex caused by c oalescence with w/o emulsion droplets containing individually prepared sodi um hydroxide. The gadolinium-loaded chitosan micro- and nanoparticles produ ced using this technique hardly released Gd-DTPA in an isotonic phosphate-b uffered solution over 7 days despite the high water solubility of Gd-DTPA, thus suggesting a strong interaction between chitosan and Gd-DTPA. The opti mized process conditions facilitated production of gadolinium-loaded chitos an nanoparticles with an extremely high Gd-DTPA content (45.3%) and a suita ble size for IV injection (452 nm). Gadolinium-loaded chitosan nanoparticle s displayed prolonged retention in tumor tissue after intratumoral injectio n in vivo. Consequently, this led to intensified tumor-growth suppression i n vivo in the gadolinium neutron-capture therapy trial by intratumoral inje ction.