Since one of the most frequent sites of human metastatic cancer is the liver, particularly in colon and rectum carcinoma, there is a special need for the development of an effective therapy. This study describes the parameters for reproducible production of poly lactic acid (PLA) microspheres with an average diameter of 37 microm and labelled with neutron-activated holmium-166 (Emax=1.84 MeV, t1/2=26. 8 h), suitable for use in internal radionuclide therapy of liver metastases. It is demonstrated that holmium-loaded PLA microspheres can be prepared by a relatively simple method, with incorporation of 17.0%+/-0.6% holmium (n=5), and that 20 GBq can be obtained from 400 mg neutron activatable microspheres. In order to produce this high amount of activity, the microspheres must be free of water and irradiation must be performed in a polyethylene vial, with a relatively low neutron flux (5x10(13) cm-2 s-1) within 1 h. Under these well-defined conditions minor surface changes were seen which barely affected total volume and consequently total radioactivity of the microspheres with a diameter of 20-50 microm. Overall structural integrity was maintained in terms of form and size. In vitro analyses showed that >99.3% of 166Ho activity was retained in the microspheres after 192 h incubation in PBS, plasma and leucocytes, while in liver homogenate retention was still 98.4%.
Intra-arterial administration of beta-emitting particles that become trapped in the vascular bed of a tumour and remain there while delivering high doses, represents a unique approach in the treatment of both primary and metastatic liver tumours. Studies on selective internal radiation therapy of colorectal liver metastases using yttrium-90 glass microspheres have shown encouraging results. This study describes the biodistribution of 40-microm poly lactic acid microspheres loaded with radioactive holmium-166, after intra-arterial administration into the hepatic artery of rats with implanted liver tumours. Radioactivity measurements showed >95% retention of injected activity in the liver and its resident tumour. The average activity detected in other tissues was < or =0.1%ID/g, with incidental exceptions in the lungs and stomach. Very little 166Ho activity was detected in kidneys (<0.1%ID/g), thereby indicating the stability of the microspheres in vivo. Tumour targeting was very effective, with a mean tumour to liver ratio of 6. 1+/-2.9 for rats with tumour (n=15) versus 0.7+/-0.5 for control rats (n=6; P<0.001). These ratios were not significantly affected by the use of adrenaline. Histological analysis showed that five times as many large (>10) and medium-sized (4-9) clusters of microspheres were present within tumour and peritumoural tissue, compared with normal liver. Single microspheres were equally dispersed throughout the tumour, as well as normal liver parenchyma.
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