Radiolabeled human serum albumin microspheres for radiotherapeutical treatment of liver malignancies


Radiolabeled human serum albumin microspheres for radiotherapeutical treatment of liver malignancies

Förster, C.; Schiller, E.; Pietzsch, H.-J.; Bergmann, R.; Pietzsch, J.; Noll, B.; Drews, A.; Johannsen, B.; Wunderlich, G.

INTRODUCTION
Radiolabelled particles are an attractive tool in the therapy of malignancies of the liver. Hepatic tumours receive their blood supply mainly from the arterial circulation, unlike normal liver tissue which is supplied by the portal vein. The intra-arterial application of microspheres with particle size > 10 m are trapped in the capillary bed and release a local radiotoxic dose with low levels of toxicity to the normal liver (1). The aim of this study was to determine the in vitro (incubation in human plasma and DTPA-Challenge) and in vivo characteristics of radiolabelled human serum albumin (HSA) microspheres and the valuation of suitability for radiotherapeutical treatment of liver malignancies. Covalent attachment of DOTA chelators onto the surface of the spheres opens up an easy access to Y-86-radiolabelled HSA microspheres. For in vivo experiments the labelled spheres were injected into the tail vein of Wistar rats. After 1, 12, 24 and 48 h the animals were sacrificed and the radioactivity concentration of isolated organs and tissue was determined. Furthermore, to investigate the influence of the surface structure we have used three different batches of HSA microspheres (smooth to rough; diameter 20-30 µm).

RESULTS AND DISCUSSION
Approximately 25 DOTA molecules per molecule HSA could be attached as estimated from elemental analysis of DOTA-HSA microspheres, independently of the surface characteristics of the spheres. They were Y-86 labelled under optimized conditions in 96 ± 1 % yield. No significant differences between smooth- and rough-surfaced spheres were found. In DTPA challenge experiments 98 % of the radioactivity was still particle-associated after 24 hours incubation at 37 °C. In vitro studies in human plasma resulted in 95 ± 4 % particle-associated radioactivity after 48 h incubation at 37 °C. In the in vivo experiments radiolabelled smooth and rough microspheres were completely trapped in the lungs, which served in our experiments as model for the vascular system of a solid tumour. Biodistribution of radioactivity was determined up to 48 h p.i. The estimated activity in the urine was below 1 %ID at 1 and 12 h p.i., and below 9 %ID at 24 and 48 h. Radioactivity level of other organs and tissues was marginal (< 2 %ID at all time points). The three batches of particles differed considerably in their radioactivity recovery in the lungs. For the clearance of radioactivity from the lungs decay-corrected half-lives of 85 h (rough microspheres) and 187 h (smooth microspheres) were calculated (2).
We found a strong dependency between the in vivo stability of radiolabel fixation on the surface and the roughness of the particle. We concluded that for the preparation of HSA-derived microspheres for radiotherapeutic application smooth-surfaced spheres are superior to rough spheres due to their higher in vivo stability.

REFERNCES
1. Murthy R et al., Yttrium-90 microsphere therapy for hepatic malignancy: devices, indications, technical considerations, and potential complications. Radiographics 25 (2005), 41-55.
2. Schiller E, Bergmann R, Pietzsch J, Noll B, Sterger A, Johannsen B, Wunderlich G, Pietzsch H-J, Yttrium-86-labelled human serum albumin microspheres: relation of surface structure with in vivo stability, Nucl. Med. Biol., doi: 10.1016/j.nucmedbio.2007.10.008.

  • Poster
    7th International Symposium on Polymer Therapeutics: From Lab to Clinic, 26.-28.05.2008, Valencia, Spain

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