Yttrium-86-labelled human serum albumin microspheres: relation of surface structure with in vivo stability

Introduction: Radiolabelled particles are an attractive tool in the therapy of malignancies of the liver. We consider particles manufactured from denatured human serum albumin (HSA) as useful carriers of therapeutic radionuclides. Covalent attachment of suitable chelators onto the surface of the spheres promises an easy access to radiolabelled HSA microspheres. Methods: We synthesized 1,4,7,10-tetraazacyclododecane-N.N',N,N'-tetraacetic acid (DOTA) bearing smooth, medium-rough and rough surfaced HSA microspheres (mean diameter: 25 mu m). In vitro stability of Y-86-labelled particles was determined after incubation in human plasma and in a DTPA challenge experiment. In vivo stability of Y-86 DOTA-HSA microspheres was determined after single intravenous application in rats. Subsequently, the particles were completely trapped in the lung microvasculature. Thus, the lung serves in our experiments as target organ. Results: DOTA-HSA microspheres were Y-86 labelled in reproducible high yields (>95%). No differences between smooth and rough surfaced spheres were found for both DOTA coupling and Y-86 labelling. Labelled microspheres showed high in vitro stability in human plasma and in DTPA solution with only 8 +/- 1 % and 2 +/- 0% loss of radioactivity from the surface, respectively, 48 h postinjection (pi). The three batches (smooth, medium-rough and rough surfaced microspheres) differed considerably in their radioactivity recovery in the lungs of rats 48 h pi. Smooth particles showed the highest in vivo stability of the radiolabel on the surface of the spheres, presumably because of slower proteolytic degradation. Conclusion: We found 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 of the radionuclide fixation. (c) 2008 Elsevier Inc. All rights reserved.