title: Yttrium-86-labelled human serum albumin microspheres: relation of surface structure with in vivo stability.
abstract: BACKGROUND
  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 microm). In vitro stability of 86 Y-labelled particles was determined after incubation in human plasma and in a DTPA challenge experiment. In vivo stability of 86 Y 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 86 Y labelled in reproducible high yields (>95%). No differences between smooth and rough surfaced spheres were found for both DOTA coupling and 86 Y 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: ROTOP Pharmaka AG, Bautzner Landstrasse 45, 01454 Radeberg, Germany. e.schiller@fzd.de
authors.forename: Eik
authors.initials: E
authors.lastname: Schiller
authors.forename: Ralf
authors.initials: R
authors.lastname: Bergmann
authors.forename: Jens
authors.initials: J
authors.lastname: Pietzsch
authors.forename: Bernhard
authors.initials: B
authors.lastname: Noll
authors.forename: Antje
authors.initials: A
authors.lastname: Sterger
authors.forename: Bernd
authors.initials: B
authors.lastname: Johannsen
authors.forename: Gerd
authors.initials: G
authors.lastname: Wunderlich
authors.forename: Hans-Jürgen
authors.initials: HJ
authors.lastname: Pietzsch
mesh_terms: D000418:Albumins / Q000737:chemistry / Q000493:pharmacokinetics*; D000818:Animals; D002614:Chelating Agents / Q000737:chemistry; D004355:Drug Stability; D006571:Heterocyclic Compounds / Q000737:chemistry / Q000493:pharmacokinetics*; D006801:Humans; D007553:Isotope Labeling / Q000379:methods; D008168:Lung / Q000098:blood supply / Q000000981:diagnostic imaging / Q000378:metabolism; D008657:Metabolic Clearance Rate; D008863:Microspheres; D009942:Organometallic Compounds / Q000737:chemistry / Q000493:pharmacokinetics*; D004369:Pentetic Acid; D010949:Plasma; D011877:Radionuclide Imaging; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics; D051381:Rats; D013499:Surface Properties; D014018:Tissue Distribution; D015021:Yttrium Radioisotopes / Q000737:chemistry / Q000493:pharmacokinetics
chemical_list: D000418:Albumins; D002614:Chelating Agents; D006571:Heterocyclic Compounds; D009942:Organometallic Compounds; D019275:Radiopharmaceuticals; D015021:Yttrium Radioisotopes; C113625:yttrium(III)-1,4,7,10-tetraazacyclotetradecane-N,N',N'',N'''-tetraacetic acid; D004369:Pentetic Acid