Synthesis and biodistribution of 211At-labeled, biotinylated, and charge-modified poly-L-lysine: evaluation for use as an effector molecule in pretargeted intraperitoneal tumor therapy.
Journal article, 2002
Poly-L-lysine (7, 21, and 204 kDa) has been evaluated as an effector carrier for use in pretargeted intraperitoneal tumor therapy. For the synthesis, the epsilon-amino groups on the poly-L-lysine were modified in three steps utilizing conjugate biotinylation with biotin amidocaproate N-hydroxysuccinimide ester (BANHS), conjugate radiolabeling with (211)At using the intermediate reagent N-succinimidyl 3-(trimethylstannyl)benzoate (m-MeATE), and charge modification using succinic anhydride, resulting in an increase in the molecular weight of approximately 80% of the final product. The labeling of the m-MeATE reagent and subsequent conjugation of the polymer were highly efficient with overall radiochemical yields in the range of 60-70%. The in vitro avidin binding ability of the modified polymer was almost complete (90-95%), as determined by binding to avidin beads using a convenient filter tube assay. Following intraperitoneal (ip) injection in athymic mice, the 13 kDa polymer product was cleared mainly via the kidneys with fast kinetics (biological half-live T(b) approximately 2 h) and with low whole-body retention. The clearance of the 38 kDa polymer was distributed between kidneys and liver, and the 363 kDa polymer was mainly sequestered by the liver with a T(b) of 8 h. Increased tissue uptake in the thyroid, lungs, stomach, and spleen following the distribution of the large effector molecules (38 and 363 kDa) suggests that degradation of the polymers by the liver may release some of the label as free astatine/astatide.
chemistry
Liver
Mice
chemistry
Nude
pharmacokinetics
pharmacokinetics
Astatine
Aminocaproic Acids
metabolism
Benzoates
chemistry
Biotinylation
Injections
Drug Carriers
Avidin
Polylysine
Intraperitoneal
chemistry
Biotin
chemistry
Female
Inbred BALB C
Trimethyltin Compounds
chemical synthesis
chemistry
Mice
Polymers
Animals
metabolism
Half-Life
Mice
analogs & derivatives
Tissue Distribution
Author
Sture Lindegren
University of Gothenburg
Håkan Andersson
University of Gothenburg
Lars Jacobsson
University of Gothenburg
Tom Bäck
University of Gothenburg
Gunnar Skarnemark
Chalmers, Department of Materials and Surface Chemistry, Nuclear Chemistry
Börje Karlsson
University of Gothenburg
Bioconjugate Chemistry
1043-1802 (ISSN) 1520-4812 (eISSN)
Vol. 13 3 502-9Subject Categories
Physiology
Radiology, Nuclear Medicine and Medical Imaging
PubMed
12009939