Tumor accumulation, degradation and pharmacokinetics of elastin-like polypeptides in nude mice.
ELPs are genetically engineered, thermally responsive polypeptides that preferentially accumulate in solid tumors subjected to focused, mild hyperthermia. In this paper, we report the biodegradation, pharmacokinetics, tumor localization, and tumor spatial distribution of (14)C-labeled ELPs that were radiolabeled during their biosynthesis in Escheriehia coli. The in vitro degradation rate of a thermally responsive (14)C-labeled ELP1 ([(14)C] ELP1) with a molecular weight of 59.4 kDa, upon exposure to murine serum, was 2.49 wt.%/day. The apparent in vivo degradation rate of ELP1 after intravenous injection of nude mice was 2.46 wt.%/day and its terminal half-life was 8.7 h. The tumor accumulation and spatial distribution of intravenously administered ELP1 and a control ELP that was designed to remain soluble in heated tumors (ELP2) were examined in both heated (41.5 degrees C) and unheated tumors. ELP1 accumulated at a significantly higher concentration in heated tumors than ELP1 in unheated tumors and ELP2 in heated tumors. Quantitative autoradiography of tumor sections provided similar tumor accumulation results as the whole tumor analysis but, in addition, showed that ELP1 had a more homogeneous distribution in heated tumors and a greater concentration in the tumor center than either control treatment.
Liu
Wenge
W
Department of Biomedical Engineering, Duke University, Box 90281, Durham, NC 27708, USA.
Dreher
Matthew R
MR
Furgeson
Darin Y
DY
Peixoto
Katia V
KV
Yuan
Hong
H
Zalutsky
Michael R
MR
Chilkoti
Ashutosh
A
D000818:Animals; D001345:Autoradiography; D001711:Biotransformation; D002250:Carbon Radioisotopes; D002294:Carcinoma, Squamous Cell / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D004337:Drug Carriers; D004591:Electrophoresis, Polyacrylamide Gel; D005260:Female; D006207:Half-Life; D006801:Humans; D006979:Hyperthermia, Induced; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D010455:Peptides / Q000097:blood / Q000737:chemistry / Q000235:genetics / Q000493:pharmacokinetics*; D011994:Recombinant Proteins / Q000493:pharmacokinetics; D013997:Time Factors
D002250:Carbon Radioisotopes; D004337:Drug Carriers; D010455:Peptides; D011994:Recombinant Proteins; C033943:elastin polypentapeptide