title: Pharmacokinetics and biodistribution of human serum albumin-TIMP-2 fusion protein using near-infrared optical imaging.
abstract: OBJECTIVE
  TIMP-2 has been studied as an attractive cancer therapeutic candidate, and a TIMP-2 fusion protein (HSA/TIMP-2) displayed effective anticancer activity, despite a lack of information about its pharmacokinetics (PK) and biodistribution. The purpose of this work was to assess the PK and biodistribution of HSA/TIMP-2 as well as to quantify accumulated HSA/TIMP-2 in tumors.
  
  
  METHODS
  Cy5.5 near-infrared (NIR) fluorescence was conjugated to the HSA/TIMP-2 protein (Cy5.5-HSA/TIMP-2) for monitoring spatio-temporal changes in vivo. For PK and biodistribution analysis, 0.2 μg/g body weight of Cy5.5-HSA/TIMP-2 was injected into MAT-LyLu prostate tumor xenografts, which were then imaged using an IVIS-200 optical imaging system. To quantify the accumulated HSA/TIMP-2 in tumors, we introduced a standard curve with depth-corrected fluorescence measurement.
  
  
  RESULTS
  In the vascular tube formation assay with human umbilical vein endothelial cells (HUVECs), Cy5.5-HSA/TIMP-2 showed an antiangiogenic effect. In prostate cancer xenografts, Cy5.5-HSA/TIMP-2 exhibited a prolongation of blood half-life to 19.6 h and relatively preferential distribution to the tumor. The amount of tumor-accumulated Cy5.5-HSA/TIMP-2 was calculated to be 4.5 ± 0.5 ng/g body weight at 2 days, representing 2.25 ± 0.25% of the initial dose.
  
  
  CONCLUSIONS
  We evaluated the pharmacokinetic profile and biodistribution of HSA/TIMP-2 with favorable results, providing new information for more effective approaches to cancer therapeutics using HSA/TIMP-2. Additionally, real-time in vivo fluorescence imaging analysis using a depth-corrected standard curve may serve as a platform to quantify biodistributed drug in anticancer therapeutic studies.
authors.affiliation: Division of Bio-Imaging, Chuncheon Center, Korea Basic Science Institute, Chuncheon 200-701, Republic of Korea.
authors.forename: Mi-Sook
authors.initials: MS
authors.lastname: Lee
authors.forename: Young Han
authors.initials: YH
authors.lastname: Kim
authors.forename: Yeon Joo
authors.initials: YJ
authors.lastname: Kim
authors.forename: Seung-Hae
authors.initials: SH
authors.lastname: Kwon
authors.forename: Jeong-Kyu
authors.initials: JK
authors.lastname: Bang
authors.forename: Sang-Mok
authors.initials: SM
authors.lastname: Lee
authors.forename: Yun Seon
authors.initials: YS
authors.lastname: Song
authors.forename: Dae-Hyun
authors.initials: DH
authors.lastname: Hahm
authors.forename: Insop
authors.initials: I
authors.lastname: Shim
authors.forename: Daeseok
authors.initials: D
authors.lastname: Han
authors.forename: Song
authors.initials: S
authors.lastname: Her
mesh_terms: D020533:Angiogenesis Inhibitors / Q000097:blood / Q000493:pharmacokinetics*; D000818:Animals; D002232:Carbocyanines / Q000737:chemistry / Q000493:pharmacokinetics; D006207:Half-Life; D061307:Human Umbilical Vein Endothelial Cells / Q000166:cytology / Q000187:drug effects; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009368:Neoplasm Transplantation / Q000379:methods; D011471:Prostatic Neoplasms / Q000097:blood / Q000378:metabolism; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000097:blood / Q000493:pharmacokinetics*; D012709:Serum Albumin / Q000493:pharmacokinetics*; D000075462:Serum Albumin, Human; D019265:Spectroscopy, Near-Infrared / Q000379:methods; D014018:Tissue Distribution; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000493:pharmacokinetics*; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
chemical_list: C422455:ALB protein, human; D020533:Angiogenesis Inhibitors; C098793:CY5.5 cyanine dye; D002232:Carbocyanines; D011993:Recombinant Fusion Proteins; D012709:Serum Albumin; D019716:Tissue Inhibitor of Metalloproteinase-2; D000075462:Serum Albumin, Human